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OBJECTIVES: Obesity is an increasing health problem that is reported to influence chemotherapy dosing. The extent to which this occurs and whether this affects outcomes in ovarian cancer was unclear. To describe chemotherapy dosing practices in normal, overweight and obese patients treated for FIGO Stage III/IV serous ovarian cancer in the Australian Ovarian Cancer Study (AOCS). To evaluate the relationship between body mass index (BMI), dose intensity of chemotherapy received, overall survival (OS) and progression free survival (PFS). METHODS: Patient characteristics including age, height, weight, FIGO stage, serum creatinine, primary chemotherapy received and outcome data were extracted from medical records and entered into the AOCS database. Outcomes were analysed against BMI and relative dose intensity (RDI) received, based on calculations derived from a standard regimen (carboplatin AUC 5 and paclitaxel 175mg/m(2)). RESULTS: 333 women were included in the analysis. 27% were overweight and 21% were obese. In cycle 1 66% of obese patients received carboplatin doses more than 5% below their optimal calculated dose, and 32% received sub-optimal paclitaxel doses, compared to 25% and 13% of normal weight patients respectively. Obese women were more likely to have received <85% RDI for carboplatin compared to normal weight women (p<0.001). BMI group and RDI of carboplatin and paclitaxel were not predictors of OS. Women who received less than 85% RDI for carboplatin had a worse PFS (univariate analysis, median PFS 11 versus 15 months; p=0.04). There was no significant association between RDI and OS or PFS in multivariate analysis. CONCLUSIONS: Obesity is common in ovarian cancer patients, and commonly results in lower chemotherapy dosing than recommended. Analysis of chemotherapy dosing from this study suggests that reduced dose intensity of carboplatin, which was more common in obese women, may impact on PFS in patients with advanced serous ovarian cancer.
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Factor VIII (FVIII) inhibitor alloantibodies react with combinations of the A2, C2 and A3-C1 domains of the FVIII molecule. Some inhibitors block binding of FVIII to both von Willebrand factor (VWF) and phospholipid, and recognize a C2 domain epitope which overlaps both binding sites. In order to determine the essential binding regions for alloantibodies inhibitory for FVIII activity, we have performed inhibitor neutralization assays and competitive inhibition assays using 10 overlapping synthetic peptides spanning the carboxy-terminal region of the C2 domain (residues 2288-2332). We found one peptide (2315-2330, L9) which neutralized the anti-FVIII activity of four out of five different C2 alloantibodies by 50%, 39%, 47% and 57%, respectively. Neutralization of these alloantibodies by recombinant C2 domain (residues 2173-2332) was 68%, 50%, 59%, 86% and >95%, respectively. The inhibitor which was not neutralized by L9 peptide and reacted by immunoblotting with peptide 2218-2307, did not prevent binding of FVIII to VWF and only partially inhibited binding of FVIII to phosphatidylserine. Mutants of the L9 peptide were prepared in which each residue from 2315-2330 was sequentially substituted by glycine. Inhibitor neutralization experiments using these peptides demonstrated that Arg2320 and Cys2326 or Glu2327 are important for the effect of L9 peptide, since their substitution by glycine reduced its neutralizing effect by 60% to >90%, suggesting that they are crucial for formation of the one of the C2 inhibitor epitopes.
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There is growing epidemiological and molecular evidence that ABO blood group affects host susceptibility to severe Plasmodium falciparum infection. The high frequency of common ABO alleles means that even modest differences in susceptibility could have a significant impact on the health of people living in malaria endemic regions. We performed an association study, the first to utilize key molecular genetic variation underlying the ABO system, genotyping >9000 individuals across three African populations. Using population- and family-based tests, we demonstrated that alleles producing functional ABO enzymes are associated with greater risk of severe malaria phenotypes (particularly malarial anemia) in comparison with the frameshift deletion underlying blood group O: case-control allelic odds ratio (OR), 1.2; 95% confidence interval (CI), 1.09-1.32; P = 0.0003; family-studies allelic OR, 1.19; 95% CI, 1.08-1.32; P = 0.001; pooled across all studies allelic OR, 1.18; 95% CI, 1.11-1.26; P = 2 x 10(-7). We found suggestive evidence of a parent-of-origin effect at the ABO locus by analyzing the family trios. Non-O haplotypes inherited from mothers, but not fathers, are significantly associated with severe malaria (likelihood ratio test of Weinberg, P = 0.046). Finally, we used HapMap data to demonstrate a region of low F(ST) (-0.001) between the three main HapMap population groups across the ABO locus, an outlier in the empirical distribution of F(ST) across chromosome 9 (approximately 99.5-99.9th centile). This low F(ST) region may be a signal of long-standing balancing selection at the ABO locus, caused by multiple infectious pathogens including P. falciparum.
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STUDY DESIGN: Case report. OBJECTIVE: To report the first case of posterior spinal artery (PSA) infarct due to patent foramen ovale (PFO). SUMMARY OF BACKGROUND DATA: Infarct in the territories of PSA are very rare: till now 38 cases are reported in the literature. Moreover only 1 case of spinal cord infarction was attributed to paradoxical embolism through PFO, but in the anterior spinal artery territory. METHODS: A 60-year-old woman was hospitalized for sudden numbness of the right leg. Neurologic examination revealed right leg mild paresis and loss of proprioception and dysesthesia at T11. Spine-MRI showed T5-T7 posterolateral cord ischemia. Transesophageal echocardiography disclosed a PFO with severe right-left shunt confirmed by transcranial Doppler. RESULTS: During the hospitalization she was treated with oral-500 mg ticlopidine, because of a mild allergic reaction to acetylsalicylic acid. No steroids were administrated. Physiotherapy was performed daily. Motor and urinary symptoms disappeared in 20 days. At 1-month clinical follow-up only suspended dysesthesia on the right side was present. At 3 months follow-up spine-MRI showed no signal abnormalities within the spinal cord but the patient still complained of dysesthesia. The therapy was changed to oral 75 mg clopidogrel, cause of leucopoenia. At 1-year follow-up dysesthesia was still present, but less complaining and no recurrence and adverse effect due to clopidogrel therapy were reported. CONCLUSION: This report describe a case of acute nontraumatic myelopathy. At 4 days after onset, PSA infarct was diagnosed on the basis of neurologic findings and MR images. After extensive diagnostic work-up, we were able to identify only PFO, so it was the first case of PSA due to probable paradoxical embolism. The patient was treated with antiplatelet therapy with good recovery and no recurrence at 1-year follow-up.
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AIM: To determine the prevalence, aetiology and clinical outcome in children with surgically treated hydrocephalus. METHODS: A population-based study of all 208 liveborn children with hydrocephalus, 124 with infantile hydrocephalus and 84 with hydrocephalus associated with myelomeningocoele, born during 1989-1998 in western Sweden. Aetiological and clinical information was collected from records. RESULTS: The prevalence of hydrocephalus was 0.82 per 1000 live births, 0.49 for children with infantile hydrocephalus and 0.33 for children with myelomeningocoele. The prevalence of infantile hydrocephalus decreased during the period from 0.55 to 0.43 per 1000. In this group, the aetiology was prenatal in 55% and peri-postnatal in 44% of the children. The origin was perinatal haemorrhage in all cases born very preterm. The mortality rate was 5% for children with either infantile hydrocephalus or myelomeningocoele. Mental retardation, cerebral palsy and epilepsy were significantly more frequent in the group with infantile hydrocephalus: 46% vs 16%, 31% vs 4% and 31% vs 10%, respectively. All children with infantile hydrocephalus born very preterm had at least one of these impairments, as did 80% of those with overt hydrocephalus at birth. CONCLUSION: A slightly decreasing trend for infantile hydrocephalus was observed during the 10-y period. Children with infantile hydrocephalus had a worse outcome than those with myelomeningocoele. The need for neurosurgical revisions for two-thirds of the children indicates the need for further development of prevention and treatment strategies.
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Studies have revealed that increased expression of interferon (IFN)-inducible Ifi202 gene (encoding p202 protein) in splenic B and T cells from B6.Nba2 congenic (congenic for Nb2 locus derived from NZB mice) female mice is associated with lupus susceptibility. However, signaling pathways that regulate Ifi202 expression in immune cells remain to be elucidated. Here we report that stimulation of T cells up-regulates the Ifi202 expression. We found that steady-state levels of Ifi202 mRNA and protein were detectable in splenic T cells from NZB mice and stimulation of T cells with anti-CD3 and anti-CD28 up-regulated expression of the Ifi202 gene. Similarly, stimulation of cells of a mouse T cell hybridoma cell line (2B4.11) also activated transcription of the Ifi202 gene. Significantly, up-regulation of Ifi202 expression in stimulated T cells was inhibited by treatment of cells with SP600125, a specific inhibitor of c-Jun N-terminal kinase (JNK). Conversely, treatment of cells with anisomycin, a potent activator of the JNK and c-Jun, up-regulated Ifi202 expression. Consistent with the activation of JNK/c-Jun pathway by T cell stimulation, forced expression of c-Jun in 2B4 T cells and in mouse embryonic fibroblasts (MEFs) also up-regulated the Ifi202 expression. Furthermore, we found that stimulation of T cells increased association of the activated c-Jun to the 5'-regulatory region of the Ifi202 gene in chromatin immunoprecipitation assays (ChIPs). Together, our observations demonstrate that stimulation of T cells up-regulates the Ifi202 expression in part through the JNK/c-Jun pathway.
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Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and CD49d molecules on eosinophils is thought to mediate the selective infiltration of eosinophils into inflamed tissues in allergic disease. IL-4 and TNF-alpha are associated with allergic conditions, and they have been shown to selectively augment VCAM-1 expression on endothelial cells, suggesting that they may be responsible for VCAM-1 expression in allergic disease. We used immunocytochemical staining analysis to examine the effect of chemical mediators, including histamine, leukotrienes and platelet-activating factor (PAF), on VCAM-1 expression in IL-4- and TNF-alpha-stimulated endothelial cells. Histamine, significantly augmented (p < 0.05 to p < 0.01) VCAM-1 expression in both IL-4- and TNF-alpha-stimulated endothelial cells. IL-4 and TNF-alpha were found to have a synergistic effect on endothelial cell VCAM-1 expression, when compared with the effect of stimulation with each of these cytokines separately, and the addition of histamine further increased VCAM-1 expression. This enhancing effect of histamine was inhibited by the presence of mepyramine and thioperamide but not by cimetidine. Another chemical mediator, PAF, failed to induce any increase in VCAM-1 expression, however, leukotrienes augmented it slightly in a narrow range of concentrations. The histamine-induced augmentation of VCAM-1 expression was reflected functionally by many more eosinophils attaching to endothelial cells than to cells stimulated with both cytokines. This attachment of eosinophils was inhibited by the presence of antibody to VCAM-1 and CD49d. Addition of histamine 10 h after stimulation with both cytokines still induced an increase in VCAM-1 expression. In addition, an inhibitor of RNA polymerase, alpha-amanitin, dose-dependently decreased this histamine-induced augmentation of VCAM-1 expression. These findings strongly suggest that histamine upregulates VCAM-1 expression at the transcriptional level through newly generated of mRNA in endothelial cells stimulated with IL-4 and TNF-alpha.
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BACKGROUND AND OBJECTIVES: All human leukocyte antigen (HLA)-DRB1 alleles associated with rheumatoid arthritis (RA) encode a conserved amino acid sequence (QKRAA, QRRAA, or RRRAA) at position 70-74 in the third hypervariable region (HVR3) of the DRbeta(1) chain, which is commonly called the shared epitope (SE). Several studies, however, have associated the HLA-DRB1 gene in RA severity and progression rather than with susceptibility. Moreover, the association with disease severity and presence of the SE varies among different ethnic populations. HLA-DRB1 alleles also influence the disease onset. In this manuscript, the role of the HLA genes in RA was examined. METHODS: A retrospective review of the literature was conducted to analyze the influence of the HLA-class II genes on the susceptibility, severity and protection against RA. RESULTS: The HLA-DRB1*0401/*0404 genotype was associated with a higher risk for early disease onset in more severe forms in patients from the United Kingdom (UK). In northwest Spain, RA onset under 40 years is strongly associated with HLA-DRB1*0401 and *0404. In contrast, RA onset above 60 years is associated with HLA-DRB1*01. The protection against RA linked to some HLA-DRB1 alleles encoding a DERAA sequence of amino acids at position 70-74 in the HVR3 of the DRbeta1 chain, and specifically aspartic acid (D) at position 70 of this chain, recently was confirmed in both UK and northwest Spanish populations. Besides HLA-class II, other genes may be implicated in RA. Polymorphism in the tumor necrosis factor (TNF) region seems to be associated with RA, even in patients without the HLA-DRB1 SE. However, other genes such as interleukin-1 (IL-1) and corticotropin-releasing hormone may play a role in susceptibility to RA. CONCLUSIONS: The additive effect of various genes may account for the development of RA and its clinical severity.
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BACKGROUND: No unanimous consensus has been reached as to the need for routine laparoscopic cholecystectomy (LC) after endoscopic sphincterotomy (ES) for choledocholithiasis in very elderly patients, who are considered as high-risk subjects for surgery. METHODS: From 1991 through 1997, 170 patients were referred to undergo preoperative ES and routine LC for common bile duct (CBD) stones. The results for 27 patients (age 80 years or older) were compared with those achieved for younger patients. Successively, in a retrospective case-control study, the results for the selected patients were compared with those for 27 very elderly patients who underwent endoscopic retrograde cholangiopancreatography (ERCP), but did not receive LC. The mean follow-up period was 126 months. RESULTS: Octogenarians showed longer surgery time (79 vs 51 min) and postoperative hospital stay (2.8 vs 1.2 days), as well as more early low-grade complications (15% vs 3%), whereas there were no differences in conversion rate or serious complications. Recurrent symptoms or complications developed in 48% of octogenarians not undergoing routine LC, and 30% finally needed surgery. One patient in the control group died after emergency cholecystectomy for acute cholecystitis. The results of surgery were significantly poorer for the control group. CONCLUSIONS: Although a "wait-and-see" policy allowed two-thirds of LCs to be avoided in octogenarians, biliary-related events developed for every second patient, often requiring delayed surgery, with poorer results. Sequential treatment (ES followed by elective LC) is a safe procedure for octogenarians, and should be considered as a standard, definitive treatment for cholecystocholedocholithiasis even after the age of 80 years.
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Liposarcomas are rare in the mediastinum. Here, we report the clinicopathologic features of 24 cases of mediastinal liposarcoma. Patients included 13 males and 11 females, with an age range of 3 to 72 years (median 58). Nine tumors were located in the anterior mediastinum, 7 in the posterior mediastinum, 1 in the superior mediastinum, and the precise location was not specified in 7 cases. Of the anterior mediastinal tumors, 3 appeared to arise from the thymus. Tumors were well-circumscribed, multinodular masses and ranged in size from 2.2 to 61 cm in greatest dimension (median 16 cm). Histologic examination revealed that most of the cases were well-differentiated liposarcomas (10), followed by dedifferentiated liposarcomas (8), pleomorphic liposarcomas (4), and myxoid liposarcomas (2). Of the pleomorphic liposarcomas, 2 had areas that resembled myxofibrosarcoma with atypical hyperchromatic spindle cells in a myxoid stroma, but the focal presence of lipoblasts confirmed the diagnoses. Clinical follow-up was obtained in 15 cases (range 1 to 59 mo; median 26). Complete surgical excision was attempted in 13 patients; however, local recurrence was common (5 cases), including 1 patient whose tumor recurred twice. Eleven patients were alive with no evidence of disease at last follow-up (5 well-differentiated, 5 dedifferentiated, and 1 myxoid liposarcoma). Two patients developed distant metastases (dedifferentiated and pleomorphic liposarcoma). One patient was alive with disease (pleomorphic liposarcoma), and 2 died of disease (pleomorphic and dedifferentiated liposarcoma). Overall, mediastinal liposarcomas appear to be similar, in clinicopathologic terms, to liposarcomas arising in the retroperitoneum.
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Rad is the prototypic member of a family of novel Ras-related GTPases that is normally expressed in heart, skeletal muscle, and lung and that has been shown to exhibit a novel form of bi-directional interaction with the nm23 metastasis suppressor. In the present study, we have investigated the expression of Rad in normal and neoplastic breast tissues by Western blot and immunohistochemistry and the functional effect of altered Rad expression in breast cancer cell lines. We found that, although Rad is frequently expressed in normal breast tissue (23/30 Rad+ve), expression is usually lost in adjacent invasive carcinoma (8/30 Rad+ve; P < 0.0001). However, where Rad expression persists in a small proportion of tumors, it is associated with higher grade, larger size, and extensive axillary nodal involvement (n = 48; P = 0.035, P = 0.016, P = 0.022, respectively). Furthermore, Rad is also highly expressed in a breast cancer cell line with high tumorigenic and metastatic potential (MDA-MB231). To further examine the role of Rad in breast cancer, we stably transfected a Rad-ve breast cancer cell line (MDA-MB435). We observed an increase in growth and marked increased colony formation in soft agar in vitro (P < 0.05) and an increase in tumor growth rate in nude mice (P < 0.05). Moreover, coexpression of nm23 with wild-type Rad inhibited the effect of Rad on growth of these cells in culture and markedly inhibited tumor growth in vivo. Additional transfection studies with mutated Rad cDNAs revealed that the growth-promoting effects of Rad appeared to be mediated through its NH2- and COOH-terminal regions, rather than its GTPase domain, and might involve acceleration of cell cycle transition. These findings suggest that Rad may act as an oncogenic protein in breast tissues and demonstrate a potential mechanism by which interaction between Rad and nm23 may regulate growth and tumorigenicity of breast cancer.
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PURPOSE: The rate of local failure is sufficiently high following sphincter conserving surgery and radiation therapy for advanced anal cancers to warrant investigation of improved local treatment techniques. This Phase I/II study was undertaken to investigate the site-specific toxicities and response of Stage II and III anal cancers to interstitial thermoradiotherapy using a hot water interstitial system. METHODS AND MATERIALS: Between September 1988 and March 1991, 14 patients with primary carcinomas of the anal canal, UICC Stage T2-3, N0-1, M0, were treated with split-course external beam irradiation to the pelvis (30 Gy + 20 Gy) and 1 or 2 interstitial Iridium-192 high dose rate (Ir-192 HDR) implants (6-8 Gy each) immediately followed by interstitial hyperthermia (HT). Patients with tumor diameters > 3 cm were scheduled to receive chemotherapy consisting of 2 courses of 5-fluorouracil and mitomycin C given concomitantly with external beam radiation. Interstitial hyperthermia was induced by circulating warm water through the needles that were implanted to hold the Ir-192 source. The treatment goal was to achieve and maintain a temperature of 42.5 degrees C over a time period of 40 min. A 3-point thermocouple probe inserted into one or two additional needles was used for thermometry. The temperatures were recorded by manual mapping along these needles at steps of 0.5 or 1 cm. RESULTS: A total of 20 Ir-192 HDR-HT implants were performed in 14 patients. All but two patients completed the external beam irradiation; five patients received concomitant chemotherapy. Analysis of thermal parameters showed that minimum intratumoral temperatures (Tmin) of 42 degrees C, 42.5 degrees C, 43 degrees C, and 44 degrees C were achieved in 64%, 37.5%, 14%, and 7% of patients, respectively. Intratumoral mean Tmin, mean average, and mean maximum temperatures for these patients were 41.7 degrees C, 42.4 degrees C, and 43.4 degrees C, respectively. Brachytherapy and HT were well tolerated. Clinical complete responses (cCR) were obtained in 11/14 (78.5%) patients, complete histopathological responses (pCR) in 10/14 (71%). Only one patient with pCR recurred and succumbed to her disease. Patients with persistent disease (1 minimal and 3 partial responders, including 1 cCR) underwent abdominal-perineal resection but subsequently died from local-regional recurrence. One patient with pCR died from unrelated causes. Median survival for all patients from onset of radiation to death or last follow-up is 26 months. Eight patients are alive disease-free after a follow-up ranging from 16-44 months (median: 30, mean: 30 months). Treatment complications were limited to two patients who developed persistent ulcers. Sphincter function was maintained in 50% of patients. CONCLUSION: This study demonstrates that interstitial warm water hyperthermia in combination with brachytherapy for anal carcinomas is feasible and did not add to complications when compared to studies employing external beam irradiation and brachytherapy alone. The thermal parameters obtained by the warm water system compare favorably to those reported by others using radiofrequency and microwave systems.
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The extracellular calcium (Ca(2+)(o))-sensing receptor (CaR) recognizes and responds to (i.e., "senses") Ca(2+)(o) as its principal physiological ligand. In the present studies, we document that the CaR is activated not only by extracellular calcium ions but also by amino acids, establishing its capacity to sense nutrients of two totally different classes. l-Amino acids, especially aromatic amino acids, including l-phenylalanine and l-tryptophan, stereoselectively mobilized Ca(2+) ions in the presence of the CaR agonists, Ca(2+)(o), gadolinium (Gd(3+)(o)), and spermine in fura-2-loaded human embryonic kidney (HEK-293) cells stably transfected with the human CaR. l-amino acid-dependent effects were observed above, but not below, a threshold level of Ca(2+)(o) of approximately 1.0 mM. l-Amino acids, particularly aromatic amino acids, also stereoselectively enhanced the sensitivity of the CaR to its agonists, Ca(2+)(o) and spermine. Branched-chain amino acids were almost inactive, and charged amino acids, including arginine and lysine, were much less effective than aromatic and other amino acids. l-amino acid mixtures emulating the amino acid composition of fasting human plasma reproduced the effects of high concentrations of individual l-amino acids on Ca(2+) mobilization and enhanced the sensitivity of the CaR to Ca(2+)(o). The data presented herein identify the CaR as a molecular target for aromatic and other l-amino acids. Thus, the CaR can integrate signals arising from distinct classes of nutrients: mineral ions and amino acids. The actions of l-amino acids on the CaR may provide explanations for several long recognized but poorly understood actions of dietary protein on calcium metabolism.
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BACKGROUND: Esophagus and stomach cancers are associated with poor prognosis. But most published population-based cancer survival estimates for stomach and esophagus cancer refer to survival experience of patients diagnosed in the 1990s or earlier years. The aim of this study was to provide up-to-date survival estimates and trends for patients with stomach and esophagus cancer in Germany. MATERIAL AND METHODS: Our analysis is based on data from 11 population-based cancer registries, covering 33 million inhabitants. Patients diagnosed with stomach and esophagus cancer in 1997-2006 were included. Period analysis was used to derive five-year relative survival estimates and trends by age, sex, cancer subsite, and stage for the time period of 2002-2006. German and US survival estimates were compared utilizing the SEER 13 database. RESULTS: Overall age-standardized five-year relative survival was 31.8% and 18.3% for stomach and esophagus cancer, respectively, compared to 27.2% and 17.4% in the US. Survival was somewhat higher among female than among male patients for both cancer sites (33.6% vs. 30.6% and 21.5% vs. 17.5%, respectively) and much higher for non-cardia stomach cancer (40.4%) than for cardia cancer (23.4%). From 2002 to 2006, a moderate increase in five-year relative survival by 2.7 percent units was observed for non-cardia stomach cancer patients in Germany (p < 0.001). CONCLUSION: Five-year relative cancer survival has reached levels around 40% for patients with non-cardia stomach cancer in Germany in the early 21st century, whereas it remained at lower levels around 20% for patients with esophagus and cardia cancer.
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High-dose chemotherapy combined with autologous transplantation using bone marrow or peripheral blood-derived stem cells (PBSC) is now widely used in the treatment of hematologic malignancies as well as some solid tumors like breast cancer (BC). However, some controversial results were recently obtained in the latter case. The presence of malignant cells in the autograft has been associated with the recurrence of the disease, and purging procedures are needed to eliminate this risk. The aim of this study was to evaluate the potential of the photosensitizer 4,5-dibromorhodamine methyl ester (TH9402), a dibrominated rhodamine derivative, to eradicate multiple myeloma (MM) and BC cell lines, while sparing more than 50% of normal pluripotential blood stem cells from healthy volunteers. The human BC MCF-7 and T-47D and MM RPMI 8226 and NCI-H929 cell lines were used to optimize the photodynamic purging process. Cell concentration and the cell suspension thickness as well as the dye and light doses were varied in order to eventually treat 1-2 L of apheresis. The light source consisted of two fluorescent scanning tubes emitting green light centered about 515 nm. The cellular uptake of TH9402 was measured during the incubation and washout periods and after photodynamic treatment (PDT) using spectrofluorometric analysis. The limiting dilution assay showed that an eradication rate of more than 5 logs is obtained when using a 40 min incubation with 5-10 microM dye followed by a 90 min washout period and a light dose of 5-10 J/cm2 (2.8 mW/cm2) in all cell lines. Agitating the 2 cm thick cell suspension containing 20 x 10(6) cells/mL during PDT was essential for maximal photoinactivation. Experiments on mobilized PBSC obtained from healthy volunteers showed that even more drastic purging conditions than those found optimal for maximal eradication of the malignant cell lines were compatible with a good recovery of hematopoietic progenitors cells. The absence of significant toxicity towards normal hematopoietic stem cells, combined with the 5 logs eradication of cancer cell lines induced by this procedure suggests that TH9402 offers an excellent potential as an ex vivo photodynamic purging agent for autologous transplantation in MM and BC treatment.
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Skin damage secondary to peristomal leakage is a fairly common complication of ileostomies in infants. Traditional conservative measures, including skin barriers, ointments, and agents to reduce bowel movements, initially may be helpful but not in all patients. The purpose of this case series was to describe a new and relatively simple procedure to temporarily manage severe peristomal dermatitis caused by ileal peristomal leakage in infants. After obtaining informed consent from the parents, a mushroom-type (de Pezzer) catheter was inserted into the ileostomy of 11 1- to 4-month-old infants (seven males, four females) with severe peristomal dermatitis. Eight had total aganglionic colon (TAC), two had meconium ileus (cystic fibrosis), and one had meconium peritonitis due to bowel perforation proximal to ileal atresia. The severity of the peristomal dermatitis improved remarkably in all patients after 2 to 3 days. In eight patients, minimal (if any) dermatitis was noted within 5 to 7 days after tube insertion. Six patients who initially had poor weight gain (mean 345 g/month) developed acceptable weight gain (mean 648 g/month) (P <0.03) within 2 to 4 months. In seven patients with TAC, the tube was maintained for 2 to 4 months until definitive pull-through procedure; in four other patients, the tube remained in place for 3 to 7 days as a step for preoperative build-up. None of the patients developed any complications. The procedure requires the presence of a pediatric or trained surgeon, and care must be taken to prevent iatrogenic damage. In this case series, an appropriate-size, mushroom-type (de Pezzer) catheter placed within the ileostomy was a practical mode for temporary control of ileal peristomal leakage that causes severe peristomal dermatitis in infants, particularly in those not responding to medical therapy. Larger studies are needed to develop evidence-based protocols of care for the prevention and management of ileostoma complications in infants.
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Patent ductus arteriosus (PDA) is highly prevalent in pre-term neonates (PTN) and has been recognized as a neonatal co-morbidity. The purpose of this study was to determine if levels of brain (or B-type) natriuretic peptide (BNP), a peptide secreted by ventricular myocytes in response to volume or pressure overload, correlate with the size of the PDA. In a prospective design, 52 PTN (no PDA: n=24; PDA: n=28) were studied after obtaining parental consent. Those with genetic anomalies and congenital heart disease, except for PDA and patent foramen ovale, were excluded. Echocardiographic estimates of the diameters of the PDA (or absence of PDA) were made concurrently with capillary blood collection for BNP assay. BNP levels in samples from PTN without PDA were 23.6 ng/L (median); 13.1 to 32.3 ng/L (IQR); initial samples (between days 3 and 7 of life) with small PDA (n=11), median 66.1 ng/L; 55.5 to 85.3 ng/L (IQR); with moderate PDA (n=6) median 284 ng/L; 204 to 622 ng/L (IQR); and with large PDA (n=11) 2410 ng/L median; 420 to 2770 ng/L (IQR). (p< 0.0001 for ANOVA; groupwise: p<0.05 for both no PDA vs. moderate and large PDA); Trend analysis suggested a strong association of BNP with size of PDA (p<0.001). Of 17 subjects with moderate to large PDA, pre and post-treatment (Ibuprofen; per standard protocol) data were obtained on 12 subjects. Pre-treatment BNP ranged from 111 to 5000 ng/L; post-treatment BNP decreased to 5.0 to 262 ng/L (p = 0.0005). Estimates of decision levels for treatment were made by examining dichotomized groups, i.e., no-to-small vs. moderate-to-large and using receiver-operator characteristic (ROC) curve analysis yielding a value of 123 ng/L. BNP may obviate repeated echocardiography as follow up after treatment, or to monitor future course of respiratory distress secondary to PDA in PTN.
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The goal of the present study was to evaluate the role of protein kinase C (PKC) in the depression of endothelium-dependent vacular response in spontaneously hypertensive Okamoto rats (SHR). Aortae from SHR demonstrated a decreased relaxant response to acetylcholine (Ach) as compared to aortae from normotensive Wistar-Kyoto (WKY) rats, while papaverine lowered the force of aorta to a similar degree in both strains of rats. PKC inhibitors, H-7 (5 x 10(-6) M) and chelerythrine chloride (10(-6) M), produced a greater decrease in the force developed by the aortae from SHR vs. WKY rats both in intact and chemically permeabilized tissues. In SHR aortae PKC inhibitors enhanced relaxation to Ach to a greater extent as compared to WKY aortae. Furthermore, in the presence of PKC inhibitors, the constrictor responses of SHR aortae to Ach were transformed into relaxant responses, and the concentration-response curve to Ach was shifted to the left. The sensitivity of aortae from SHR to authentic nitric oxide (NO) was lowere compared to WKY rats. EC50s for authentic NO in SHR and WKY rat aortae were different: -2.9 +/- 0.15 x 10(-6) M and 4.58 +/- 0.1 x 10(-7) M (n = 15, p < 0. 001), respectively. Bioassay experiments using SHR aortae showed that the addition of chelerythrine (10(-6) M) to the detector superfusate caused relaxation during treatment of the donor segment with Ach, indicating that the sensitivity of the aortae to NO had been restored. When SHR detector ring was substituted for denuded aortae from WKY rats and PKC inhibitors were not added to the detector superfusate, the relaxation of the detector aortae was also close to the normal Ach-induced relaxation. WKY aortae demonstrated a positive relationship between Ach-stimulated NO release and relaxant response amplitudes (correlation coefficient r = 0.905, p < 0.001, n = 10). In contrast, there was a significant negative correlation in SHR aortae (r = -0.712, p < 0.05, n = 10). Detection of NO release by chemiluminescence showed no significant difference in NO release in SHR and WKY aortae. Taken together, these data suggest that the blunted endothelium-dependent relaxations seen in SHR aortae are mainly due to a decreased sensitivity of vascular smooth muscle to EDRF/NO resulting from an increased PKC activity.
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PURPOSE: To evaluate the incidence and associated risk factors of solid cancers after bone marrow transplantation (BMT). PATIENTS AND METHODS: We analyzed 2,129 patients who had undergone BMT for hematologic malignancies at the City of Hope National Medical Center between 1976 and 1998. A retrospective cohort and nested case-control study design were used to evaluate the role of pretransplantation therapeutic exposures and transplant conditioning regimens. RESULTS: Twenty-nine patients developed solid cancers after BMT, which represents a two-fold increase in risk compared with a comparable normal population. The estimated cumulative probability (+/- SE) for development of a solid cancer was 6.1% +/- 1.6% at 10 years. The risk was significantly elevated for liver cancer (standardized incidence ratio [SIR], 27.7; 95% confidence interval [CI], 1.9 to 57.3), cancer of the oral cavity (SIR, 17.4; 95% CI, 6.3 to 34.1), and cervical cancer (SIR, 13.3; 95% CI, 3.5 to 29.6). Each of the two patients with liver cancer had a history of chronic hepatitis C infection. All six patients with squamous cell carcinoma of the skin had chronic graft-versus-host disease. The risk was significantly higher for survivors who were younger than 34 years of age at time of BMT (SIR, 5.3; 95% CI, 2.7 to 8.6). Cancers of the thyroid gland, liver, and oral cavity occurred primarily among patients who received total-body irradiation. CONCLUSION: The risk of radiation-associated solid tumor development after BMT is likely to increase with longer follow-up. This underscores the importance of close monitoring of patients who undergo BMT.
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OBJECTIVE: The aim of this study was to investigate whether milk fortified with folic acid enhances the folate status of humans and whether the presence of folate-binding proteins (FBP) in pasteurised milk affects the bioavailability of folic acid from fortified milk. In untreated and pasteurised milk, folate occurs bound to FBP, while FBP is (partly) denatured in ultra-high-temperature (UHT)-treated milk. The effect of FBP on folate bioavailability is still unclear. DESIGN, SUBJECTS AND SETTING: Healthy, free-living subjects (n=69) aged 18-49 y participated in a 4-week double-blind, placebo-controlled dietary intervention study. INTERVENTION: In addition to a fully controlled diet, the subjects consumed each day 500 ml of pasteurised or UHT milk, either fortified or not with 200 mug folic acid. RESULTS: Consumption of fortified milk increased folate concentrations in serum and in red blood cells (RBC) by 6.6-7.0 nmol/l (P<0.001) and 32-36 nmol/l (P<0.01), respectively. Similarly, plasma homocysteine concentrations were lowered 0.88-0.89 micromol/l (P=0.001) in subjects who consumed fortified milk. The bioavailability of folic acid from pasteurised milk relative to that of folic acid from UHT milk was 74-94% (NS), depending on the parameter used. CONCLUSIONS: Milk fortified to supply an additional 200 microg of folic acid/s substantially increased folate status, and decreased plasma total homocysteine concentrations in young, healthy subjects. Milk is therefore a suitable matrix for fortification to enhance the folate status in humans. No significant effect of endogenous FBP was found on the bioavailability of folic acid from milk.
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OBJECTIVES: To compare the value of different magnetic resonance sequences in the detection of brain lesions in dogs with multi-focal intracranial neurolocalised lesions and abnormal cisternal cerebrospinal fluid analysis. METHODS: T2-weighted, T1-weighted, T1-weighted-Gd, FLAIR (fluid attenuated inversion recovery) images of 73 dogs with multi-focal intracranial localised lesions were reviewed retrospectively. Control dogs (19) were selected on the basis of normal neurological examination, magnetic resonance images and cerebrospinal fluid analysis. Two board-certified radiologists blindly reviewed the magnetic resonance images. Magnetic resonance sequence sensitivities were compared using the chi-squared test and logistic regression, accounting for clustering at the patient level. Statistical significance was set at the 5 per cent level. RESULTS: The FLAIR sequence was found to have the highest sensitivity (84 per cent, 61 of 73), followed by T2-weighted (63 per cent, 46 of 73), T1-weighted postcontrast (62 per cent, 45 of 73) and T1-weighted (23 per cent, 17 of 73) (P<0.001). FLAIR images were 106.1 times (95 per cent confidence interval 25.2 to 447.5) more likely to correctly identify cerebrospinal fluid-positive patients than T1-weighted, 6.4 times (95 per cent confidence interval 2.2 to 18.2) than T1-weighted postcontrast and 5.8 times (95 per cent confidence interval 2.0 to 16.4) than T2-weighted. FLAIR identified 14 per cent of cases that were classified as normal based on the three others sequences. CLINICAL SIGNIFICANCE: Routine use of FLAIR sequence should be encouraged in dogs undergoing a brain magnetic resonance imaging and probably more specifically in cases of suspected inflammatory brain disease.
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OBJECTIVE: To examine the relationship between clinical markers of autoimmune thyroid disease and the risk of thyroid cancer in patients with thyroid nodules. METHODS: A retrospective cohort analysis was performed in a single clinical practice. In 2,500 consecutive patients, fine-needle aspiration biopsy (FNAB) was performed on all 3,658 ultrasonography-positive thyroid nodules that were >/= 1.0 cm in diameter or >/= 0.5 cm in diameter with ultrasound features suspicious for thyroid cancer. Serum concentrations of thyroglobulin antibodies (TgAb), thyroid peroxidase antibodies, and thyroid-stimulating hormone were measured before FNAB. Diagnosis of thyroid cancer was based on pathologic analysis of thyroidectomy tissue. Associations of thyroid cancer with the independent variables were determined by multivariate logistic regression analysis and reported as the adjusted odds ratio (OR) with the 95% confidence interval (CI). RESULTS: There were 202 patients with malignant thyroid nodules, 51 patients with microscopic unsuspected thyroid cancer distal to the nodule under investigation (found at thyroidectomy), and 2,247 patients with benign thyroid nodules. To evaluate the association of clinical markers for autoimmune thyroid disease with thyroid cancer, we included all 253 patients with thyroid cancer in the malignant cohort. Thyroid cancer was associated with elevated levels of TgAb (OR = 1.57; CI = 1.11 to 2.23) and age <55 years (OR = 2.01; CI = 1.45 to 2.78), and a strong trend was demonstrated for association with male sex (OR = 1.45; CI = 0.99 to 2.12). Thyroid cancer was not associated with elevated levels of thyroid peroxidase antibodies. CONCLUSION: In patients who have thyroid nodules with indications for FNAB, elevated levels of TgAb are associated with thyroid cancer.
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BACKGROUND: Polyarteritis nodosa is a systemic necrotizing vasculitis with a pathogenesis that is poorly understood. We identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, consistent with autosomal recessive inheritance. In most cases, onset of the disease occurred during childhood. METHODS: We carried out exome sequencing in persons from multiply affected families of Georgian Jewish or German ancestry. We performed targeted sequencing in additional family members and in unrelated affected persons, 3 of Georgian Jewish ancestry and 14 of Turkish ancestry. Mutations were assessed by testing their effect on enzymatic activity in serum specimens from patients, analysis of protein structure, expression in mammalian cells, and biophysical analysis of purified protein. RESULTS: In all the families, vasculitis was caused by recessive mutations in CECR1, the gene encoding adenosine deaminase 2 (ADA2). All the Georgian Jewish patients were homozygous for a mutation encoding a Gly47Arg substitution, the German patients were compound heterozygous for Arg169Gln and Pro251Leu mutations, and one Turkish patient was compound heterozygous for Gly47Val and Trp264Ser mutations. In the endogamous Georgian Jewish population, the Gly47Arg carrier frequency was 0.102, which is consistent with the high prevalence of disease. The other mutations either were found in only one family member or patient or were extremely rare. ADA2 activity was significantly reduced in serum specimens from patients. Expression in human embryonic kidney 293T cells revealed low amounts of mutant secreted protein. CONCLUSIONS: Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).
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TNF-alpha is crucial in defense against intracellular microbes. Host immune cells use type 3 complement receptors (CR3) to regulate excess TNF-alpha production during physiological clearance of apoptotic cells. BAD1, a virulence factor of Blastomyces dermatitidis, is displayed on yeast and released during infection. BAD1 binds yeast to macrophages (Mphi) via CR3 and CD14 and suppresses TNF-alpha, which is required for resistance. We investigated whether blastomyces adhesin 1 (BAD1) exploits host receptors for immune deviation and pathogen survival. Soluble BAD1 rapidly entered Mphi, accumulated intracellularly by 10 min after introduction to cells, and trafficked to early and late endosomes. Inhibition of receptor recycling by monodansyl cadaverine blocked association of BAD1 with Mphi and reversed TNF-alpha suppression in vitro. Inhibition of BAD1 uptake with cytochalasin D and FcR-redirected delivery of soluble BAD1 as Ag-Ab complexes or of wild-type yeast opsonized with IgG similarly reversed TNF-alpha suppression. Hence, receptor-mediated entry of BAD1 is requisite in TNF-alpha suppression, and the route of entry is critical. Binding of soluble BAD1 to Mphi of CR3(-/-) and CD14(-/-) mice was reduced to 50 and 33%, respectively, of that in wild-type mice. Mphi of CR3(-/-) and CD14(-/-) mice resisted soluble BAD1 TNF-alpha suppression in vitro, but, in contrast to CR3(-/-) cells, CD14(-/-) cells were still subject to suppression mediated by surface BAD1 on wild-type yeast. CR3(-/-) mice resisted both infection and TNF-alpha suppression in vivo, in contrast to wild-type and CD14(-/-) mice. BAD1 of B. dermatitidis thus co-opts normal host cell physiology by exploiting CR3 to subdue TNF-alpha production and foster pathogen survival.
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BACKGROUND: Implantation of devices into the coronary sinus (CS)/great cardiac vein (GCV) to reshape the mitral annulus (MA) is being investigated, despite these structures not being within the same plane and coronary arteries frequently traversing between them. Furthermore, dynamic changes in their relationship have never been studied. We analyzed the CS/GCV dimensions and its relationship with the MA and the coronary arteries. METHODS AND RESULTS: Of 390 consecutive computed tomography angiographies reviewed, 56 met the inclusion criteria. Mean age of the patients was 68.9 + or - 13.1 years (26.8% men). The dimensions of the CS/GCV and the distance between this structure and the MA were measured at 10 different spatial points along the CS/GCV trajectory and at 3 different time points along the cardiac cycle (phases 0%, 40%, and 75% of the RR interval) by using curved multiplanar reconstruction technique. The CS/GCV was larger in phase 40% than in phase 75% and was smallest in phase 0% (P<0.001). The distance between the CS/GCV and the MA was longest in phase 40% and shortest in phase 0% (P=0.013). The diameter of the MA was measured in oblique 2- and 4-chamber reconstructions, being largest in phase 0% and smallest in phase 40% (P=0.019). A coronary artery traversed between the CS/GCV and the MA in 85.7% of the patients. CONCLUSIONS: This study demonstrated dynamic changes in the relationship between the CS/GCV and the MA and also that coronary arteries frequently traverse between both structures. Whether these findings are of clinical relevance for patients undergoing percutaneous mitral annuloplasty needs to be prospectively evaluated.
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BACKGROUND: Angiopoietin-2 (Ang-2) is an antagonistic ligand of the endothelial-specific Tie2 receptor. Patients on dialysis have markedly elevated Ang-2 levels, and those correlate with their atherosclerotic burden. The aim of the current study was to investigate the relationship between the circulating levels of Ang-2 and renal function throughout all stages of chronic kidney disease (CKD). In addition, we aimed to detect a potential link between the nitric oxide (NO) synthase inhibitor asymmetric dimethylarginine (ADMA) and the Ang-2 levels. METHODS: Glomerular filtration rate (GFR) was assessed by the inulin clearance technique ((i)GFR) and compared to serum Ang-2 (immunoluminometric assay) and ADMA levels (liquid chromatography-electrospray tandem mass spectrometry) in 44 untreated non-smokers at the different stages of CKD 1-4. Ang-2 was also measured in 19 patients on dialysis (CKD stage 5). In addition, the Ang-2 and (c)GFR (cystatin C) measurements were taken in 15 healthy individuals before and 72 h after kidney donation. RESULTS: The median Ang-2 levels steadily increased across the following groups: healthy controls: 0.77 (0.32-1.08) ng/mL; CKD 1: 0.83 (0.67-1.09) ng/mL; CKD 2: 0.93 (0.74-1.15) ng/mL; CKD 3: 1.13 (0.87-1.49) ng/mL; CKD 4: 1.75 (1.23-2.61) ng/mL; and CKD 5: 4.87 (3.22-7.59) ng/mL, respectively (non-parametric ANOVA P < 0.0001). Ang-2 was associated with the degree of CKD as evidenced by an inverse correlation with the (i)GFR (r = -0.509, P < 0.0001) and positive correlations with homocysteine (r = 0.365, P = 0.015) and phosphate (r = 0.53, P < 0.0001). Additionally, Ang-2 correlated with the ADMA levels (r = 0.35, P = 0.01). We detected a close inverse correlation between the mean changes in GFR and circulating Ang-2 at 72 h after kidney donation (r = -0.54, P = 0.03). CONCLUSIONS: Circulating Ang-2, a putative marker and potential mediator of accelerated atherosclerosis, is inversely related to GFR and increases with advanced CKD. The correlation between Ang-2 and ADMA points towards the hypothesis that the ADMA-driven NO deficiency might trigger Ang-2 release and account for the Ang-2 increase in CKD patients.
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Proper assembly of the class I heavy chain (HC), beta 2-microglobulin (beta 2m), and peptide must occur in the endoplasmic reticulum (ER) in order for MHC class I molecules to be expressed on the cell surface. Newly synthesized class I HC bind calnexin, an ER resident chaperone. These calnexin-associated class I HC appeared to lack the stable association with beta 2m in peptide transporter-deficient T2 cells since beta 2m-unassociated class I HC-specific HC10 antibody, but not beta 2m-associated class I HC-specific W6/32 antibody, coimmunoprecipitated calnexin. To determine the precursor-product relationship of the pool of HC that bind peptide, class I-restricted peptides were added to lysates of T2 cells in vitro. These peptides stabilized preexisting beta 2m-associated HC complexes (beta 2m+:HC:pep-), but had no significant effect on the preexisting pool of calnexin-associated HC that lack beta 2m. Release of HC from calnexin appeared to be controlled by the binding of beta 2m, since beta 2m-deficient FO-1 cells showed a prolonged association of class I HC with calnexin, while beta 2m-transfected FO-1 cells displayed a more rapid dissociation of class I HC from calnexin. Consistent with this result, the dissociation of class I HC from calnexin did not appear to be dependent on peptide binding since the dissociation rates were similar in peptide transporter-deficient T2 cells and in wild-type T1 cells. From these observations, we speculate that in the stepwise assembly of class I molecules, calnexin may mediate dimerization of class I HC with beta 2m, and that the unstable beta 2m+:HC:pep- complexes, after dissociation from calnexin, subsequently bind peptide to complete the assembly.
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BACKGROUND: In patients with systolic heart failure (HF), coexisting sleep apnea may promote arrhythmia. Ambulatory Holter electrocardiogram (ECG) monitoring (AECG) is a method of arrhythmia and apnea evaluation. We hypothesized that 24-hour AECG in patients with HF who have a high risk of serious arrhythmia may be less accurate than AECG extended to 48 hours and that, moreover, arrhythmia may be related to apnea. METHODS: Eighty-four recordings of 48-hour AECG in 84 patients with ischemic HF (mean ejection fraction 34 +/- 7%) were analyzed. Day 1, Day 2 were checked for ventricular tachycardia (VT) and supraventricular tachycardia (SVT). Estimated apnea-hypopnea index (est.AHI) was calculated using Holter, monitoring where est.AHI >15 indicates apnea. RESULTS: In 48-hour AECG, VT occurred in 34 patients (40.5%) whereas SVT in 17 patients (20.2%), and patients with est.AHI > 15 had higher VT occurrence. In two-sample one-sided test for proportions, 24-hour AECG from Day 1 showed a significantly lower percentage of patients with detected VT than 48-hour AECG-it was 23.8% (20 patients), meaning a significant underestimation with P = 0.0089. We assessed VT underestimation in the subgroups with regard to est.AHI, and found that it was present in Day 1 monitoring in the subgroups with est.AHI > 15. It was absent in the subgroups with est.AHI </= 15 and also in Day 2 monitoring. CONCLUSIONS: In patients with systolic HF, 24-hour AECG may have insufficient sensitivity regarding serious arrhythmia occurrence. If significant apnea was detected in the first day, extending the monitoring may be recommended.
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Uncaria rhynchophylla (Miq.) Jack (UR) and Gastrodia elata BI. (GE) are traditional Chinese herbs that are usually used in combination to treat convulsive disorders, such as epilepsy, in China. The aim of this study was to compare the anticonvulsive and free radical scavenging activities of UR alone and UR in combination with GE in rats. For the in vitro studies, brain tissues from 6 male Sprague-Dawley (SD) rats were treated with 120 microg/ml kainic acid (KA), with or without varied concentrations of UR or UR plus GE. For the in vivo studies, male SD rats (6 per group) received intraperitoneal (i.p.) injection of KA 12 mg/kg to induce epileptic seizures and generation of free radicals, with or without oral administration of UR 1 g/kg alone or UR 1 g/kg plus GE 1 g/kg. Epileptic seizures were verified by behavioral observations, and electroencephalography (EEG) and electromyography (EMG) recordings. These results showed that UR alone decreased KA-induced lipid peroxide levels in vitro, whereas UR plus GE did not produce a greater effect than UR alone. UR significantly reduced counts of wet dog shakes (WDS), paw tremor (PT) and facial myoclonia (FM) in KA-treated rats and significantly delayed the onset time of WDS, from 27 min in the control group to 40 min in the UR group. UR plus GE did not inhibit seizures more effectively than UR alone, but did further prolong the onset time of WDS to 63 min (P < 0.05 vs. UR alone). UR alone reduced the levels of free radicals in vivo, as measured by lipid peroxidation in the brain and luminol-chemiluminescence (CL) counts and lucigenin-CL counts in the peripheral whole blood, but the combination of GE and UR did not reduce free radical levels more markedly than UR alone. In conclusion, our results indicate that UR has anticonvulsive and free radical scavenging activities, and UR combined with GE exhibit greater inhibition on the onset time of WDS than UR alone. These findings suggest that the anticonvulsive effects of UR and GE may be synergistic. However, the mechanism of interaction between UR and GE remains unknown.
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OBJECTIVE: Some studies suggest that cholesterol may promote prostate cancer development. High serum cholesterol levels are commonly treated with statins, which have been associated with decreased prostate cancer risks. Statin use has increased in this country during the 1990s while prostate mortality rates have gone down. In this study, we compare high cholesterol levels to prostate cancer mortality rates among states over time periods in which statin use has changed. We hypothesize that prostate cancer risks from high cholesterol may be reduced when statin use is high. METHODS: State-specific, high cholesterol levels for white males (2001-2003) were compared with age-adjusted prostate cancer mortality rates for each year from 1992 to 2000. To control for medical care access and socioeconomic status, urbanization, family income, and health insurance status were considered. RESULTS: High cholesterol levels correlate inversely with prostate cancer mortality for: 2000 (R = -0.40, P < 0.01); 1999 (R = -0.37, P < 0.01); and 1998 (R = -0.32, P < 0.05), but there was no significant correlation from 1992 to 1997. Statin use was 46%, 47%, and 49% in 1998, 1999, and 2000, respectively, and ranged from 7% in 1992 to 42% in 1997. Urbanization correlated at the P < 0.05 level from 1994 to 2000 but family income and health insurance status did not correlate. CONCLUSIONS: High cholesterol levels were associated with lower prostate cancer mortality rates when statin use was high, but not low, suggesting that statins reduce prostate cancer mortality risks.
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OBJECTIVE: Hepatic steatosis is a common incidental finding at radiologic imaging. The natural history of nonalcoholic fatty liver disease (NAFLD) and its associated risks for cardiovascular complications are not well established in this context. Our purpose was to investigate the clinical outcome of moderate-to-severe hepatic steatosis detected incidentally at CT. MATERIALS AND METHODS: Liver attenuation was measured at unenhanced CT in 4412 consecutive adults scanned over a 12-month period. Moderate-to-severe steatosis was diagnosed by liver attenuation less than or equal to 45 HU, which is essentially 100% specific for histologic grading of 30% or more fat content. The control group was defined by a high-normal liver attenuation of 60-65 HU. The main exclusion criteria were preexisting liver disease (beyond asymptomatic NAFLD), alcoholism, or less than 1 year of clinical follow-up. A medical record review assessed for the development of symptomatic liver disease (including nonalcoholic steatohepatitis and cirrhosis) and seminal cardiovascular events (myocardial infarction, cerebrovascular accident, transient ischemic attacks, or coronary bypass or stent). Data for body mass index, diabetes, and liver enzyme levels were also recorded. RESULTS: Five hundred three adults (11.4%) had unenhanced CT liver attenuation of 45 HU or less, yielding a final steatosis cohort of 282 patients after exclusions; the control group consisted of 768 patients after exclusions. The mean (+/- SD) patient age (51.4 +/- 14.7 vs 50.8 +/- 17.4 years), sex (53.9% vs 54.7% female), and mean follow-up intervals (7.3 +/- 3.2 vs 7.7 +/- 3.2 years) were similar between groups. No patient in either group had progression of liver disease beyond incidental steatosis. Subsequent cardiovascular events were more common in the steatosis cohort (9.9% vs 5.9%; p = 0.028), but steatosis was not an independent risk factor after controlling for diabetes and body mass index in multiple logistic regression analysis. CONCLUSION: This longitudinal study failed to show progression of moderate-to-severe hepatic steatosis to symptomatic forms of fatty liver disease over a 5- to 10-year time horizon. Aggressive workup of hepatic steatosis found incidentally on imaging does not appear to be warranted. Steatosis was a biomarker for subsequent cardiovascular events but not an independent risk factor.
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Clinical and pathologic features of 24 patients with large cell lymphomas that expressed the activation antigen Ki-1 are described. Phenotypic and/or genotypic studies characterized these neoplasms as T-cell (16 cases), B-cell (six cases), or null cell (two cases) type. Males predominantly were affected. Age of patients ranged from 19 to 73 years, with a bimodal distribution, with peaks in the third and seventh decades. Lymphadenopathy was present in nearly all patients. Extranodal involvement, including skin, soft tissue, bone, central nervous system, lung, or small intestine was observed in a total of 54% of the patients, either at presentation or during the course of disease. "Prototypic" features of large cell anaplastic lymphomas were observed for eight T-cell lymphomas, with morphologic heterogeneity noted for the remainder. Eight patients, all with T-cell neoplasms (only one with prototypic morphology), have died of lymphoma (median survival, 5 months). An antecedent history of a lymphoproliferative disorder (mycosis fungoides, B-cell lymphoma, immunoblastic lymphadenopathy) was apparent in seven patients. An 8-year history of Crohn's disease occurred in one patient with a T-cell lymphoma involving small intestine. Phenotypically, loss of one or more markers was typically noted for T-cell neoplasms. Leukocyte common antigen was detected in all cases, although partial loss of immunoreactivity was noticed in some cases. Nearly all cases evaluated for Ia antigen or alpha-1-antichymotrysin were reactive. Eleven of 16 T-cell, two of six B-cell, and two null cell lymphomas expressed epithelial membrane antigen. Ki-1-positive large cell lymphomas are characterized by clinical, morphologic, and immunophenotypic heterogeneity.
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PURPOSE: This study evaluated parapharyngeal-space (PPS) tumors in regard to clinical pathological features, preoperative assessment, surgical approaches, perioperative complications, and patterns of recurrence. PATIENTS AND METHODS: We performed a retrospective review of patients with PPS tumors referred to the stomatological hospitals of Sichuan University and Xi'an Jiaotong University between 1990 and 2004. RESULTS: Beginning in 1990 and ending in 2004, 162 patients with PPS tumors were evaluated in our unit. The gender distribution was 94 (58.08%) males and 68 (41.98%) females. The median age was 36.4 years. The main presenting symptom was neck swelling. All cases were evaluated with at least a computed tomography scan. The most common class of lesion was salivary-gland neoplasm, accounting for 74 cases (45.68%). The next most common group of tumors was neurogenic, representing 68 cases (41.98%). Only 22 patients (13.58%) presented with malignant disease. Three surgical approaches were commonly used in the management of these lesions: transcervical-transparotid in 93 patients (57.41%), transcervical in 51 patients (31.48%), and transcervical-transmandibular in 18 patients (11.11%). Twenty patients with malignant disease underwent adjuvant chemotherapy and/or radiotherapy. All cases were followed for a mean of 36 months. There was no perioperative mortality. Two patients suffered local failure, and 4 patients developed distant metastasis during the observation period. CONCLUSIONS: Surgery is the mainstay treatment for PPS tumors. Surgical approaches were dictated by size of the tumor, its location, its relationship to the great vessels, and suspicion of malignancy. The most common approach was transcervical-transparotid for benign tumors.
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BACKGROUND: The prevalence of childhood obesity is increasing rapidly in China. However, research on its modifiable environmental determinants to inform preventive interventions is limited. PURPOSE: This paper reports a cross-sectional study that aimed to identify family and neighborhood environmental correlates of overweight and related health behavior among Chinese primary school-aged children in urban areas. METHODS: Routinely collected height and weight data of third year students (8-10 years) from four primary schools in socioeconomically distinct districts of two southern cities of China was obtained. Using the WHO 2007 reference values, children were categorized into overweight/obese or non-overweight. Parents of the same children completed a questionnaire, comprising mainly validated questions, about family and perceived neighborhood environments, parental physical activity habits, and the child's dietary and physical activity patterns. Multiple logistic regression analysis was performed to examine the association between these environmental factors and childhood overweight or whether or not the child engages in at least 1 h daily moderate to vigorous physical activity. Multiple linear regression analysis was undertaken to examine the association between environmental factors and the frequency of consumption of unhealthy snacks, fruit, and vegetables in children. RESULTS: Data on 497 children were available. Children who were mainly cared for by their grandparents were over twice as likely to be overweight/obese (adjusted OR 2.03; 95% CI 1.19-3.47) and to have higher consumption of unhealthy snacks and sugar-added drinks (B = 2.13, 95% CI 0.87-3.40), compared with children who were mainly cared for by their parents or other adult. Children who lived with at least two grandparents in the household were at higher risk for being overweight/obese than children who lived without any grandparent (adjusted OR 1.72; 95% CI 1.00-2.94). No evidence was found for associations between perceived neighborhood environmental characteristics and child's weight status and obesogenic behaviors in this study. CONCLUSIONS: Children's family environment, particularly the living-in grandparents, should be targeted in future preventive interventions among China's southern urban populations.
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Evidence supports the hypothesis that an impaired capacity of insulin to antagonize norepinephrine-induced vasoconstriction increases alpha-adrenergic tone in overweight young men with insulin resistance and mild hypertension. Therefore, the effects of regionally infused insulin at 100 microU/mL on forearm blood flow (milliliters per deciliter per minute) and responses to norepinephrine were measured in seven obese hypertensive and eight lean normotensive men younger than 45 years old. The obese hypertensive men were hyperinsulinemic and insulin resistant compared with the normotensive men, as evidenced by abnormal values for fasting insulin (15.5 +/- 1.6 versus 7.2 +/- 0.8 microU/mL, P < .001), the insulin area under the curve in response to a 2-hour oral glucose tolerance test (12.0 +/- 1.5 versus 6.7 +/- 1.1 mU x min/dL, P < .01), and the disappearance rate of glucose during a 15-minute insulin tolerance test (2.7 +/- 0.3 versus 4.1 +/- 0.3 mg%/min, P < .05). The logarithm of the norepinephrine EC50 was not significantly different in obese hypertensive men (mean, 95% confidence interval: -8.15, -8.42 to -7.87) versus lean normotensive men (-7.91, -8.23 to -7.59). The 2-hour regional insulin infusion at 100 microU/mL did not significantly alter the EC50 for norepinephrine in either group. Insulin at this concentration induced significant and similar increases of forearm blood flow in the hypertensive and normotensive groups (1.7 +/- 0.4 versus 1.7 +/- 0.6 mL/100 mL per minute, P = NS). At approximately 100 microU/mL, insulin does not antagonize norepinephrine-induced vasoconstriction in the forearm circulation of either obese hypertensive or lean normotensive men.(ABSTRACT TRUNCATED AT 250 WORDS)
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Vascular access represents a lifeline for children undergoing hemodialysis. A failure of vascular access among patients receiving regular hemodialysis is associated with increased morbidity, mortality and costs. We assessed the possibility of using soluble adhesion molecules as reliable predictors of vascular access failure in children on hemodialysis. Moreover, we evaluated whether there is an association among the different studied adhesion molecules in hemodialysis patients with thrombosed and non-thrombosed arteriovenous fistula fistulas (AVFs). This study included 55 hemodialysis children, 36 with good access and 19 with access failure, and 20 healthy volunteers. Forty-four patients had native AVFs and 11 patients had tunneled permanent catheter (11with thrombosed and 33 with non-thrombosed AVFs). Serum-soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin) and soluble P-selectin (sP-selectin) were measured using ELISA technique. A significant increase was found in the levels of sVCAM-1, sICAM-1, sE-selectin and sP-selectin versus controls and all hemodialysis patients, hemodialysis patients with good access and hemodialysis patients with access failure (P=0.001 for sVCAM-1 and sICAM-1 and P=0.0001 for sE-selectin and sP-selectin). A significant increase was found in the levels of sVCAM-1, sE-selectin and sP-selectin in both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs versus controls (P=0.0001 for all parameters). There was significant difference between both chronic hemodialysis patients with thrombosed and non-thrombosed native AVFs as regard to sVCAM-1 (54.64+/-30.82 versus 25.69+/-27.96ng/ml, P=0.04). Both sICAM-1 and sP-selectin were positively correlated with the erythropoietin (EPO) dose in hemodialysis children (r=0.31, P=0.04 and r=0.32, P=0.04, respectively). A significant positive association was found between E-selectin and sP-selectin in hemodialysis patients with thrombosed AVFs (r=0.83, P=0.04). There was a significant correlation between sVCAM-1 and EPO dose in thrombosed AVF group (r=0.84, P=0.01). The assessment of serum sVCAM-1 might be useful for the identification of the chronic hemodialysis patients at an increased risk for native AVFs thrombosis. The role of EPO in vascular access failure should be taken into consideration. The clinical relevance of these observations warrants further investigations.
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BACKGROUND: Interferon-alpha has proven effective in the treatment of metastatic renal cell carcinoma. However, the optimal schedule has not yet been determined. The authors have studied the efficacy and toxicity of prolonged use interferon-alpha2a (IFN-alpha) in metastatic renal cell carcinoma (RCC). Interferon-alpha was administered intermittently for outpatients. METHODS: Seventy-five patients with metastatic RCC without prior biochemotherapy were treated. During the first month, the IFN-alpha dose was increased from 4.5 to 18 million units (MU) 3 times a week to define the individual maximal tolerated dose for each patient. The treatment was continued at the maximal tolerated dose with a 1-week pause each month until either progression or intolerable toxicity was observed or up to 2 years. RESULTS: The overall response rate (5 complete response [CRs] and 8 partial responses [PRs]) was 17% (95% confidence interval, 10-28%). Stable disease was observed in 32 patients (43%). Three late objective responses (4%) occurred after 12 months treatment. The median progression free time of all patients was 12.3 months, and median survival time was 19.3 months. The median duration of response in CR/PR patients was 16 months. In multivariate analysis independent prognostic factors were poor performance status (P = 0.004), presence of bone metastases (P = 0.001), and time to metastases less than 24 months (P = 0.003), which predicted poor survival. Six patients (8%) discontinued the treatment because of fatigue, elevation of liver enzymes, or cardiac arrhythmias. No life-threatening side effects were observed. CONCLUSIONS: Prolonged and intermittently administered IFN-alpha2a three times per week in 3 weekly cycles in metastatic RCC is a feasible and effective therapy. A prolonged treatment duration of more than 12 months for stable and responding patients is beneficial and may improve the outcome of patients with RCC.
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BACKGROUND: The use of biodegradable screws in anterior cruciate ligament reconstruction has grown in popularity. PURPOSE: To compare the clinical and radiographic results in arthroscopically assisted anterior cruciate ligament reconstruction using 4-strand hamstring tendon grafts and either metallic (metal group) or biodegradable (PLLA group) interference screw fixation. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A randomized series of 77 patients, all with a unilateral anterior cruciate ligament rupture, was included in the study. The preoperative assessments in both groups were similar in gender, Tegner activity level, Lysholm score, KT-1000 arthrometer measurements, and single-legged hop test results. In both groups, interference screw fixation of the graft was used at both ends, and 68 of 77 (88%) patients returned for a radiographic examination at 6 and 24 months, respectively. RESULTS: At follow-up, no significant differences were found between the 2 groups in KT-1000 arthrometer laxity measurements, Tegner activity level, or Lysholm score. The PLLA group had a significantly better outcome in the single-legged hop test and the final International Knee Documentation Committee classification (P = .007 and P = .03, respectively). At 6 and 24 months after the index operation, the PLLA group displayed significantly larger drill holes on the radiographs than did the metal group on both the tibial (8.1 vs 6.6 mm at 6 months [P = .0007]; 6.0 vs 3.2 mm at 24 months [P < .0001]) and femoral sides (7.8 vs 5.6 mm at 6 months [P < .0001]; 6.3 vs 1.9 mm at 24 months [P < .0001]). CONCLUSION: There were significantly larger radiographically visible drill holes on both the tibial and femoral sides in the PLLA group compared with the metal group at 6 and 24 months. Clinical examination at 2 years revealed no major differences between the groups. The larger drill holes in the PLLA group did not correlate with inferior clinical results.
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OBJECTIVE: To investigate whether or not peri/intraventricular hemorrhages (PIVHs) occurring in the first 12 hours of life (early PIVHs) are related to respiratory distress syndrome (RDS)-associated inflammatory factors in contrast to PIVHs developing after 12 hours of life (late PIVHs). STUDY DESIGN: Blood samples obtained at 0 to 12 hours, 48 to 72 hours, and 168 hours of life were evaluated for determination of the proinflammatory cytokines interleukin (IL)-8 and IL-6, tumor necrosis factor (TNF)-alpha, and malondialdehyde (MDA) as measures of lipid peroxidation. Simultaneously, cranial ultrasonography was performed in 114 neonates under 32 weeks gestational age. RESULTS: Out of the total study group of 114 neonates, 67 (59%) had RDS. Early PIVH occurred in 16 neonates, 14 of whom (88%) had RDS. Late PIVHs occurred in 12 neonates. Neonates with RDS had higher IL-8 and IL-6 levels at 0 to 12 hours (P < .0001; < .0001) and at 48 to 72 hours (P < .001; < .01) than those without RDS. Neonates with early PIVH had higher IL-8 (P < .02), IL-6 (P < .02), and MDA (P < .01) levels at 0 to 12 hours than those with late PIVH or no PIVH. Those with early PIVH had higher IL-8 levels at 48 to 72 hours than those without PIVH (P < .02). Multiple linear regression revealed an association between RDS/early PIVH and IL-8, IL-6, and MDA levels. CONCLUSIONS: An RDS-associated increase in proinflammatory cytokine and MDA levels was associated with early PIVHs, but not with late PIVHs, suggesting a different etiopathogenesis in early versus late PIVHs.
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BACKGROUND: The tissue-suture interface remains the most common site of failure in rotator cuff repairs. It is currently unknown if arthroscopic sliding knots injure the tissue and weaken the suture-tendon interface. PURPOSE: To evaluate the effect sliding knots have on the strength of the suture-tendon interface. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 32 sheep infraspinatus tendons were randomized among 4 groups of stitches (n = 8): simple-static, simple-sliding, mattress-static, and mattress-sliding. All high-strength, No. 2 suture stitch-knot combinations were created in an arthroscopic simulated environment, and sliding knots were tied with shortening of the suture and sliding of the knot down to the tissue interface to simulate surgical technique. Each graft was cyclically loaded on a mechanical testing system from 5 to 20 N for 20 cycles and then loaded to failure. A least squares analysis of variance model was used to test significance of sliding stitches upon cyclic elongation, peak-to-peak displacement, and ultimate load. Estimated means and standard deviations are reported from the regression model. RESULTS: A mattress-static stitch (116 N) was significantly stronger than a mattress-sliding stitch (70 N; P < .001). The ultimate loads for the simple-static (46 N) and sliding (50 N) stitches were not statistically different. For cyclic elongation, the only difference was the mattress-sliding stitch (0.95 mm) having a greater elongation than the simple-static (0.61 mm; P = .01) and simple-sliding (0.68 mm; P = .04) stitches. Both mattress stitches had significantly less peak-to-peak displacement (0.39 and 0.41 mm) than the simple stitches (0.47 and 0.46 mm; P < .001). CONCLUSION: Sliding suture through tissue weakens the suture-tendon interface in mattress stitch constructs but not in simple stitch constructs. Mattress stitches have superior holding strength compared with simple stitches. CLINICAL RELEVANCE: Clinical relevance is uncertain. In situations with poor tissue quality or concern regarding tension across the repair, consideration should be given to using static knots as opposed to sliding knots when placing mattress stitches.
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PURPOSE: To determine the safety, pharmacokinetics (PK), and maximum-tolerated dose (MTD) up to a prespecified target dose of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase 1b study, patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4 or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs), adverse events, and antidulanermin antibodies were assessed. PK parameters were recorded for each agent. Tumor response was measured by modified Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-four patients received at least one dose of dulanermin plus PCB, six in each treatment cohort. There were no DLTs. An MTD was not reached, and the drug combination was well tolerated. Treatment-emergent adverse events were generally as expected for the PCB regimen. Adverse events attributed to dulanermin were grade 1/2; no significant hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin. There was one confirmed complete response and 13 confirmed partial responses. The overall response rate was 58% (95% CI, 37 to 78). Median progression-free survival was 7.2 months (95% CI, 4.7 to 10.3). CONCLUSION: Dulanermin plus PCB was well tolerated with no occurrence of DLTs and demonstrated antitumor activity in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for 2 days every 3 weeks in combination with PCB is being studied in a phase II trial.
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PURPOSE: To test the efficacy and safety of pharmacokinetic modulating chemotherapy combined with cisplatin (PMC-cisplatin) as induction chemotherapy (ICT) before definitive treatment in patients with respectable locally advanced head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Patients with stage III-IV resectable locally advanced HNSCC were enrolled. All eligible patients received PMC-cisplatin regimen as ICT containing intravenous leucovorin 250 mg/m(2) and 5-FU 600 mg/m(2) on day 1, oral tegafur-uracil (UFUR) 250 mg/m(2)/day on days 1-5, repeated every week for six courses. Cisplatin 100 mg/m(2 )was given during the first and fourth courses of PMC. For ICT responders, concurrent chemoradiotherapy (CRT) with cisplatin/tegafur-uracil/70 Gy radiotherapy was performed. Salvage surgery plus postoperative CRT was given to ICT non-responders. RESULTS: The overall response rate of PMC-cisplatin as ICT was 76%, including a complete remission rate of 23%. The overall organ preservation rate of the multimodality treatment was 75%, with 97% in ICT responders. At a median follow-up of 25 months, 47% of the patients were still alive and disease-free. The superiority of disease-free survival was demonstrated in ICT responders. The 3-year overall survival rate was 67%. The toxicity of treatment was acceptable. CONCLUSIONS: Application of PMC-cisplatin as the induction chemotherapy before definitive treatment provides a promising result in treatment response and survival of advanced HNSCC. This regimen is effective and safe, and further studies considering the combination of PMC with other chemotherapeutics such as taxanes to improve the clinical outcome of advanced HNSCC is warranted.
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Bis(dichloropropyl) ether isomers have been identified in a petrochemical plant effluent through a toxicity identification evaluation study in the United States. They have also been observed in the microgram per liter range along one of the largest rivers in Europe, the Elbe River. In the present investigation, the genotoxic and transforming activity of a bis(dichloropropyl) ether isomer, bis(2,3-dichloro-1-propyl) ether, was assayed in vitro. The results demonstrate that bis(2,3-dichloro-1-propyl) ether is a potent mutagen in Salmonella typhimurium strains TA 100, TA 1535, and to a lesser extent in strain TA 98, but only when tested in the presence of a metabolic activation system (S9 mix). We have also investigated the induction of micronuclei by bis(2,3-dichloro-1-propyl) ether in the metabolically competent cell line, MCL-5. A linear, dose-dependent increase in micronuclei was observed following exposure to bis(2,3-dichloro-1-propyl) ether. The DNA strand-breaking capacity of this chemical was assessed in the alkaline single-cell gel electrophoresis ("comet") assay with MCL-5 cells. Bis(2,3-dichloro-1-propyl) ether clearly induced DNA strand breaks in the 4.5-45.5 microg/ml dose range. The ether also induced malignant transformation in C3H/M2 mouse fibroblasts after metabolic activation (S9 mix). Thus, it must be suspected that bis(2, 3-dichloro-1-propyl) ether may possess a carcinogenic potential. Since the compound along with its isomers is present in considerable concentrations in surface water, their elimination is a matter of significant public concern.
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The aim of this study was to examine the effects of L-arginine, a nitric oxide (NO) precursor, on protein expression of endothelial nitric oxide (eNOS), nitrite/nitrate content, protein expression of mitogen-activated protein kinase phosphatase-1 (MKP-1) and the activity of mitogen-activated protein kinase (MAPK) in cardiac tissues in renovascular hypertensive rats (RHR). The Goldblatt renovascular hypertensive model was established by two-kidney one clip method. The rats were divided into four groups, respectively treated with 50, 150 and 450 mg/kg L-arginine and 150 mg/kg L-arginine plus 10 mg/kg L-NAME (an eNOS inhibitor) (i.p.). Another group did not receive specific treatment from the 5th week after renal artery constriction. Control group was sham-operated. Mean arterial blood pressure (MABP) and the ratio of left ventricular weight to body weight (LVW/BW) were measured 8 weeks after treatment. eNOS protein expression, nitrite/nitrate content, MKP-1 protein expression and MAPK activity in cardiac tissues were detected using Western blot analysis, enzyme-reduction method and substrate in-gel kinase assay, respectively. It was found that L-arginine significantly inhibited the increase of MABP and LVW/BW, attenuated the activity of MAPK, increased protein expression of eNOS and MKP-1 and potentiated production of NO in cardiac tissue with the most effective dosage of 150 mg/kg, and these effects of L-arginine could be inhibited by L-NAME. These results suggest that MKP-1 may play an important role in the NO-induced inhibition of myocardial hypertrophy. The anti-hypertrophic effects of L-arginine may involve increase of eNOS protein expression and NO production, potentiation of MKP-1 protein expression, and inhibition of MAPK activity in the cardiac tissue of RHR.
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In spite of proven immunoregulatory effects in vitro of recombinant human interferon-gamma (rhIFN-gamma) in trauma, clinical trials remain inconclusive in such patients. To investigate the in vivo effect of rhIFN-gamma perioperatively in surgical patients we did a pilot study in 46 patients termed anergic by negative delayed-type hypersensitivity (DTH) skin test, who were undergoing major surgery (22 women and 24 men). They received 100 micrograms of rhIFN-gamma subcutaneously (treated [T]; n = 24) in a double-blind, placebo- (control [C]; n = 22) controlled manner on preoperative days -7, -5, and -3. Whole-blood cultures were stimulated on days -7, -1, 4, 7, and 10 for 12 h with or without LPS (1 microgram/mL). Mild side effects such as fever, headache, or chills were observed in 7/24 patients. No major complications occurred and no significant effect of rhIFN-gamma on HLA-DR, IL-1, and IL-8 was demonstrated. PGE2, TNF-alpha and IL-6 levels were elevated perioperatively in T. versus C. Neopterin, a metabolite of activated monocytes and macrophages, was significantly activated on days -1 (C: 7.6 +/- 1.2 versus T: 20.5 +/- 2.4 nmol/mL; P < 0.001), day 1 (C: 8.3 +/- 1.4 nmol/mL versus T: 24.9 +/- 2.8 nmol/mL; P < 0.001), and day 4 (C: 9.5 +/- 1.1 nmol/mL versus T: 16.0 +/- 1.8 nmol/mL; P < 0.05). Due to the overall lack of infectious complications during the investigation, no clinical effect was shown for rhIFN-gamma treatment. DTH skin testing failed to detect high-risk individuals in the patient population studied. In conclusion, we demonstrated in our pilot study that pre-operative immunomodulation with rhIFN-gamma in surgical anergic patients did not show severe side effects and modulated in vitro immunoresponse. A larger clinical trial in better-defined high-risk patients may show whether a reduction of infectious complications can be achieved.
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BACKGROUND: African Americans have greater risk of cardiovascular events than comparator populations of white European origin. A potential reason for this is reduced nitric oxide bioavailability in African Americans, resulting in increased prevalence of factors that contribute to ventricular dysfunction. We investigated the effects of nebivolol with the diuretic hydrochlorothiazide (HCTZ) in hypertensive African Americans with echocardiographic evidence of diastolic dysfunction. METHODS: A total of 42 African American patients were assigned to nebivolol and HCTZ in an open-label fashion for a 24-week period. Changes in blood pressure (BP), echocardiographic parameters, and success in attaining target BP were determined. As an indirect determinant of endothelial function, serum total nitric oxide (NOx) levels and asymmetric dimethyl arginine (ADMA) levels were performed at baseline and after the treatment period. RESULTS: The systolic BP decreased from 150 +/- 13 to 136 +/- 16 mm Hg (P < .005). Diastolic BP decreased from 94 +/- 13 to 84 +/- 9 mm Hg (P = .008). Of the patients that completed the study, 77% achieved a combined target BP of systolic BP <140 mm Hg and a diastolic BP <90 mm Hg. Serum NOx increased by 41% and 39% in patients that were treated with 10 mg and 20 mg daily nebivolol, respectively. The ADMA levels decreased by 44% following treatment. The change in systolic BP was strongly correlated to the change in ADMA (r = .54; P = .024). Furthermore, in comparison to a group of age-matched patients controlled with diuretic therapy only, the ADMA levels were significantly lower in the nebivolol posttreatment group (controlled BP with diuretic: 0.32 +/- 0.07mumol/L; nebivolol posttreatment: 0.24 +/- 0.06 mumol/L; P < .05). CONCLUSION: Reduced BP with nebivolol in hypertensive African Americans and echocardiographic evidence of diastolic dysfunction correlates with improved endothelial function. Furthermore, improvement in endothelial function and increased nitric oxide bioavailability suggests a potential mechanism of efficacy of nebivolol in these patients.
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The Health Systems in Transition (HiT) profiles are country-based reports that provide a detailed description of a health system and of policy initiatives in progress or under development. HiTs examine different approaches to the organization, financing and delivery of health services and the role of the main actors in health systems; describe the institutional framework, process, content and implementation of health and health care policies; and highlight challenges and areas that require more in-depth analysis. Various indicators show that the health of the population has improved over the last few decades. However, inequalities in health across socioeconomic groups have been increasing since the 1970s. The main diseases affecting the population are circulatory diseases, cancer, diseases of the respiratory system and diseases of the digestive system. Risk factors such as the steadily rising levels of alcohol consumption, the sharp increases in adult and child obesity and prevailing smoking levels are among the most pressing public health concerns, particularly as they reflect the growing health inequalities among different socioeconomic groups. Health services in England are largely free at the point of use. The NHS provides preventive medicine, primary care and hospital services to all those ordinarily resident. Over 12% of the population is covered by voluntary health insurance schemes, known in the United Kingdom as private medical insurance (PMI), which mainly provides access to acute elective care in the private sector. Responsibility for publicly funded health care rests with the Secretary of State for Health, supported by the Department of Health. The Department operates at a regional level through 10 strategic health authorities (SHAs), which are responsible for ensuring the quality and performance of local health services within their geographic area. Responsibility for commissioning health services at the local level lies with 151 primary care organizations, mainly primary care trusts (PCTs), each covering a geographically defined population. Health services are mainly financed from public sources, primarily general taxation and national insurance contributions (NICs). Some care is funded privately through PMI, some user charges, cost sharing and direct payments for health care delivered by NHS and private providers. While the reform programme that developed since 1997 proved to be massive in its scope, some basic features of the English NHS, such as its taxation-funding base, the predominantly public provision of services and division between purchasing (commissioning) and care delivery functions, remain unchanged. Nevertheless, in addition to the unprecedented level of financial resources allocated to the NHS since 2000, the most important reform measures included the introduction of the payment by results (PbR) hospital payment system; the expanded use of private sector provision; the introduction of more autonomous management of NHS hospitals through foundation trusts (FTs); the introduction of patient choice of hospital for elective care; new general practitioner (GP), consultant and dental services contracts; the establishment of the National Institute for Health and Clinical Excellence (NICE); and the establishment of the Care Quality Commission (CQC) to regulate providers and monitor quality of services. The English NHS faces future challenges as 2010 draws to a close, with significant restrictions on expenditure and a newly elected government that has announced its intention to introduce further widespread reform.
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1. We investigated the neural mechanisms of the increases in blood flow produced by synaptic activity using the parallel fiber (PF) system of the cerebellum as a model. The midline cerebellum was exposed in anesthetized rats and the PFs were stimulated with tungsten microelectrodes. Cerebellar blood flow (BFcrb) was recorded using a laser-Doppler probe, whereas field potentials were recorded using glass micropipettes. PF stimulation produced increases in BFcrb that were related to the frequency and intensity of stimulation (+60 +/- 9%, mean +/- SE, at 100 microA and 30 Hz; n = 6). The greatest increases were confined to a band stretching along the major axis of the stimulated folium and corresponding to the beam of activated PFs. The increase in evoked by PF stimulation was associated with a corresponding increase in glucose utilization, assessed by the 2-deoxyglucose method. The increases in BFcrb and the field potentials evoked by PF stimulation were abolished by tetrodotoxin (1 microM; n = 6). Ringer solution containing 12 mM Mg2+ and 0 mM Ca2+ blocked synaptic activity in the PFs and abolished the increases in flow (P > 0.05 from baseline; n = 5). The broad-spectrum glutamate receptor antagonist kynurenate (5 mM) prevented depolarization of Purkinje cells and interneurons and abolished the increase in BFcrb evoked by PF stimulation (P > 0.05; n = 6). Treatment with tetrodotoxin, Mg2+, or kynurenate did not affect the increase in BFcrb elicited by systemic hypercapnia or by topical application of the nitric oxide donor 3-morpholino sydnonimine (P > 0.05 from Ringer solution). We conclude that the increases in flow produced by synaptic activity are linked to glutamate-induced depolarization of Purkinje cells and interneurons. These findings provide evidence that activation of glutamate receptors participates in the mechanisms of functional hyperemia, and they support the validity of the PF system as a model for study of the relationship between synaptic activity and blood flow in the CNS.
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OBJECTIVE: Brain abscess (BA) is a neurosurgical emergency and despite significant medical advances, it remains a surgical challenge. A single institution's two decade computed tomography era management experience with BA is reported. METHODS: A retrospective analysis of patients with BA, admitted to the Department of Neurosurgery, Wentworth Hospital, Durban, KwaZulu-Natal, South Africa, was performed. The medical records were analyzed for demographic, clinical, neuroimaging, neurosurgical and otolaryngology management, microbiological characteristics, and their relationship to outcome. RESULTS: During a 20-year period (1983-2002), 973 patients were treated. The mean age was 24.36 +/- 15.1 years (range: 0.17-72 years) and 74.2% (n = 722) were men. The mean admission Glasgow Coma Score was 12.5 +/- 2.83. The majority of BAs were supratentorial (n = 872, 89.6%). The causes were otorhinogenic (38.6%), traumatic (32.8%), pulmonary (7%), cryptogenic (4.6%), postsurgical (3.2%), meningitis (2.8%), cardiac (2.7%), and "other" (8.6%). Surgical drainage was performed in 97.1%, whereas 19 patients had nonoperative management. The incidence of BA decreased during the study period. Patient outcomes were good in 81.3% (n = 791), poor in 5.3% (n = 52), and death (13.4%, n = 130) at discharge. The management morbidity, which included postoperative seizures, was 24.9%. Predictors of mortality were cerebral infarction (odds ratio [OR] 31.1), ventriculitis (OR 12.9), coma (OR 6.8), hydrocephalus (OR 5.1), dilated pupils (OR 4.8), bilateral abscesses (OR 3.8), multiple abscesses (OR 3.4), HIV co-infection (OR 3.2), papilledema (OR 2.6), neurological deterioration (OR 2.4), and fever (OR 1.7). CONCLUSIONS: Optimal management of BA involves surgical drainage for medium-to-large abscesses (>/=2.5 cm) with simultaneous eradication of the primary source, treatment of associated hydrocephalus, and administration of high doses of intravenous antibiotics. The incidence of BA is directly related to poor socioeconomic conditions and therefore, still poses a public health challenge in developing countries.
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BACKGROUND: Acute respiratory distress syndrome (ARDS) is a common diagnosis in intensive care units (ICUs) and is frequently correlated with acute kidney injury (AKI). OBJECTIVES: To investigate the outcomes of critically ill patients with ARDS and to shed light on the association between prognosis and risk of renal failure, injury to kidney, failure of kidney function, loss of kidney function and end-stage renal failure (RIFLE) classification. METHODS: This retrospective study investigated the medical records of 60 critically ill patients with ARDS who underwent open lung biopsy (OLB) in 2 medical intensive care units of a tertiary care hospital from December 1999 to May 2005. RESULTS: The overall mortality rate was 55% (33/60). The increase in mortality was progressive and significant (chi(2) for trend, p < 0.001) with increasing severity of the RIFLE classification. The Glasgow coma scale, alveolar-arterial O(2) tension difference and maximum RIFLE (RIFLE(max)) score for days 1 and 3 in the ICU and on the day of OLB were independent predictors of hospital mortality by forward conditional logistic regression. Hosmer-Lemeshow goodness-of-fit test results demonstrate that RIFLE(max) has a good fit. The area under the receiver operating characteristic curve (AUROC) and RIFLE(max) score indicate good discriminative power (AUROC 0.750 +/- 0.063, p = 0.001). Cumulative survival rates at the 6-month follow-up following hospital discharge differed significantly (p < 0.05) for non-AKI versus RIFLE(max)-risk, RIFLE(max)-injury and RIFLE(max)-failure patients. CONCLUSION: In patients with ARDS undergoing OLB, the use of the RIFLE score improves prediction of outcome.
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BACKGROUND: The Personal Digital Assistant (PDA) has become nowadays a powerful and essential tool for many physicians. Its promising success in the near future and the lack of information in regard to its use in Lebanon led to this transverse study. METHODS: A questionnaire was submitted to the doctors, residents and interns of Hotel-Dieu de France (HDF) Hospital (Beirut), during March-April 2004 in order to evaluate the use of PDAs, the preferences and the needs of the medical personnel and to propose solutions which can meet its needs. RESULTS: The answers' rate to the questionnaire is 70.3% (303 answers). The PDA possession rate is 3036%; it is significantly more important in physicians compared to surgeons. Among those having a PDA, the operating system Palm dominates with 60% with a current tendency towards the purchase of Pocket PC; the operating system Pocket PC dominates the Phone PDAs. Approximately one third use their PDA ineffectively and admit having difficulties which greatly reduce its use in the medical field. Lexi-Drugs is the most used pharmaceutical guide, Sanford Guide the most used microbiological guide, iSilo the most used medical textbooks reader. More than 85% do not use any program to follow up their patients or read medical journals. Two thirds recognize the beneficial role of the PDA on the quality and the speed of the medical practice, one third consider that it reduces medical errors. The availability of medical programs is significantly more important for Palm. Among the subjects not having a PDA, 47% hope to buy one in the year to come; the possession rate of PDAs is estimated to reach 69.3% in 2010. Computerization of the medical data, installation of a wireless network, courses on the use of PDAs in the medical field, etc., are needs considered to be useful by 60-80% of the responders. CONCLUSION: Many medical utilities are already computerized. They still have to be presented in a format compatible with PDAs to answer a great part of the needs. A guided hospital policy and an educational program are needed to increase the usefulness of PDAs in the medical field.
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Cefadroxil was administered orally at a daily dose of 30-40 mg/kg to 8 cases of the infection of upper respiratory tract mainly due to beta-hemolytic Streptococcus, and efficacy was obtained in 7 cases, this rate being considered to be satisfactory, though the cases were too few to reach a conclusion. As to pathogens of bacterial infection of upper respiratory tract, beta-hemolytic Streptococcus and Staphylococcus aureus were encountered especially frequently, and in view of antibacterial activity against these 2 bacteria, our results could be approved. Further investigations should be performed carefully, however, to determine if cefadroxil may be a drug of first choice in the treatment of severe bacterial pneumonia and pyothorax. No side effects were observed throughout our treatment, though digestive tract disorders, especially diarrhea, are most frequent in literatures. As to pharmacokinetical characteristic of cefadroxil, almost the same results were obtained to other reports, though our data are insufficient as our experience was limited in only 1 case. Serum levels were determined after 35.7 mg/kg of cefadroxil were administered once orally, and a peak of about 38 mcg/ml appeared 2 hours later, and a high level of about 30 mcg/ml was maintained at 5 hours, though an oral dose was high. Efficacy for large area of bacterial infections may be expected from these serum levels. From urine collected simultaneously, about 74% of cefadroxil was recovered within more than 4 hours. This showed that cefadroxil was well absorbed from digestive tract, and a major part was excreted rapidly through kidney. From the results of our experiment, characteristics of cefadroxil may be summarized as follows. Cefadroxil is absorbed well after oral administration, antibacterial action is fully expected from serum level, a major part is excreted through kidney, and clearance is good. Cefadroxil will be recommended especially for bacterial infections of upper respiratory tract due to beta-hemolytic Streptococcus and Staphylococcus aureus.
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BACKGROUND: Complex craniosynostoses (i.e., multisutural, nonsyndromic) are rare and present unique treatment challenges. The authors sought to assess long-term outcomes, including postsurgical growth and development, to develop evidence-based treatment algorithms. METHODS: A retrospective review of all patients identified as having multiple sutural synostosis excluding bicoronal and FGFR- and TWIST-associated synostoses was conducted. Data were summarized using descriptive statistics. RESULTS: Over an 18-year period, 858 patients underwent craniosynostosis correction, and 31 patients (3.6 percent) satisfied inclusion criteria. Average number of affected sutures was 2.9 (lambdoid, 36 percent; sagittal, 31 percent; coronal, 18 percent; metopic, 15 percent), and 1.7 procedures were performed per patient (mean follow-up, 3.5 years). Average hospital stay was 2.3 days, 21 percent required blood transfusions, and there were no major complications. For synostosis patterns isolated to one side of the anterior sagittal suture (anterior or posterior skull halves), 93 percent were corrected with a single procedure. When the synostosis pattern crossed both skull halves, 80 percent underwent two procedures (p<0.001). Forty percent developed acquired Chiari deformations; of these, 60 percent required decompression. The incidence of Chiari deformations increased from 7 percent to 70 percent with lambdoid sutural involvement (p<0.002). Anthropometric data revealed postoperative growth impairment. Gross developmental delays were noted in 20 percent (mild, 16 percent; moderate to severe, 4 percent). CONCLUSIONS: Complex craniosynostoses are associated with a higher incidence of acquired Chiari deformations (especially with lambdoid involvement), require multiple operative procedures, and may have more developmental delays than the isolated single sutural synostoses. The authors recommend surgical paradigms based on sutural involvement, compensatory surgical overcorrection, and routine magnetic resonance imaging monitoring for Chiari deformations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
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INTRODUCTION: Interleukin-6 (IL-6) is a pleiotropic regulator of prostate cancer cell growth. Oncostatin M (OSM), an IL-6-type cytokine, affects the growth of prostate cancers in a paracrine and autocrine manner. In order to understand better the mechanisms controlling proliferation and intracellular signaling by these cytokines in advanced prostate carcinoma, we performed studies in 22Rv1 cells derived from the relapsed xenograft CWR22R. METHODS: Expression of IL-6 and OSM receptors (OSMR-beta) and elements of signal transduction pathways in 22Rv1 cells were investigated by RT-PCR. Proliferation was assessed by cell counting after treatment with either IL-6 or OSM. IL-6 secretion was measured in conditioned medium from 22Rv1 cells by ELISA. Expression and phosphorylation status of signal transducers and activators of transcription factor (STAT) 3, mitogen-activated protein kinases (MAPK) p44/p42 and p38, and protein kinase B (Akt) was investigated by Western blot. RESULTS: 22Rv1 cells express both subunits of the IL-6 receptor (gp80 and gp130) and leukemia inhibitory factor receptor-beta (LIFR-beta) but not OSMR-beta. Their proliferation was stimulated by IL-6 or OSM and the maximal effect was observed at a concentration of 10 ng/ml of either cytokine. Interestingly, neither IL-6 nor OSM induced phosphorylation of STAT3. OSM modestly increased the phosphorylation of p38 and both cytokines exerted an effect on Akt phosphorylation. CONCLUSIONS: IL-6 and OSM stimulate proliferation of 22Rv1 cells, at least in part through activation of the phosphatidylinositol 3-kinase (PI 3-K) signaling pathway. Our data provide additional evidence for the growth-stimulatory role of IL-6 and related cytokines in advanced prostate cancer and may serve as a basis for the development of novel experimental therapies.
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BACKGROUND: Three strategies are used to prevent relapse in patients with acute myeloid leukaemia in first remission. Most of those with suitable donors are offered allogeneic haemopoietic-stem-cell transplant. Other patients may receive intensive chemotherapy or autologous transplantation; we undertook this randomised prospective trial to assess which is the better option. METHODS: After three courses of intensive chemotherapy, bone marrow was harvested from patients (<56 years of age) in remission who lacked an HLA-matched sibling donor. These patients were then randomised to receive, after one more course of chemotherapy, no further treatment (n=191) or an autologous bone-marrow transplant (BMT) after preparation with cyclophosphamide and total-body irradiation (n=190). Outcome comparisons were by intention to treat with adjustment for the most important risk factors for relapse. FINDINGS: 381 patients were randomised (38% of those eligible). Of the 190 patients allocated autologous BMT, 126 received it. On intention-to-treat analysis the number of relapses was substantially lower in the autologous BMT group than in the group assigned no further treatment (64/190 [37%] vs 101/191 [58%], p=0.0007), resulting in superior disease-free survival at 7 years (53 vs 40%; p=0.04). These benefits were observed in all risk groups and age-groups. There were more deaths in remission in the autologous BMT group than in the no further treatment group (22 [12%] vs 7 [4%], p=0008). In children (<15 years) and patients with good-risk disease, survival from relapse in the no further treatment group was 35% and 38% at 2 years. There was an overall survival advantage in the autologous BMT group at 7 years (57 vs 45%, p=0.2). INTERPRETATION: The addition of autologous BMT to four courses of intensive chemotherapy substantially reduces the risk of relapse in all risk groups, leading to improvement in long-term survival. The good chance of salvage for children or patients with good-risk disease who relapse from chemotherapy, and the mortality, morbidity, late effects, and expense of autologous BMT, suggest that delay of autograft until second remission in these two groups may be appropriate.
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OBJECTIVES: This prospective, randomized, double-blind, placebo-controlled study compared the efficacy and safety of amiodarone and sotalol in the prevention of atrial fibrillation (AF) following open heart surgery. BACKGROUND: The incidence of supraventricular arrhythmias following open heart surgery ranges from 20% to 40%, with AF being the most common. Both amiodarone and sotalol have been shown to be effective in reducing postoperative arrhythmias, but no direct comparison of these agents has been conducted. METHODS: A total of 160 patients were randomized, of whom 134 underwent coronary artery bypass graft surgery (CABG) alone, 17 underwent CABG and concomitant aortic valve replacement surgery (AVR), 9 underwent AVR only, and 1 patient's surgery was canceled. Patients with signs or symptoms of congestive heart failure (CHF), ejection fraction < or =30%, estimated creatinine clearance <30 mL/min, or serum creatinine > or =2.5 mg/dL were excluded. Patients were randomized to receive either sotalol 80 mg 2 times per day (n = 76) or intravenous amiodarone 15 mg/kg over 24 hours followed by oral amiodarone 200 mg 3 times per day (n = 83). Study drug was started at the time of surgery and continued for 7 days or until discharge, whichever came first. RESULTS: AF occurred in 17% of patients randomized to amiodarone and 25% of the patients randomized to sotalol (P =.21). However, the duration of AF was significantly shorter in amiodarone-treated patients (169 +/- 224 min) compared to sotalol treated patients (487 +/- 505 min; P =.04). In a subgroup analysis, the incidence of AF in patients undergoing AVR or CABG with AVR was significantly less with amiodarone (1/15, 7%) compared to sotalol (9/11, 82%) (P <.001). Blood pressure was lower immediately after surgery with amiodarone but comparable to sotalol at 24 hours. Of the hemodynamic indices measured, only stroke volume was significantly lower in patients randomized to sotalol at 24 hours (P =.035). CONCLUSIONS: Amiodarone and sotalol share similar efficacy and safety in reducing postoperative AF. Hemodynamic effects were similar between both drugs at 24 hours, with the exception that stroke volume was lower in sotalol-treated patients. In patients undergoing more complex surgery, postoperative AF occurred more frequently with sotalol than with amiodarone.
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OBJECTIVES: We compared the efficacy and safety of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) in young, middle-aged, and elderly patients. BACKGROUND: Intersociety guidelines suggest based on limited evidence that young patients with medically refractory symptoms of obstructive HCM should undergo surgical myectomy while elderly patients may be more appropriate for ASA. METHODS: Data for 360 patients undergoing 389 ASAs were prospectively collected and retrospectively analyzed according to age. RESULTS: Young (<45 years), middle-aged (45-64 years), and elderly (>/=65 years) patients comprised 28, 40, and 32% of the study population, respectively. Young patients had thicker left ventricular septal walls at baseline, and elderly patients had more comorbidity and dyspnea. Resting, mean left ventricular outflow tract gradients (LVOTGs) were similar across the age groups at baseline (62, 66, and 68 mm Hg, respectively; P = NS for all comparisons). LVOTGs and dyspnea were significantly and similarly improved in all age groups immediately after ASA and through 12 months of follow-up (P < 0.001 for before and after comparisons; P = NS for intergroup comparisons). Complication rates were similar for young and middle-aged patients but higher for elderly patients (9.1 and 6.3% vs. 20.8%, respectively; P </= 0.016 for elderly vs. others). Mortality rates for young and middle-aged patients were lower than for elderly patients, but the differences were not statistically significant. CONCLUSIONS: Patients undergoing ASA had significant and similar improvements in LVOTGs and symptoms regardless of age. Procedural complications were increased in elderly patients, who had numerically but not statistically significantly higher mortality rates.
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CONTEXT: Physician gender has been viewed as a possible source of variation in the interpersonal aspects of medical practice, with speculation that female physicians facilitate more open and equal exchange and a different therapeutic milieu from that of male physicians. However, studies in this area are generally based on small samples, with conflicting results. OBJECTIVE: To systematically review and quantify the effect of physician gender on communication during medical visits. DATA SOURCES: Online database searches of English-language abstracts for the years 1967 to 2001 (MEDLINE, AIDSLINE, PsycINFO, and Bioethics); a hand search was conducted of reprint files and the reference sections of review articles and other publications. STUDY SELECTION: Studies using a communication data source, such as audiotape, videotape, or direct observation, and large national or regional studies in which physician report was used to establish length of visit, were identified through bibliographic and computerized searches. Twenty-three observational studies and 3 large physician-report studies reported in 29 publications met inclusion criteria and were rated. DATA EXTRACTION: The Cohen d was computed based on 2 reviewers' (J.A.H. and Y.A.) independent extraction of quantitative information from the publications. Study heterogeneity was tested using Q statistics and pooled effect sizes were computed using the appropriate effects model. The characteristics of the study populations were also extracted. DATA SYNTHESIS: Female physicians engage in significantly more active partnership behaviors, positive talk, psychosocial counseling, psychosocial question asking, and emotionally focused talk. There were no gender differences evident in the amount, quality, or manner of biomedical information giving or social conversation. Medical visits with female physicians are, on average, 2 minutes (10%) longer than those with male physicians. Obstetrics and gynecology may present a different pattern than that of primary care, with male physicians demonstrating higher levels of emotionally focused talk than their female colleagues. CONCLUSIONS: Female primary care physicians engage in more communication that can be considered patient centered and have longer visits than their male colleagues. Limited studies exist outside of primary care, and gender-related practice patterns in some subspecialties may differ from those evident in primary care.
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BACKGROUND: This study tested two hypotheses: 1) regional left ventricular radius-to-wall thickness ratios (R/T) are uniform in normal subjects, and 2) patients with left ventricular hypertrophy secondary to compensated volume overload normalize global and regional R/T. METHODS AND RESULTS: Ultrafast computed tomography was used to measure regional short-axis ventricular R/T in 11 normal subjects and 13 patients with compensated aortic insufficiency (AI) of moderate severity (regurgitant fraction, greater than or equal to 25%). Radius and wall thickness dimensions were calculated by two different methods. In method 1, the average radius and wall thickness were determined for each planimetric transaxial tomographic image. In method 2, the left ventricle was three-dimensionally reconstructed; then, new radii and wall thickness were recalculated as if all the images were acquired orthogonal to the endocardial surface at each tomographic level. In normals, the mean R/T ratio was 1.75 +/- 0.11 (SEM) with method 1 and 1.80 +/- 0.07 with method 2. The R/T ratios varied as a function of the relative apex-to-base position. R/T ratios at the basal four levels were relatively uniform, whereas R/T at the lower three tomographic levels were significantly less than those at the base (p less than 0.01). Patients with AI had a mean regurgitant fraction of 44 +/- 3.8% (range, 25-63%). The mean R/T ratio was 2.18 +/- 0.16 with method 1 and 2.55 +/- 0.18 with method 2. Similar to the pattern observed in normals, the regional R/T ratios at the lower three or four levels were significantly less than the basal R/T ratios (p less than 0.01). Regional comparison of the normal to the volume-overloaded ventricles demonstrated that R/T ratios in the AI patients were significantly greater at the upper five levels with method 1 and at all eight levels with method 2 (p less than 0.01-0.001, AI versus normal). CONCLUSIONS: These findings demonstrate that regional R/T ratios are heterogeneous in both normals and patients with left ventricular hypertrophy secondary to compensated aortic insufficiency. Furthermore, these findings challenge the accepted hypothesis that global and regional R/T ratios normalize in patients with compensated volume-overload hypertrophy.
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The usefulness and limitations of the carcinoembryonic antigen (C.E.A.) radioimmunoassay for the evaluation of tumour resection and for the detection of tumour relapse were studied in patients with large-bowel carcinoma. The level of plasma-C.E.A. was determined before any treatment in a group of 101 patients with histologically proven adenocarcinoma of the colon and rectum. 71% of all patients and 63% of cases with localised tumour (Dukes A and B) had a preoperative C.E.A. value of 5 ng. per ml. or higher. This limit was reached by only 1 of 90 apparently healthy, non-smoking blood-donors. Among 45 patients for whom a complete tumour resection was reported, all patients except 5 showed a drop of C.E.A. to normal values after surgery. The 5 patients whose C.E.A. did not fall to below 5 ng. per ml. showed a subsequent rise in C.E.A. level and were all found later to have a tumour relapse. The results indicate that an incomplete drop of circulating C.E.A. level one month after surgery has a bad prognostic significance. 22 of these patients were followed up by repeated C.E.A. radioimmunoassay for several months after surgery. 8 showed a progressive increase in C.E.A. levels preceding clinical diagnosis of tumour relapse by two to ten months. 6 other patients showed a moderate increase in C.E.A. levels, suggesting a tumour relapse not yet clinically detectable. The remaining 8 patients showed no increase in C.E.A. level above 5 ng. per ml. and no clinical symptoms of relapse. The results demonstrate that relapses of colon and rectum carcinoma can be detected by increased C.E.A. levels months before the appearance of any clinical evidence.
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BACKGROUND: Restenosis after percutaneous transluminal coronary intervention (PCI) remains a serious complication in the treatment of coronary artery disease. Although beta-adrenergic receptor blockers (BBs) effectively reduce many cardiac events, no large prospective studies have examined the association of BBs with restenosis. METHODS: We prospectively evaluated the association of BBs (prescribed at hospital discharge) with clinical restenosis in 4840 patients who underwent stent placement (60%), balloon angioplasty (32%), or rotational atherectomy (8%). Clinical restenosis was defined as repeat target lesion revascularization or coronary artery bypass grafting within 6 months of PCI. Other end points included 9-month clinical restenosis, repeat target lesion PCI (only), long-term (5-year) target lesion repeat-PCI, and major adverse cardiac events (MACE). Multivariable regression adjusted the effect of BBs on clinical restenosis for 15 covariables. RESULTS: The average patient age was 63 years, 75% were men, and 37% received a BB prescription. The incidence of clinical restenosis was 12% overall and was lower among those prescribed a BB (10.0% for BB, 13.5% for none, adjusted odds ratio [OR] 0.76, P =.004). Other predictors of decreased restenosis included stent use, age, and smoking; predictors of increased restenosis included diabetes, atherectomy, and number of treated vessels. BBs also reduced 9-month clinical restenosis (10.3% vs 13.5%, OR 0.75, P =.004), MACE (16.5% vs 20.9%, OR 0.75, P <.001), 6-month target lesion restenosis (7.8% vs 10.2%, OR 0.75, P =.006), and 5-year target lesion restenosis (12.0% vs 14.0%, OR 0.83, P =.046). CONCLUSIONS: beta-Adrenergic receptor blockers prescribed after PCI reduced the risk of clinical restenosis, target lesion restenosis, and MACE in this cohort of 4840 patients. The mechanism by which beta-blockers conferred a protective effect against restenosis remains to be determined.
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OBJECTIVE: To introduce a new free composite flap for the treatment of electric injuries of hands, which can repair the skin, blood vessels, tendons and nerves injuries in just one operation. It may improve the prognosis of electric hand injuries. METHODS: 5 patients with electric injuries at wrist were treated by the free composite flap. The procedure is followed: The composite flap was harvested from medial lateral crural skin flap. Its blood supply was from tibial posterior vessels. The perforans arteries to flap and the branches to plantaris were preserved, and the nerve suralis and tendon plantaris were compound into the flap by carefully dissection of crural fascia. At the same time, 3-4 tendons of extensor digitorum longus were inserted into the superficial crural fascia. Thus, blood vessels, nerves and tendons were combined into the flap before transplantation. The composite flap was then transplanted into the recipient site of the electric injuries of hand to repair the long defects of the skin, blood vessels,nerves and tendons in one operation. The evaluation methods of the prognosis are the follows: the active motion function of finger was assessed by flexion and extension function of the fingers. The sensibility function was tested by the standards recommended by British Medical Association. RESULTS: The patients were followed up from 3 to 12 months. All the flaps were survived. Six months after operation, the flexion distance from tip to palmar crease and extension distance from tip to horizontal level of 3 patients were 4-5 cm and 3-4 cm respectively, and the other 2 patients were recovered from 6 cm and 5 cm to 4 cm and 4 cm respectively. The sensibility of finger skin reached to S2 level, and skin temperature rose. CONCLUSION: The free medial lateral crural composite flap was an ideal one to cure electric injuries at wrist, for it repairs skin, nerves, vessels and tendons defects in just one operation.
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MOTIVATION: Scientific data pertaining to GABA receptors, which are of medical importance, are widely scattered throughout numerous heterogeneous Internet resources. This situation has made the integrated acquisition of such data difficult and substantially time consuming even for researchers who are Internet aficionados. Thus, there exists a genuine need for the development of Internet applications, such as GABAagent, which provide efficient and timely access to concise and integrated information. RESULTS: We report here the establishment of a novel server (GABAagent) which has been written in Perl script, and which is freely accessible through the Internet. GABAagent is designed to assist researchers in retrieving focused and integrated information related to GABA receptors from various public domain databases. GABAagent relies on server-side flat-file databases that have been created through data mining from Internet sources such as the PubMed, DDBJ, SWISS-PROT and TrEMBL, in addition to the many World Wide Web (Web) sites which are accessible through Excite (E-Web). These warehouse databases are regularly updated and contain among other things, information concerning: (i) GABA receptor publications, (ii) DNA and protein sequences and (iii) the contents of related E-Web sites along with their addresses. Our system also provides hard links to the above-mentioned Web sites and E-Web sites; the feature which adds to it the character of virtual federation type of database. The current version of GABAagent provides two user-friendly services. The first is a search engine possessing intelligent query reformulation support (GABAengine), the second an elaborate email alert service was designed into the system (GABAalert). The GABAengine allows the user to search server-side databases exclusively for GABA receptor-related queries. Whereas, GABAalert allows the user, by means of subscription, to receive immediate and/or monthly updates automatically. AVAILABILITY: GABAagent is freely accessible at the following Web address http://www.ust.hk/gaba.
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Vascular perfusion was assessed in 10 dogs without prostatic abnormalities and 26 dogs with prostatic disease using contrast-enhanced ultrasound. The time to reach peak contrast intensity (TTP) and peak perfusion intensity (PPI) were measured, and histological biopsies were collected from each dog. Biopsies confirmed normal prostate (n = 10), benign prostatic hyperplasia (n = 11), mixed benign pathology (n = 9), prostatitis (n = 1), prostatic malignancy [adenocarcinoma (n = 4); leiomyosarcoma (n = 1)]. In normal dogs, mean PPI was 16.8% +/- 5.8 SD, and mean TTP was 33.6 +/- 6.4 s. Benign conditions overall were not statistically different from normal dogs (p > 0.05); for benign prostatic hyperplasia, mean PPI was 16.9 +/- 3.8%, and mean TTP was 26.2 +/- 5.8 s; for mixed benign pathology mean PPI was 14.8 +/- 7.8%, and mean TTP was 31.9 +/- 9.7 s; for prostatitis, PPI was 14.2%, and TTP was 25.9 s. The malignant conditions overall had perfusion values that differed from the normal dogs (p < 0.05), although evaluation of the data for individual malignancies did not demonstrate a consistent trend; for adenocarcinomas, the PPI was numerically higher with a mean of 23.7 +/- 1.9%, and the mean TTP was 26.9 +/- 4.8 s, whilst for the dog with leiomyosarcoma values were numerically lower with a PPI of 14.1% and TTP of 41.3 s. Contrast-enhanced ultrasound appears to offer some ability to document differences in perfusion that may differentiate between malignant and benign lesions, although studies with larger numbers of animals are required to confirm this contention.
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The objective was to extend a zero-inflated Poisson (ZIP) model to account for correlated genetic effects, and to use this model to analyze the number of clinical mastitis cases in Norwegian Red cows. The ZIP model is suitable for analysis of count data containing an excess of zeros relative to what is expected from Poisson sampling. A ZIP model was developed and compared with a corresponding Poisson model. The Poisson parameter followed a hierarchical structure, and a residual term accounting for overdispersion was included. In both models, the Poisson parameter was regressed 1) on the year, month, and age at first calving; 2) on the logarithm of the number of days elapsed from calving to the end of first lactation; and c) on herd and sire effects. Herd and sire effects were assigned normal prior distributions in a Bayesian analysis, corresponding to a random effects treatment in a frequentist analysis. An analysis of residuals favored the Poisson model when there were 2 or more cases of mastitis during first lactation, with very small differences between the ZIP and Poisson models at 0 and 1 cases. However, the residual assessment was not satisfactory for either of the models. The ZIP model, on the other hand, had a better predictive ability than the corresponding Poisson model. Posterior means of the sire, herd, and residual variances in the ZIP model (log scale) were 0.09, 0.37, and 0.36, respectively, highlighting the importance of herds as a source of variation in clinical mastitis. The correlation between sire rankings from the ZIP and Poisson models was 0.98. A weaker correlation would be expected in a population with more severe inflation at zero than the present one. The estimate of the perfect state probability p was 0.32, indicating that 32% of the animals would be in the perfect state, either because they are resistant or because they were not exposed to mastitis.
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Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P(1) receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P(1) enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E(2) production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-alpha, IL-6, IL-1beta, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-alpha, IFN-gamma, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.
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T lymphocytes and immunoregulatory cytokines play an important role in the host response to hepatitis C virus (HCV) infection. Zinc is required for a wide spectrum of immune functions, including T-cell activity. To determine the clinical significance of the cytokines sIL-2R, IL-6, TGF-beta1, neopterin, and of zinc in chronic heptatitis C virus (HCV) infection, we investigated their concentrations in the serum of 16 patients with chronic HCV infection before, during and at the end of therapy with interferon (IFN) alpha (Roferon A), and after 6 months follow-up. Elevated concentrations of sIL-2R, IL-6, TGF-beta1, and neopterin were found in the serum of all patients prior to therapy, as compared to healthy controls. sIL-2R patterns differed in responders and non-responders. While the mean concentration of sIL-2R (335.75 pg/ml) before therapy was about 40% higher in complete responders (n=4) than in controls (272.20 pg/ml), the mean concentration in non-responders (n=6) was 4-fold higher than in controls (1153.33 pg/ml). During therapy, sIL-2R levels in responders decreased by about 40%. Mean IL-6 concentrations in both complete and partial responders (n=6) decreased continuously during treatment, while mean concentrations in non-responders decreased for only a short time, and increased again after cessation of therapy. Mean levels of TGF-beta1 behaved similarly to those of IL-6. Only negligible differences in mean neopterin levels were found between responders and non-responders over the entire observation time. The mean serum zinc concentrations slightly decreased in all 3 patient groups, the greatest reduction occurring in 3 of the 4 responders. The present findings underscore the importance of the immune system in the pathogenesis of chronic HCV infection. Serum sIL-2R levels may be used as a serological marker of outcome following IFN-alpha treatment.
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The Fick principle (cardiac output [Q(c)] = oxygen uptake [Vo(2)]/arteriovenous oxygen difference) can be used to calculate Q(c), with VO(2) frequently estimated by derived equations. To compare the accuracy of measured versus estimated VO(2), data were analyzed from 2 studies in which VO(2) at rest was measured using the Douglas bag technique. One study comprised adults with diabetes, and the other was an exercise study of healthy adults. VO(2) at rest was estimated as VO(2) (ml/min) = 125 ml/min/m(2) x body surface area (m(2)), with sensitivity analyses evaluating 2 other commonly used equations. Mean absolute difference (milliliters per minute) and ordinary least products regression were used to assess agreement between measured and estimated VO(2). Overall, mean measured versus estimated VO(2) differed significantly (307.2 +/- 75.2 vs 259.9 +/- 36.7 ml/min, p <0.0001), with a mean absolute difference of 52.9 +/- 43.2 ml/min (p <0.0001); 20% of the estimates differed by >25% from the measured VO(2). Mean absolute difference increased from 36.7 ml/min in the lowest body mass index group (<25 kg/m(2)) to 91.7 ml/min in the highest group (>/=40 kg/m(2)) (p for trend = 0.001) and was significantly higher in men than in women (65.6 vs 33.9 ml/min, p = 0.001); error was similar by median-split age (p = 0.65) and race (p = 0.34). Similar results were obtained when evaluating each of the other 2 estimating equations. Estimation of VO(2) at rest is inaccurate, especially in men and with increasing adiposity. In conclusion, when clinical hemodynamic assessment is performed, VO(2) should be measured, not estimated.
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Clinical electrocardiographic evaluation and complete non-invasive assessment including nuclear magnetic resonance (NMR) are reported for 7 subjects with cardiac arrest (CA), 6 due to ventricular fibrillation (VF) and 1 to ventricular tachycardia (VT). Two more subjects, one with and one without a family history of non-resuscitated sudden death (NRSD), were included. All 9 subjects showed the typical pattern of the Brugada's syndrome (BS), characterized by incomplete right bundle branch block, ST T elevation in V1 V3. We globally evaluated 64 subjects belonging to the 9 families examined, 5 of whom were identified in Bologna, 3 in Florence and one in Parma. BS is characterized in the experience described in the present paper by a family distribution of the ECG pattern in different members. Furthermore, a family distribution of NRSD, even at a young age, was observed. Electrocardiographic features were consistent with variable degrees and aspects of the intraventricular conduction delay (ICD) and of the ST T elevation pattern. NMR has been performed so far in 23 out of 64 members examined by echo, and was normal in 17/23, with only 6 showing pathological aspects such as mild dilatation of the right ventricle, reduced thickness of the right free wall, isolated dilatation of the right ventricular infundibulum and other minor pathological aspects. Preliminary genetic screening (GS), performed on 20 members of three families, was negative for the typical genetic patterns of right ventricular dysplasia (ARVD). In six families, GS is still ongoing. Genetic screening of sodium channel pathology is in progress in the same families. In conclusion, BS has been documented in the present paper as a hereditary syndrome, both for clinical and ECG aspects, associated with CA due to VF, which required an AICD implantation, at least in symptomatic subjects. There may exist a CONGENITAL form of BS due to pathology of sodium channels, without a demonstrable structural heart disease and an ACQUIRED form of BS secondary to an initial ARVD. From the clinical point of view, a complete evaluation, including serial ECG, pharmacological testing and programmed electrical stimulation of other subjects in the families, may be important in preventing sudden death, mainly in symptomatic subjects who always require an implantable cardioverter defibrillator.
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Germ cell tumors (GCTs) are thought to develop from totipotent primordial germ cells. Although the epithelial cell adhesion molecule (EPCAM) is expressed on embryonic stem cells as well as different tumor cells, it has not yet been extensively studied in GCTs. We analyzed EPCAM expression by quantitative RT-PCR in 48 fresh-frozen GCT specimens of different histology (10 mature teratoma, MT; 6 immature teratoma, IT; 7 dysgerminoma; 6 mixed malignant GCTs; 19 yolk sac tumor, YST) and in the GCT cell lines NCCIT, TE76.T, JAR and 2102Ep, and correlated its expression with AFP and hCG protein levels, histologic differentiation, and clinical follow-up data. EPCAM protein was visualized by immunohistochemistry of selected corresponding paraffin embedded tumor tissues. EPCAM was expressed in malignant but not in benign GCTs irrespective of age, sex, site and clinical stage of tumor (P = 0.001). In primary teratomas, EPCAM expression increased with their grade of immaturity (mean 2(-DeltaCt) values: MT 0.23, IT 1.61, P = 0.007) and significantly correlated with serum AFP (P = 0.03) and hCG (P = 0.03) levels in malignant GCTs. Particularly high EPCAM levels were found in nonseminomatous GCTs such as YSTs (8.49) and choriocarcinoma (13.54). Immunohistochemical analysis verified gene expression data showing a distinct EPCAM staining in YST. Similarly in vitro, highest EPCAM expression was measured in GCT cell lines comprising yolk sac (2102Ep: 5.59) or choriocarcinoma (JAR: 10.65) components. This first comprehensive analysis of EPCAM in GCTs revealed high EPCAM expression in YSTs and choriocarcinomas. Thus, these nonseminomatous GCTs may be interesting targets for EPCAM immunotherapy, which has to be evaluated in further studies.
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There are numerous techniques for the surgical management of thumb carpometacarpal (CMC) joint arthritis. The four senior authors of this study employ three such techniques: trapeziectomy with hematoma distraction arthroplasty, hemitrapeziectomy with osteochondral allograft, and ligament reconstruction tendon interposition (LRTI). This study examines the three commonly utilized procedures at a single institution. This study examines the 10-year experience from 1995-2005 with a minimum 3-month follow-up. Disabilities of the arm, shoulder, and hand (DASH) scores, pre-and postoperative pinch strength, and operative time were examined. After approval from the institutional review board of our institution was obtained, all patients treated surgically by three of the senior authors were contacted via mail and phone. Each patient was asked to complete and return a DASH questionnaire. Of the 115 patients treated during that period, 60 participated in this study. Each patient's final postoperative pinch measurement was obtained from occupational therapy and clinic records. This pinch strength was compared to the preoperative pinch and contralateral pinch strength. Lastly, the total operative time for each procedure was obtained from the operative record. The only significant finding in this study was a shorter mean operative time with the trapeziectomy group (76.90 min) and osteochondral allograft group (90.45 min) when compared to the LRTI group (139.00 min; p = 0.001 and p = 0.001, respectively). We found no significant difference between groups in terms of DASH score and pinch strength. There was no difference between the techniques in terms of postoperative pinch strength and patient satisfaction measured by DASH scores. The operative times for trapeziectomy and hematoma interposition as well as the osteochondral allograft were significantly shorter than that of the LRTI. This presents further evidence that potentially, "less is more" in the treatment of thumb CMC arthritis. We used a retrospective study design to evaluate potential differences between the three surgical techniques described above, therapeutic, levels III-IV.
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The present paper reviews the results obtained with different modalities of treatment employed in isolated fractures of the zygomatic complex. Seventy-three patients were re-examined with respect to infraorbital nerve function. The results obtained suggest that the incidence of hypoaesthesia of the infraorbital nerve following fracture of the zygomatic complex can be reduced if rigid fixation is applied on the infraorbital rim. The zygomatic bone is a protruding part of the human skeleton and is therefore easily affected by trauma to the facial region. The etiology and clinical appearance of fractures of the zygomatic complex are well known and previously described in detail (Afzelius and Rosen 1980, Ellis et al. 1985, Jungell and Lindqvist 1987). Fractures of the zygomatic complex are rarely fractures of the zygoma itself but of its connection to the skull and facial skeleton, e.g. the frontozygomatic suture, the zygomatico-maxillary suture, the zygomatic arch and the infraorbital rim. A fracture of the infraorbital rim usually involves the infraorbital foramen or bone close to it. Such a fracture also extends into the orbital floor through or adjacent to the infraorbital canal. Dislocation of the fractured zygomatic complex may thus result in injury to or compression of the infraorbital nerve. Such an injury may cause numbness/hypoaesthesia/dysaesthesia in the distribution of the nerve. Accordingly, reduced infraorbital nerve function is a frequently reported sequela of fractures of the zygomatic complex. Thus impaired infraorbital nerve function prior to treatment has been reported to occur in approximately 80% of such cases (Table 1). With respect to persistent impaired function of the infraorbital nerve, the literature demonstrates varying results following different types of treatment, ranging from 22% to 50% persistent hypoaesthesia (Table 1). Interestingly, the return of infraorbital nerve function continues with an extended observation period between treatment and follow-up and it has been claimed that infraorbital nerve function may continue to improve even after one year following injury/surgery (Afzelius and Rosen 1980). Cases with persistent and disturbing impaired function of the infraorbital nerve may be considered for decompressive nerve surgery or microsurgical reconstruction of the infraorbital nerve (Mozsary and Middleton 1983). The present report is a retrospective study and aimed to evaluate the recovery of infraorbital nerve function obtained with different modalities of treatment of isolated fractures of the zygomatic complex.
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Microparticles (MPs) are small membrane-bound vesicles that display proinflammatory and prothrombotic properties. These particles can be released by macrophages stimulated by ligands of the Toll-like receptors (TLRs) in a process that depends on nitric oxide (NO) production. Since sex hormones can modulate macrophage responses, we investigated the effects of progesterone and estradiol on macrophage particle release in vitro, comparing the responses with those induced by the glucocorticoid dexamethasone. As a model system for particle release, RAW 264.7 cells were stimulated in vitro with poly(I:C), a ligand of TLR3. Microparticles were measured by flow cytometry, while NO was measured by the Griess reaction. As the results of these studies showed, progesterone but not estradiol can block particle release by RAW264.7 cells treated with poly(I:C); dexamethasone was also active. Furthermore, while progesterone and dexamethasone inhibited NO production under the same culture conditions, neither agent blocked the production of particles stimulated by the NO donors dipropylenetriamine NONOate {(z)-1-[N-(3-aminopropyl)-N-(3-ammoniopropyl)amino] diazen-1-ium-1,2-diolate} and (z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2-diolate. Studies using RU486 to assess the role of hormone receptors indicated that while this agent blocked the inhibition of particle and NO production by dexamethasone, it did not affect the inhibition by progesterone. Together, these results indicate that progesterone but not estradiol can inhibit particle release by stimulated macrophages and suggest a mechanism that may contribute to the immunomodulatory effects of this sex hormone.
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Studies on baboons and preliminary observations in three patients with sickle cell anemia (SS) suggested that high doses of pulse administered recombinant human erythropoietin (rHuEPO) stimulate F-reticulocyte production. We now report on the administration of rHuEPO in a double-blind format to ascertain frequency of response and potential precipitation of side effects. Ten patients were enrolled, but one was discontinued due to the indication of a blood transfusion. Of the other nine, five received rHuEPO in escalating doses (from 400 to 1,500 U per kg twice daily [BID] per week), alternating with a placebo, in blinded fashion. The second group, consisting of four patients, followed an identical protocol (except starting dose was 1,000 U/Kg, BID per week) and were iron supplemented during treatment. The criterion of response was a transient doubling (as a minimum) of the steady-state F-reticulocyte level. We found that none of the five patients in the first group responded to rHuEPO, and two of them became iron deficient, as judged by a significant decrease in ferritin. Of the second group, four patients responded with F-reticulocyte increases. In three patients, open label administration of rHuEPO confirmed the effect. We observed seven painful episodes during this study, two during the EPO administration and five during the placebo arm. Three patients were phlebotomized because the hemoglobin level increased 1.5 g/dL more than steady-state levels. Of the six patients followed-up by percent dense cell determinations, one exhibited increased levels during periods of the treatment, whereas the other five showed no change. No anti-rHuEPO antibodies were detected. We conclude that rHuEPO can stimulate F-reticulocyte response in some patients with sickle cell anemia, without apparent negative clinical side effects. The state of iron stores may be critical. Whether higher doses of rHuEPO and/or a different regimen might induce sustained F cells and fetal hemoglobin increases remains to be determined.
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Kidney volume was measured during pregnancy in insulin-dependent diabetic women by an ultrasound technique and prognostic value of these measurements evaluated. A prospective study was performed on 87 pregnant women with insulin-dependent diabetes attending the maternity clinic of Aarhus Kommunehospital. Patients with proliferative retinopathy alone, hydronephrosis, or nephrotic syndrome were excluded. The patients were grouped according to onset and duration of diabetes and to vascular lesions; group I (n = 35, White class B+C), group II (n = 11, White class D0), group III (n = 26, White class D+), and group IV (n = 15, White class F+F/R). The patients visited the hospital every 2 weeks during pregnancy for general obstetric and glycaemic control and blood sampling. The volume of both kidneys was measured by a computerized nephrosonograph during the three terms of pregnancy, the puerperium and 4 months postpartum. The kidney volume increased significantly in all four groups from first to third trimester. In the third trimester the kidney volumes were 375 +/- 68 ml (I), 341 +/- 50 ml (II), 362 +/- 63 ml (III), and 343 +/- 54 ml (IV). The kidney volume in the third trimester was positively correlated with creatinine clearance (r = 0.33, P < 0.01) and inversely correlated with creatinine in serum (r = -0.27, P = < 0.02). Total kidney volume decrease (in percent) defined as the difference of maximal volume and value at 4 months postpartum was inversely correlated to albuminuria in the third trimester (r = -0.25, P < 0.05) and vascular lesions of the patients: (mean +/- SEM) 37 +/- 4% (I), 25 +/- 7% (II), 19 +/- 5% (III), and 11 +/- 7% (IV), P < 0.01. In the puerperium, kidney volume decreased significantly from third trimester in groups I, II, and III, whereas we observed no change in group IV. Six of 15 women in groups II and III with kidney volume < 300 ml and normoalbuminuria in the first trimester developed persistent microalbuminuria after pregnancy (P < 0.02). The renal volume in insulin-dependent diabetic women increases significantly during pregnancy and is inversely related to the vascular lesions of the patients. The decrease in renal volume after pregnancy is related to the albuminuria at the end of pregnancy. Women with longstanding diabetes, White class D (= groups II+III), and kidney volume < 300 ml in the first trimester have a high risk of developing permanent microalbuminuria after pregnancy.
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PURPOSE: Bacillus Calmette-Guerin is an effective immunotherapy for carcinoma in situ of the bladder and it reduces recurrence from resected papillary transitional cell carcinoma of the bladder. Many patients receiving bacillus Calmette-Guerin therapy are concurrently taking statin agents, which have known immunomodulatory properties and may alter the performance of bacillus Calmette-Guerin. Some data have suggested that patients taking a statin while on bacillus Calmette-Guerin therapy experience reduced clinical efficacy. MATERIALS AND METHODS: We conducted a retrospective review of 952 consecutive patients from 1978 through 2006. Time to recurrence and progression to surgery were compared between those taking and those not taking a statin by Kaplan-Meier methods and multivariable Cox regression controlling for stage and grade. RESULTS: There were 245 (26%) patients taking a statin before bacillus Calmette-Guerin therapy and 707 not on statin therapy (74%). A total of 796 patients had recurrence overall with 214 in the statin group and 582 in the other group. Median time to recurrence was similar between those who did and those who did not use a statin. On multivariable analysis statin use was not significantly associated with recurrence (hazard ratio 1.04; 95% CI 0.81, 1.34; p = 0.7) or progression to surgery (hazard ratio 0.77; 95% CI 0.52, 1.13; p = 0.17) after bacillus Calmette-Guerin therapy. CONCLUSIONS: This retrospective study in a large cohort of patients showed no statistically significant association between statin use and recurrence or progression to open surgery in patients treated with bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. Based on these data patients should not be discouraged from taking statins while undergoing bacillus Calmette-Guerin treatment.
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AIM: To evaluate the association between the foveal external limiting membrane (ELM) status and visual acuity (VA) in diabetic macular oedema (DMO). METHODS: We retrospectively reviewed the spectral domain optical coherence tomography images of 127 eyes from 127 patients with DMO and evaluated the correlation between the logarithm of the minimal angle of resolution (logMAR) VA and the statuses of the foveal ELM, inner segment/outer segment (IS/OS) and cone outer segment tips (COST); foveal macular thickness (FMT); and presence or absence of hard exudates (HE), serous retinal detachment (SRD) and vitreous adhesion. The integrity of the ELM, IS/OS, and COST was classified into three categories (absent, disrupted and complete). RESULTS: There was a strong correlation between VA and the statuses of the ELM (r=0.699, p<0.001), IS/OS (r=0.716, p<0.001) and COST (r=0.471, p<0.001). There was no correlation between FMT and logMAR VA (r=-0.036, p=0.687). However, when we analysed the correlation between FMT and VA by dividing patients into those with FMT </=250 mum and those with FMT >250 mum, there was a positive correlation between FMT and VA in eyes with FMT </=250 mum (r=-0.601, p<0.0001) and a negative correlation in eyes with FMT>250 mum (r=0.290, p<0.01). Other factors HE, SRD and vitreous adhesion did not correlate with VA. CONCLUSIONS: In DMO, the ELM status may be as closely related to VA as the IS/OS status.
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BACKGROUND AND OBJECTIVE: The CD117 molecule is an antigen more frequently found on early normal and leukemic hematopoietic cells, but its correlation with the FAB subtypes and with other lineage and stage associated antigens is still not well established. In this study we investigated the surface expression of CD117 antigen in 135 patients with acute leukemia in relationship to de novo or secondary origin of AML, subtypes of FAB classification, expression of other antigens such as CD34, HLA-DR, CD15, CD14, CD45RA, CD45RO, CD11b, CD11c, CD4, CD7, mixed antigen co-expression (LyAg + AML and MyAg + ALL) and features of leukemic mass. DESIGN AND METHODS: The CD117 antigen expression (clone 95C3) was determined by flow cytometry in a series of 135 patients with acute leukemia at diagnosis consecutively observed during the years 1995-1997: 82 AML (including 51 cases of de novo AML, 22 cases of AML following myelodysplastic syndromes (MDS), 9 cases of myeloid blastic crisis of chronic myeloid leukemia (BC-CML) and 53 ALL. All cases were stratified in CD117+ and CD117- groups and the differences were analyzed by using appropriate statistical analyses. RESULTS: CD117 antigen was found over 10% in 74% of AML without significant differences of positivity between AML after MDS or BC-CML and de novo AML. We did not note a significant correlation between FAB classification and CD117 which was expressed in 100% of M1 and M7 cases, in 80% of M0 cases, in 75% of M2 cases, in 70% of M3 cases and in 82% of M4 cases. Instead, in M5 subtype CD117 was strictly restricted to earlier stages: ten of the eleven M5b (91%) cases completely lacked CD117 antigen expression, whereas 100% of M5a cases were positive. The results of Pearson's coefficient showed: 1) a significant inverse relationship between CD117 and CD15, CD4 and CD14 (only in M5 subtypes) and CD11b, CD11c and CD45RO (in all cases); 2) a significant direct correlation between CD117 and CD34 and CD45RA (in all cases); and 3) an independent expression between CD117 and CD15 associated with a low correlation between CD117 and HLA-DR antigen (only in non-monocytic cases). In ALL, whether of B or T lineages, surface expression of CD117 was never observed. INTERPRETATION AND CONCLUSIONS: We conclude that the CD117 antigen shows a high specificity for AML, independently upon FAB classification, and represents a reliable marker in characterizing the differentiative degree of the monocytic blasts.
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BACKGROUND AND OBJECTIVE: Lead exposure is a well known cause of cardiovascular damage, including atherosclerosis. Paraoxonase 1 (PON1), a high-density lipoprotein-associated antioxidant enzyme, is capable of hydrolyzing oxidized lipids and thus it protects against atherosclerosis. The mechanism by which heavy metals inhibit serum PON1 activity is still not clear. Our aim was to detect the association between lead exposure and serum PON1 activity and lipid profile and also to study the polymorphism of the PON1 gene. DESIGN AND SETTING: A case-control, cross-sectional study conducted from June 2008 until May 2009. SUBJECTS AND METHODS: Male workers (n=100) in a lead battery manufactory were recruited for this study. They were compared with 100 male age-matched workers not exposed to lead (control group). Serum lipid profile, paraoxonase activity and lead were measured in blood samples. The DNA was extracted for detecting the Q192R polymorphism of the PON1 gene by polymerase chain reaction followed by restriction fragment length polymorphism. RESULTS: There was significant difference in triglycerides, total cholesterol and high-density lipoprotein cholesterol (HDL-C) (P=.01, .05 and .04, respectively) between cases and controls. Multiple linear regression analysis showed that blood lead levels were significantly associated with decreased serum paraoxonase activity (P=.03) in lead workers. The paraoxonase genotype QR was the most prevalent in 34/53 subjects (64%) among the lead-exposed groups, while the genotype QQ was more prevalent in the control group, in 15/25 subjects (60%), with a significant difference between the control and other groups (P<.05). CONCLUSION: Lead exposure is associated with increased triglycerides, total cholesterol and low-density lipoprotein cholesterol and decreased HDL-C. Because of the protective role of PON1 in the development of atherosclerosis, a decrease in serum PON1 activity due to lead exposure may render individuals more susceptible to atherosclerosis.
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OBJECTIVES: This study sought to compare dynamic versus single-phase high-pitch computed tomography (CT) acquisitions for the assessment of myocardial perfusion in a porcine model with adjustable degrees of coronary stenosis. BACKGROUND: The incremental value of the 2 different approaches to CT-based myocardial perfusion imaging remains unclear. METHODS: Country pigs received stent implantation in the left anterior descending coronary artery, in which an adjustable narrowing (50% and 75% stenoses) was created using a balloon catheter. All animals underwent CT-based rest and adenosine-stress myocardial perfusion imaging using dynamic and single-phase high-pitch acquisitions at both degrees of stenosis. Fluorescent microspheres served as a reference standard for myocardial blood flow. Segmental CT-based myocardial blood flow (MBFCT) was derived from dynamic acquisitions. Segmental single-phase enhancement (SPE) was recorded from high-pitch, single-phase examinations. MBFCT and SPE were compared between post-stenotic and reference segments, and receiver-operating characteristic curve analysis was performed. RESULTS: Among 6 animals (28 +/- 2 kg), there were significant differences of MBFCT and SPE between post-stenotic and reference segments for all acquisitions at 75% stenosis. By contrast, although for 50% stenosis at rest, MBFCT was lower in post-stenotic than in reference segments (0.65 +/- 0.10 ml/g/min vs. 0.75 +/- 0.16 ml/g/min, p < 0.05), there was no difference for SPE (128 +/- 27 Hounsfield units vs. 137 +/- 35 Hounsfield units, p = 0.17), which also did not significantly change under adenosine stress. In receiver-operating characteristic curve analyses, segmental MBFCT showed significantly better performance for ischemia prediction at 75% stenosis and stress (area under the curve: 0.99 vs. 0.89, p < 0.05) as well as for 50% stenosis, regardless of adenosine administration (area under the curve: 0.74 vs. 0.57 and 0.88 vs. 0.61, respectively, both p < 0.05). CONCLUSIONS: At higher degrees of coronary stenosis, both MBFCT and SPE permit an accurate prediction of segmental myocardial hypoperfusion. However, accuracy of MBFCT is higher than that of SPE at 50% stenosis and can be increased by adenosine stress at both degrees of stenosis.
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INTRODUCTION: The aim of this prospective, originally designed, clinical--diagnostic study including 200 chronic hypoxemic patients was to assess the possibility of implementation of noninvasive diagnostic strategy and to investigate the incidence of pulmonary embolism and parameters of diagnostic accuracy of radiological findings according to Shintz criteria, echocardiography, lung perfusion scanning according to PIOPED criteria. MATERIAL AND METHODS: The study included 200 chronic hypoxemic patients divided into 2 groups, the group I consisting of 42 women and 58 men and the group II consisting of 48 women and 52 men. RESULTS AND CONCLUSION: Out of 200 hypoxemic patients, 49 patients (24.5%) were found to have pulmonary embolism. In the group I of 100 patients (42 women and 58 men) with chronic hypoxemia and secondary erythrocytosis the diagnosis of pulmonary embolism was confirmed in 39%, that being statistically significantly different (p < 0.001) from 100 patients (48 women and 52 men) in the group II with chronic hypoxemia without secondary erythrocytosis, where pulmonary embolism was found in 10% of the patients. The predictive value was positive for direct radiological signs in 92.3% of patients in the group I for PTE, for indirect ones in 74.35%, and in the group II it was positive for direct radiological signs in 60% and for indirect ones in 90%. The predictive value of perfusion scan was positive in 59% of the group I and in only 22% of the group II. The predictive value for high pressure in the pulmonary artery was positive in 93.7% of the group I and in 66.6% of the group II. The following were found to be a variable predictor: hypoxemia, enlargement of the pulmonary artery, peripheral oligemia and elevation of diaphragm. Logistic regression according to backward--conditional method showed that the chronic hypoxemic patients with secondly erythrocytosis, who had radiological sign of peripheral oligemia--Westermark sign, had 2.286 times higher probability of having pulmonary embolism than similar patients without this sign.
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To investigate the calcium dependence of salt-induced hypertension we concurrently measured blood pressure and serum ionized calcium in conscious normotensive female dogs undergoing five infusions: 1) sodium chloride (0.9%) 2) calcium chloride (10 mg/kg), 3) combined sodium chloride and calcium chloride, 4) nicardipine (1 micrograms/kg/min), and 5) combined sodium chloride and calcium chloride in the presence of nicardipine. While saline and calcium chloride infusions individually did not affect blood pressure, saline combined with calcium chloride significantly and consistently raised mean arterial pressure (MAP) (delta MAP = 7 +/- 2 mm Hg, P less than .001 v baseline). Serum ionized calcium (Caio) levels increased within the normal range with the infusion of calcium alone (1.32 +/- 0.03 to 1.48 +/- 0.01 mmol/L, P less than .005). Extracellular Caio rose less with the combined NaCl-CaCl2 infusion (delta Caio 0.10 +/- 0.01 v 0.16 +/- 0.02 mmol/L, P less than .02). The difference in calcium elevations could not be attributed to volume expansion alone, since saline infusion itself did not affect serum ionized calcium (1.32 +/- 0.3 to 1.31 +/- 0.01 mmol/L, P = NS). Furthermore, nicardipine prevented the pressor effect of the combined saline-calcium infusion. (delta MAP = -2 +/- 3 v 7 +/- 2 mm Hg, P less than .001), and restored the rise in extracellular Caio to that seen with the nonpressor calcium infusion (delta Caio 0.15 +/- 0.01 mmol/L v 0.16 +/- 0.02 mmol/L, P = NS). Altogether, these data demonstrate that the rise in blood pressure and ionized calcium following an acute infusion of sodium and calcium chloride are interdependent.(ABSTRACT TRUNCATED AT 250 WORDS)
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OBJECTIVE: Continuous glucose monitoring could be helpful for glucose regulation in critically ill patients; however, its accuracy is uncertain and might be influenced by microcirculation. We investigated the microcirculation and its relation to the accuracy of 2 continuous glucose monitoring devices in patients after cardiac surgery. METHODS: The present prospective, observational study included 60 patients admitted for cardiac surgery. Two continuous glucose monitoring devices (Guardian Real-Time and FreeStyle Navigator) were placed before surgery. The relative absolute deviation between continuous glucose monitoring and the arterial reference glucose was calculated to assess the accuracy. Microcirculation was measured using the microvascular flow index, perfused vessel density, and proportion of perfused vessels using sublingual sidestream dark-field imaging, and tissue oxygenation using near-infrared spectroscopy. The associations were assessed using a linear mixed-effects model for repeated measures. RESULTS: The median relative absolute deviation of the Navigator was 11% (interquartile range, 8%-16%) and of the Guardian was 14% (interquartile range, 11%-18%; P = .05). Tissue oxygenation significantly increased during the intensive care unit admission (maximum 91.2% [3.9] after 6 hours) and decreased thereafter, stabilizing after 20 hours. A decrease in perfused vessel density accompanied the increase in tissue oxygenation. Microcirculatory variables were not associated with sensor accuracy. A lower peripheral temperature (Navigator, b = -0.008, P = .003; Guardian, b = -0.006, P = .048), and for the Navigator, also a higher Acute Physiology and Chronic Health Evaluation IV predicted mortality (b = 0.017, P < .001) and age (b = 0.002, P = .037) were associated with decreased sensor accuracy. CONCLUSIONS: The results of the present study have shown acceptable accuracy for both sensors in patients after cardiac surgery. The microcirculation was impaired to a limited extent compared with that in patients with sepsis and healthy controls. This impairment was not related to sensor accuracy but the peripheral temperature for both sensors and patient age and Acute Physiology and Chronic Health Evaluation IV predicted mortality for the Navigator were.
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OBJECTIVE: To determine the prevalence of digenic mutations in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS). DESIGN: Molecular analysis of DNA in IHH/KS patients. SETTING: Academic medical center. PATIENT(S): Twenty-four IHH/KS patients with a known mutation (group 1) and 24 IHH/KS patients with no known mutation (group 2). INTERVENTION(S): DNA from IHH/KS patients was subjected to polymerase chain reaction-based DNA sequencing of the 13 most common genes (KAL1, GNRHR, FGFR1, KISS1R, TAC3, TACR3, FGF8, PROKR2, PROK2, CHD7, NELF, GNRH1, and WDR11). MAIN OUTCOME MEASURE(S): The identification of mutations absent in >/=188 ethnically matched controls. Both SIFT (sorting intolerant from tolerant) and conservation among orthologs provided supportive evidence for pathologic roles. RESULT(S): In group 1, 6 (25%) of 24 IHH/KS patients had a heterozygous mutation in a second gene, and in group 2, 13 (54.2%) of 24 had a mutation in at least one gene, but none had digenic mutations. In group 2, 7 (29.2%) of 24 had a mutation considered sufficient to cause the phenotype. CONCLUSION(S): When the 13 most common IHH/KS genes are studied, the overall prevalence of digenic gene mutations in IHH/KS was 12.5%. In addition, approximately 30% of patients without a known mutation had a mutation in a single gene. With the current state of knowledge, these findings suggest that most IHH/KS patients have a monogenic etiology.
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OBJECTIVE: Treadmill pre-training can ameliorate blood brain barrier (BBB) dysfunction in ischemia-reperfusion injury, however, its role in ischemic brain edema remains unclear. This study assessed the neuroprotective effects induced by treadmill pre-training, particularly on brain edema in transient middle cerebral artery occluded model. METHODS: Transient middle cerebral artery occlusion to induce stroke was performed on rats after 2 weeks of treadmill pre-training. Magnetic resonance imaging (MRI) was used to evaluate the dynamic impairment of cerebral edema after ischemia-reperfusion injury. In addition, measurements of wet and dry brain weight, Evans Blue assay and Garcia scores were performed to investigate the cerebral water content, BBB permeability and neurologic deficit, respectively. Moreover, during ischemia-reperfusion injury, the expression of Aquaporin 4 (AQP4) was detected using immunofluorescence and Western bloting analyses. RESULTS: Treadmill pre-training improved the relative apparent diffusion coefficient (rADC) loss in the ipsilateral cortex and striatum at 1 hour and 2.5 hours after cerebral ischemia. In the treadmill pre-training group, T2W1 values of the ipsilateral cortex and striatum increased less at 7.5 hours, 1 day, and 2 days after stroke while the brain water content decreased at 2 days after ischemia. Regarding the BBB permeability, the semi-quantitative amount of contrast agent leakage of treadmill pre-training group significantly decreased. Less Evans Blue exudation was also observed in treadmill pre-training group at 2 days after stroke. In addition, treadmill pre-training mitigated the Garcia score deficits at 2 days after stroke. Immunofluorescence staining and Western blotting results showed a significant decrease in the expression of AQP4 after treadmill ischemia following pre-training. CONCLUSIONS: Treadmill pre-training may reduce cerebral edema and BBB dysfunction during cerebral ischemia/reperfusion injury via the down-regulation of AQP4.
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OBJECTIVE: Most studies on the diagnostic value of serum thyroglobulin (Tg) concentrations in differentiated thyroid carcinoma (DTC) use fixed cut-off levels in heterogeneous groups of patients with respect to initial therapy and do not provide prognostic data. The objective was to investigate the prognostic values of serum Tg for disease-free remission and death, measured at fixed time-points after initial therapy using receiver operator characteristic (ROC) curve analyses. DESIGN: Single-centre observational study with 366 consecutive patients with DTC, who had all been treated according to the same protocol for initial therapy and follow-up. METHODS: Tg concentrations were measured at five fixed time-points after initial surgery. Tg cut-off values with the highest accuracy were calculated with ROC analyses. RESULTS: During the 8.3 +/- 4.6 years of follow-up, 84% of the patients were cured. Pre-ablative Tg levels were an independent prognostic indicator for disease-free remission (Tg cut-off value 27.5 microg/l, positive predictive value 98%). The highest diagnostic accuracies of serum Tg for tumour presence were found during TSH-stimulated Tg measurements, 6 months after initial therapy (Tg cut-off value 10 microg/l; sensitivity 100%, specificity 93%). DTC-related mortality was 14%. TSH-stimulated Tg levels before ablation and 6 months after initial therapy were independent prognostic indicators for death. CONCLUSION: Optimal institutional Tg cut-off levels for diagnosis and prognosis should be defined using ROC analyses for each condition and time-point. Tg measurements 6 months after initial therapy during TSH stimulation had an excellent diagnostic value. Tg levels are independent prognostic indicators for disease-free remission and death. Using this strategy, high-risk patient groups can be selected based on Tg levels, in addition to conventionally used prognostic indicators.
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Background: Asthma is a chronic condition that is responsible for substantial morbidity. Direct costs for physicians, hospital care and medications in Canada are conservatively estimated at $306 million per year for persons with asthma. Existing evidence suggests that considerable reductions in morbidity could be achieved by early prevention and timely treatment. Much of the costs of asthma care are related to poor disease control due to under-use of effective prophylactic therapies, inadequate monitoring of disease severity, and insufficient patient education. A recent Canadian survey found that only 64% of patients with poor asthma control had been prescribed an inhaled corticosteroid, and of these only 52% made use of the medication on a daily basis. Further, although asthma self-management has been shown to reduce the relative risk of hospitalization for asthma by 39%, only 21% of asthma patients are provided with an action plan to institute for disease exacerbation and only 22% of primary care physicians provide action plans for their asthma patients on a regular basis. Computerized decision-support systems have provided a new set of tools for enabling integrated evidence-based care, by providing physicians with patient-specific reminders and alerts for needed preventive care and management, and timely feedback from patients. However, there has been limited use of computer-enabled decision-support in primary care, and only one reported study in chronic disease management. A key barrier to success has been the challenge of providing primary care physicians with a computerized solution that will produce value-added benefits and can be integrated easily into their routine workflow. Our prior research has shown that an integrated electronic prescribing and drug management system can provide value-added benefits for physicians because it is linked to information on dispensed medications, and alerts for prescribing problems. Early uptake and utilization of this computerized drug management system by primary care physicians provides an opportunity to develop and evaluate the effectiveness of an integrated asthma management decision-support system to enhance the use of prophylactic therapies and timely monitoring of asthma severity in primary care.
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PURPOSE: To report findings on knowledge and skill acquisition following a 3-day training session in the use of short message service (SMS) texting with non- and low-literacy traditional midwives. DESIGN: A pre- and post-test study design was used to assess knowledge and skill acquisition with 99 traditional midwives on the use of SMS texting for real-time, remote data collection in rural Liberia, West Africa. METHODS: Paired sample t-tests were conducted to establish if overall mean scores varied significantly from pre-test to immediate post-test. Analysis of variance was used to compare means across groups. The nonparametric McNemar's test was used to determine significant differences between the pre-test and post-test values of each individual step involved in SMS texting. Pearson's chi-square test of independence was used to examine the association between ownership of cell phones within a family and achievement of the seven tasks. FINDINGS: The mean increase in cell phone knowledge scores was 3.67, with a 95% confidence interval ranging from 3.39 to 3.95. Participants with a cell phone in the family did significantly better on three of the seven tasks in the pre-test: "turns cell on without help" (chi(2) (1) = 9.15, p= .003); "identifies cell phone coverage" (chi(2) (1) = 5.37, p= .024); and "identifies cell phone is charged" (chi(2) (1) = 4.40, p= .042). CONCLUSIONS: A 3-day cell phone training session with low- and nonliterate traditional midwives in rural Liberia improved their ability to use mobile technology for SMS texting. CLINICAL RELEVANCE: Mobile technology can improve data collection accessibility and be used for numerous health care and public health issues. Cell phone accessibility holds great promise for collecting health data in low-resource areas of the world.
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Oncotype DX(TM) is an RT-PCR-based assay used to predict chemotherapy benefit in patients with estrogen receptor (ER) positive breast cancers. We were interested if routinely available pathologic parameters could predict Oncotype DX Recurrence Scores (RS) in subsets of patients. We identified 173 breast cancers with available RSs and used 104 of these as a test set and 69 cases as a validation set. Pathologic characteristics including size, histologic type, Nottingham grade, and lymphatic invasion were recorded. Test set cases were stained for ER, progesterone receptor (PR), HER2, Ki67, CyclinD1, BCL2, D2-40, and P53. Statistical correlations with RS and regression tree analysis were performed. The validation set was subjected to analysis on the basis of grade, PR, and Ki67. In the test set, grade, PR levels and Ki67 had the strongest correlation with RS (P = 0.0002-0.0007). Regression tree analysis showed grade and PR as factors that could segregate cases into RS categories, with Ki67 adding value in certain subsets. A subset of cancers with a high likelihood of having a low RS (0-18) was identified with the following characteristics: grade 1, strong PR expression (Allred score >/= 5) and Ki67 </= 10%. No cases with these characteristics had a high RS (>/= 31) and 73% had a low RS. Cancers highly likely to have a high RS were grade 3, low to absent PR expression (Allred score <5) and Ki67 > 10%. 80% of cases with these characteristics had a high RS and no cases had a low RS. Our validation set had similar findings in these two subsets. In conclusion, When cost and time are a consideration and the added value of Oncotype DX(TM) testing is in question, it may be reasonable to assume the results of this test in two specific subsets of breast cancers: (1) grade 1, high PR, low Ki67 cancers (low RS), and (2) grade 3, low PR, high Ki67 cancers (high RS).
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BACKGROUND: Gabapentin (GBP) may be useful in bipolar disorders, including as adjunctive therapy for bipolar depression, although controlled studies suggest inefficacy as primary treatment for mania or treatment-resistant rapid cycling. METHODS: We performed a 12-week trial of open GBP (mean dose 1725 mg/day) added to stable doses of mood stabilizers or atypical antipsychotics in 22 (10 women, mean age 38.4 years) depressed (28-item Hamilton Depression Rating Scale (HDRS) > 18] bipolar (10 bipolar I, 12 bipolar II) disorder outpatients. Mean illness duration was 18.6 years, current depressive episode duration was 18.0 weeks. Prospective 28-item HDRS, Young Mania Rating Scale (YMRS) and Clinical Global Impression-Severity (CGI-S) ratings were obtained. RESULTS: Overall, HDRS ratings decreased 53% from 32.5 +/- 7.7 at baseline to 16.5 +/- 12.8 at week 12 (p < 0.0001). Twelve of 22 (55%) patients had moderate to marked improvement (HDRS decrease = 50%) with HDRS decreasing 78% from 27.9 +/- 6.2 to 6.2 +/- 4.5 (p < 0.0001). Eight of 22 (36%) patients remitted (HDRS > or = 8). In non-responders, HDRS decreased from 38.0 +/- 5.4 to 28.9 +/- 6.7 (p = 0.005). Ten of 13 (77%) mild to moderately depressed (baseline HDRS > 18 and <35) patients responded, while only two of nine patients (22%) with severe depression (HDRS > or = 35) responded (p < 0.03). Both groups, however, had similar, statistically significant HDRS decreases. GBP was well tolerated. CONCLUSION: Open adjunctive GBP was effective and well tolerated in patients with mild to moderate bipolar depression. This open pilot study must be viewed with caution, and randomized controlled studies are warranted.
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A subpopulation of plasma membrane-associated estrogen receptor (ER)alpha interact directly with G proteins and mediate nonnuclear receptor signaling. This mechanism underlies numerous processes, including important cardiovascular protective actions of estradiol (E(2)), such as the activation of endothelial NO synthase (eNOS) and endothelial cell growth and migration. In the present work we sought a genetic approach to differentiate nonnuclear from nuclear ERalpha actions. We generated single alanine substitutions within the Galphai-binding domain of ERalpha (amino acids 251-260) and tested signaling to eNOS or ERK1,2 and activation of luciferase (Luc) reporters signifying transactivation via direct or indirect ERalpha-DNA binding in HeLa cells. The point mutants ERalpha-R256A, ERalpha-K257A, ERalpha-D258A, and ERalpha-R260A were all incapable of activating eNOS in response to E(2), and ERalpha-R256A and ERalpha-D258A also showed loss of ERK1,2 activation. In contrast, ERalpha-R256A, ERalpha-K257A, ERalpha-D258A, and ERalpha-R260A all displayed normal capacity to invoke E(2)-induced transactivation of estrogen response element (ERE)-Luc or Sp1-Luc. However, whereas activator protein 1-Luc activation by ERalpha-R256A and ERalpha-D258A was intact, ERalpha-K257A and ERalpha-R260A were incapable of activator protein 1-Luc activation. In in vitro pull-down assays with the two mutants that lack all nonnuclear functions tested and retain all nuclear functions tested, ERalpha-R256A and ERalpha-D258A, there was normal direct interaction between Galphai and ERalpha-R256A and an absence of interaction between Galphai and ERalpha-D258A. When expressed in endothelial cells, these two mutants prevented E(2)-induced migration and eNOS activation mediated by endogenous receptor, indicative of dominant-negative action. Thus, the point mutants ERalpha-R256A and ERalpha-D258A in the receptor GalphaI-binding domain provide genetic segregation of nonnuclear from nuclear ERalpha function.
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The present study tested the hypotheses that: (1) defensive rage behavior elicited from the midbrain periaqueductal gray (PAG) in the cat is facilitated from the basal complex of amygdala; and (2) such facilitation from this region of amygdala is mediated via a pathway in which excitatory amino acids acting upon NMDA receptors within the PAG are utilized as a neurotransmitter. In the first phase of this study, cannula electrodes were implanted into PAG sites for the elicitation of defensive rage behavior as well as for drug delivery. Then, a second monopolar electrode was implanted into the basal nucleus of amygdala from which facilitation of defensive rage could be obtained. As a result of dual stimulation of the basal amygdala and PAG, response latencies for defensive rage were significantly lowered relative to PAG stimulation alone (P < 0.01). In the second phase of this experiment, 3 doses of a selective NMDA receptor antagonist, AP-7 (0.1, 0.5, 1.0 mg/kg), were peripherally (i.p.) administered in 5 animals. The results indicated a significant decrease in the facilitatory effects of amygdaloid stimulation in a dose and time dependent manner (P < 0.001). In the third phase, AP-7 was administered intracerebrally into PAG defensive rage sites in doses of 0.2 and 2.0 nmol. It was noted that intracerebral microinjections of AP-7 at the higher dose (2.0 nmol) also significantly suppressed the facilitatory effects of amygdaloid stimulation (P < 0.01); however, these effects were somewhat less potent then those observed following peripheral drug administration. A fourth phase of the study was conducted at the completion of the pharmacological experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
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BACKGROUND: Hepatitis C virus (HCV) infection is a global health problem. In Western countries, illicit drug users (IDUs) constitute the largest proportion of HCV patients. International guidelines no longer regard ongoing illicit drug use as a contraindication to antiviral therapy for chronic hepatitis C (CHC). Nonetheless, in clinical practice, few IDUs have access to HCV treatment, likely because many physicians believe these patients will have poor adherence or a lack of treatment efficacy. OBJECTIVE: The aim of this study was to assess effectiveness and tolerability of combination treatment with ribavirin plus recombinant or pegylated interferon-alpha in the treatment of CHC in IDUs. METHODS: MEDLINE, EMBASE, and the Cochrane Library were searched for relevant studies published in English between 2000 and December 2008. The following terms were searched: chronic hepatitis C, interferons, antiviral agents, methadone, and substance-related disorders. Full-text articles and abstracts were searched using predefined criteria. A manual search of abstracts from 8 international meetings of hepatologists was also conducted. Only prospective studies with a sample size >15 and a homogeneous treatment schedule were included. Articles were extracted independently by 2 of the authors using an electronic standardized form including study quality indicators. RESULTS: Sixteen prospective studies were included, and data from a cohort of 953 IDUs were analyzed. The estimated overall sustained virologic response (SVR) and dropout (DO) rates in IDUs were 52% (95% CI, 44%-60%) and 26% (18%-35%, 95% CI), respectively. The rate of psychiatric severe adverse events (SAEs) that led to treatment discontinuation was 2% (95% CI, 1%-3%). These prevalences were not significantly different from those reported in registration trials of treatment of CHC that excluded IDUs from the study population (SVR, 50% [95% CI, 39%-61%]; DO, 26% [95% CI, 12%-41%]; and psychiatric SAEs, 2% [95% CI, 0%-6%]). By subgroup analysis, active ongoing drug use negatively affected the rate of treatment success (39% [95% CI, 30%-49%] vs 55% [95% CI, 45%-64%]; P = 0.02). CONCLUSION: Based on data from 16 prospective clinical studies of CHC treatment in IDUs published in the past 10 years, findings on effectiveness and tolerability are comparable to those in the general population.
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To investigate a possible relationship between the presence of anti-neutrophil cytoplasm antibodies (ANCA), rheumatoid factors (RF), anti-nuclear antibodies (ANA), disease severity and HLA-DR phenotypes, 46 consecutive ANCA+ and 48 ANCA-, clinically well-documented RA patients were studied for RF, ANA and HLA-DR phenotypes. The 46 ANCA+ patients showed predominantly an atypical perinuclear staining pattern (89%). ANCA positivity was associated with higher RF titres (P < 0.005) and advanced functional Steinbrocker grades III/IV (P < 0.015). ANCA+ patients were also more often positive for ANA than ANCA- patients (P < 0.008). There was no correlation between ANCA positivity and certain HLA-DR phenotypes although the frequency of DR4+ (67% vs 52%) and, in particular, of DR4+ blanks (phenotypically homozygous) was increased in ANCA+ as compared to ANCA- patients (20% vs 8%). DR4-DR1-RA patients were twice as frequent in the ANCA- than in the ANCA+ group (22.9% vs 8.7%). Correspondingly, the DR4+DR1- phenotype was increased among ANCA+ RA patients. Regarding functional Steinbrocker grades, the DR4+ phenotypes were slightly but not significantly increased in grades III and IV whereas ANCA positivity was significantly associated with severe functional Steinbrocker grades III/IV (66% ANCA+ vs 39% ANCA-, P < 0.015). ANCA positivity identified a population of RA patients with a long-standing and severe clinical course of the disease. There was no correlation between ANCA positivity and certain HLA-DR phenotypes.
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OBJECTIVE: Penile augmentation surgery is still a controversial issue because of the uncertain indication, the possibility of severe complications and a variety of surgical techniques. The purpose of this study is to provide two surgical procedures of penile corpora cavernosa augmentation and to investigate its effect by implanting autogenous saphenous vein grafts or expanded polytetrafluoroethylene (ePTFE) vessel patches. METHODS: Between January 2001 and December 2005, 20 patients underwent surgeries in which bilateral longitudinal incisions were placed on the tunica albuginea and the penile corpora cavernosa were extended by means of implantation of saphenous grafts or PTFE artificial vessel patches. The patients included in this study presented either with congenital idiopathic micropenis or normal penile length and perimeter (dysmorphophobia). Before the operation, the penile length and perimeter in the flaccid and erectile states were as follows: flaccid length 2.5-7.5 cm and flaccid perimeter 3.0-7.5 cm; erectile length 4.9-10.5 cm and erectile perimeter 4.5-10.0 cm. RESULTS: Immediately after surgery, the penile corpus circumferential measurements (on table), showed remarkable increases which were 1.0-2.3 cm and 1.5-3.0 cm in the flaccid and erectile states, respectively; then, at 12 months to 5 years' follow-up, these girth gains had reduced by 0.5-1 cm in some cases. All cases in the two groups obtained satisfactory surgical results with satisfactory erection and no serious complications, such as infection and fistula. In 20 cases, 17 married cases resumed regular and satisfactory sexual activities 1 month after the operation without any functional limitation. CONCLUSION: The two kinds of surgical procedures for augmenting penile corpora cavernosa were proved to be effective and reliable, with few complications. Both saphenous grafts and ePTFE artificial vessel patches are excellent materials for reconstructing the tunica albuginea. These augmenting phalloplasties can not only be used for patients with micropenis, but also applied to satisfy the cosmetic and functional requests of patients with normal penile length and perimeter. However, the long-term outcomes of these surgical procedures need a further, detailed follow-up study.
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BACKGROUND: Pigmented villonodular synovitis (PVNS) (also known as diffuse-type giant cell tumor) and tenosynovial giant cell tumors (TGCT) are rare, usually benign neoplasms that affect the synovium and tendon sheaths in young adults. These tumors are driven by the overexpression of colony stimulating factor-1 (CSF1). CSF1 is expressed by a minority of tumor cells, which, in turn attract non-neoplastic inflammatory cells that express CSF1 receptor (CSF1R) through a paracrine effect. METHODS: Imatinib mesylate (IM) blocks CSF1R, and previous case reports indicated that it also exerts antitumor activity in PVNS. The authors conducted a multi-institutional retrospective study to assess the activity of IM in patients with locally advanced/metastatic PVNS/TGCT. RESULTS: Twenty-nine patients from 12 institutions in Europe, Australia, and the United States were included. There were 13 men, the median age was 41 years, and the most common site of disease was the knee (n = 17; 59%). Two patients had metastatic disease to the lung and/or bone. Five of 27 evaluable patients had Response Evaluation in Solid Tumor (RECIST) responses (overall response rate, 19%; 1 complete response and 4 partial responses), and 20 of 27 patients (74%) had stable disease. Symptomatic improvement was noted in 16 of 22 patients (73%) who were assessable for symptoms. Despite a high rate of symptomatic improvement and a favorable safety profile, 6 patients discontinued because of toxicity, and 4 patients decided to discontinue IM for no clear medical reason. CONCLUSIONS: IM displayed interesting activity in patients with PVNS/TGCT, providing proof of concept for targeting CSF1R in this disease. The authors concluded that the benefits of alleviating morbidity in patients with localized PVNS/TGCT must be balanced against the potential toxicity of chronic drug therapy.
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Lixisenatide (AVE0010) is a once-daily glucagon-like peptide-1 (GLP-1) receptor agonist used in the treatment of type 2 diabetes. Phase II dose-finding and pharmacodynamic studies identified the 20 microg once-daily dose as having the optimum combination of efficacy, convenience and tolerability. Lixisenatide was prospectively investigated in a series of 11 multinational, randomised, controlled phase III trials (GLP-1 agonist AVE0010 in paTients with type 2 diabetes mellitus for Glycemic cOntrol and sAfety evaLuation [GetGoal] programme) that included a direct head-to-head study with exenatide. The GetGoal programme established the efficacy and safety profile of lixisenatide 20 microg once daily across the spectrum of patients with type 2 diabetes, including patients not treated with anti-diabetic agents, those failing on oral agents and as an adjunct to basal insulin therapy. The main efficacy endpoints were met in all studies, with the baseline to endpoint reductions in HbA1c consistently ranging from 0.7% to 1.0%. In a head-to-head comparison with exenatide 10 mug twice daily, lixisenatide 20 mug once daily was non-inferior for HbA1c reduction, achieved with threefold fewer patients with symptomatic hypoglycemia events and better gastrointestinal tolerability. Three randomised trials of lixisenatide treatment added to basal insulin showed significantly improved glycemic control over placebo, with pronounced postprandial glucose reductions and good tolerability. Discontinuations for adverse events were consistently low, ranging from 2.5% to 10.4%. As the provision of individualized care moves center stage in diabetes management, lixisenatide with once-daily dosing, a single maintenance dose and fixed-dose pens offers an important treatment option for type 2 diabetes.
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