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Terms modified by IU Selected AbstractsImplementation, performance, and science results from a 30.7 TFLOPS IBM BladeCenter clusterCONCURRENCY AND COMPUTATION: PRACTICE & EXPERIENCE, Issue 2 2010Craig A. Stewart Abstract This paper describes Indiana University's implementation, performance testing, and use of a large high performance computing system. IU's Big Red, a 20.48 TFLOPS IBM e1350 BladeCenter cluster, appeared in the 27th Top500 list as the 23rd fastest supercomputer in the world in June 2006. In spring 2007, this computer was upgraded to 30.72 TFLOPS. The e1350 BladeCenter architecture, including two internal networks accessible to users and user applications and two networks used exclusively for system management, has enabled the system to provide good scalability on many important applications while being well manageable. Implementing a system based on the JS21 Blade and PowerPC 970MP processor within the US TeraGrid presented certain challenges, given that Intel-compatible processors dominate the TeraGrid. However, the particular characteristics of the PowerPC have enabled it to be highly popular among certain application communities, particularly users of molecular dynamics and weather forecasting codes. A critical aspect of Big Red's implementation has been a focus on Science Gateways, which provide graphical interfaces to systems supporting end-to-end scientific workflows. Several Science Gateways have been implemented that access Big Red as a computational resource,some via the TeraGrid, some not affiliated with the TeraGrid. In summary, Big Red has been successfully integrated with the TeraGrid, and is used by many researchers locally at IU via grids and Science Gateways. It has been a success in terms of enabling scientific discoveries at IU and, via the TeraGrid, across the US. Copyright © 2009 John Wiley & Sons, Ltd. [source] Effect of Perilesional Injections of PEG-Interleukin-2 on Basal Cell CarcinomaDERMATOLOGIC SURGERY, Issue 11 2000Baruch Kaplan MD Background: Multiple modalities are available for the treatment of basal cell carcinoma (BCC). The most commonly used modalities include simple excision, Mohs micrographic surgery, curettage and electrodessication, cryosurgery, and irradiation therapy. Interleukin-2 (IL-2) is a cytokine produced chiefly by activated T lymphocytes and has effects on various components of the immune system. Until now the primary clinical use of IL-2 has been in advanced stages of metastatic melanoma and renal cell carcinoma. Systemic administration of IL-2 is known to cause significant toxicity. Objective: The objective of this study was to evaluate the therapeutic efficacy and safety of perilesional PEG-IL-2 injections in patients with BCC in an open label, uncontrolled pilot study. Methods: Patients with histologically confirmed primary BCC over 18 years of age were included in the study. Lesions were treated by injecting a total volume of 0.5 cc of IL-2 in a radial fashion in the subcutaneous tissue. Injection dosages ranged from 3000 to 1,200,000 IU in one to four weekly dosages. A total of 12 tumors were treated in eight patients. Results: Overall response rates were as follows: complete response in 8 of 12 treated tumors (66.6% cure rate), partial response in 3 of 12 injected tumors (25% partial response rate), stable disease with no improvement in 1 treatment site (8.4%). Side effects included local pain, swelling, and erythema, and in one patient flulike symptoms. There were no significant changes of blood tests as compared to baseline levels. Conclusions: The therapeutic response induced by perilesional PEG-IL-2 injections was found to be an encouraging, safe, and well-tolerated treatment of BCC. Further studies including a larger patient population and long-term follow-up are necessary in order to substantiate these findings. [source] Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 2 2010T. Vilsbøll Objective: To evaluate the efficacy and tolerability of sitagliptin when added to insulin therapy alone or in combination with metformin in patients with type 2 diabetes. Methods: After a 2 week placebo run-in period, eligible patients inadequately controlled on long-acting, intermediate-acting or premixed insulin (HbA1c , 7.5% and , 11%), were randomised 1:1 to the addition of once-daily sitagliptin 100 mg or matching placebo over a 24-week study period. The study capped the proportion of randomised patients on insulin plus metformin at 75%. Further, the study capped the proportion of randomised patients on premixed insulin at 25%. The metformin dose and the insulin dose were to remain stable throughout the study. The primary endpoint was HbA1c change from baseline at week 24. Results: Mean baseline characteristics were similar between the sitagliptin (n = 322) and placebo (n = 319) groups, including HbA1c (8.7 vs. 8.6%), diabetes duration (13 vs. 12 years), body mass index (31.4 vs. 31.4 kg/m2), and total daily insulin dose (51 vs. 52 IU), respectively. At 24 weeks, the addition of sitagliptin significantly (p < 0.001) reduced HbA1c by 0.6% compared with placebo (0.0%). A greater proportion of patients achieved an HbA1c level < 7% while randomised to sitagliptin as compared with placebo (13 vs. 5% respectively; p < 0.001). Similar HbA1c reductions were observed in the patient strata defined by insulin type (long-acting and intermediate-acting insulins or premixed insulins) and by baseline metformin treatment. The addition of sitagliptin significantly (p < 0.001) reduced fasting plasma glucose by 15.0 mg/dl (0.8 mmol/l) and 2-h postmeal glucose by 36.1 mg/dl (2.0 mmol/l) relative to placebo. A higher incidence of adverse experiences was reported with sitagliptin (52%) compared with placebo (43%), due mainly to the increased incidence of hypoglycaemia (sitagliptin, 16% vs. placebo, 8%). The number of hypoglycaemic events meeting the protocol-specified criteria for severity was low with sitagliptin (n = 2) and placebo (n = 1). No significant change from baseline in body weight was observed in either group. Conclusion: In this 24-week study, the addition of sitagliptin to ongoing, stable-dose insulin therapy with or without concomitant metformin improved glycaemic control and was generally well tolerated in patients with type 2 diabetes. [source] Should liver function tests be included in definitions of metabolic syndrome?DIABETIC MEDICINE, Issue 5 2008Evidence from the association between liver function tests, components of metabolic syndrome, prevalent cardiovascular disease Abstract Aims The definition of metabolic syndrome (MS) continues to be debated and does not include abnormal liver function tests (LFTs). This study aims to determine: (1) the association between the five ATP3 MS diagnostic components and different LFTs, and (2) the association between raised LFTs and prevalent cardiovascular disease (CVD). Methods A total of 1357 patients, without alcoholism or known liver disease, from randomly selected households from rural Victoria, Australia, attended for biomedical assessment. Receiver operating characteristic (ROC) areas under the curve (AUC) were determined for associations between the ATP3 diagnostic components, and between LFTs and ATP3 diagnostic components. Results The range of ROC AUC for ATP3 diagnostic components was 0.60,0.77. Waist had the strongest association and blood pressure the weakest. The strength of association between ATP3 diagnostic components and gamma GT (GGT) was similar (0.63,0.72), but was less for alanine transaminase and aspartate transaminase. Using the ROC-derived GGT cut-off (men 27 IU, women 20 IU), those with MS and a high GGT had more CVD than those with MS and a low GGT, and those without MS (18% vs. 10% vs. 7%, respectively; P < 0.001). Among those with MS, after adjusting for covariates, the odds ratio of CVD was 2.66 (1.18,5.96) for a high GGT compared to a low GGT. CVD was not significantly more prevalent in MS patients with a low GGT compared to non-MS patients. Conclusions We suggest that including a raised GGT in the criteria for MS could increase its predictive nature for CVD. Prospective studies are needed to confirm this finding. [source] Combined treatment of achalasia , botulinum toxin injection followed by pneumatic dilatation: long-term resultsDISEASES OF THE ESOPHAGUS, Issue 2 2010R. Kroupa SUMMARY Injection of botulinum toxin (BT) and pneumatic dilatation are available methods in nonsurgical treatment of achalasia. Authors anticipate beneficial effect of prior BT injection on the success of pneumatic dilatation and duration of its effect. There are no long-term data available to assess efficacy of combined treatment. From 1998 to 2007, 51 consecutive patients (20 men and 31 women, age 24,83) with achalasia were included and prospectively followed up. Each patient received injection of 200 IU of BT into the lower esophageal sphincter (LES) during endoscopy and 8 days later pneumatic dilatation (PD) under X-ray control was performed. The follow-up was established every 3 months first year and then annually. The efficacy was evaluated by a questionnaire concerning patient's symptoms and manometry. Results were compared with 40 historical controls (16 men and 24 women, age 26,80) treated by PD alone using the same method and follow-up. Fifty-one patients underwent combined treatment. Four patients failed in follow-up and were not included for analysis. The mean duration of follow-up was 48 months with range 12,96 months. Thirty-four of forty-seven (72%) patients were satisfied with results with none or very rare and mild troubles at the time of the last visit. Forty-one patients were followed up more than 2 years. Effect of therapy lasted in 75% (31/41) of them. In 17 patients, more than 5 years after treatment, effect lasted in 12 (70%). Mean tonus of LES before therapy was 29 mm Hg (10,80), 3 months after therapy decreased to 14 mmHg (5,26). The cumulative 5 years remission rate (±95% CI) in combined treated patients 69% ± 8% was higher than in controls 50% ± 9%; however it, was not statistically significant (P= 0.07). In control group 1, case of perforation (2.5%) occurred. Eight patients (17%) with relapse of dysphagia were referred to laparoscopic Heller myotomy with no surgical complication. The main adverse effect was heartburn that appeared in 17 patients (36%). Initial injection of BT followed by PD seems to be effective for long-term results with fewer complications. But the combined therapy is not significantly superior to PD alone. [source] Microflow Vessel Improving Reproducibility and Sensitivity of Electrochemical MeasurementsELECTROANALYSIS, Issue 23 2008Jan Krejci Abstract A new microflow system was designed and developed for electrochemical measurements. The electrochemical electrodes prepared using thick film technology were used in this arrangement. Results of various measurements such as simple amperometric measurement on the example of H2O2 detection, measurement with glucose oxidase (GOx) biosensor, soluble enzyme activity measurement etc. carried out using this system are reported. It was observed that the sensitivity and reproducibility of the electrochemical measurements is improved significantly. The new device performance was proved on H2O2 detection, activity of GOx measurement and heavy metals detection (measured concentration range: H2O2 10,9 to 10,1,M, glucose 10,6 to 10,2,M, activity of GOx 10,1 to 102,IU, heavy metals (Cu, Pb) 10,4 to 10,3,M). The microflow insert greatly reduces the overall size of the electrolyte vessel and measurements with sample quantity as low as 2,mL can be accomplished. [source] A Sheep Model for the Study of Focal Epilepsy with Concurrent Intracranial EEG and Functional MRIEPILEPSIA, Issue 8 2002Helen I. Opdam Summary: ,Purpose: We describe a sheep model of penicillin-induced seizure activity using electroencephalography (EEG) and functional MRI (fMRI). Methods: Ten adult sheep were used. Spikes and seizures were generated by instillation of 8,000,10,000 IU of penicillin into the right prefrontal cortex via a specially designed port. Bilateral intracranial EEG was acquired by using carbon fiber electrodes. Animals had behavioral characterization of their seizures and were then anesthetized for fMRI studies. Functional MRI was performed at 1.5 and 3 Tesla by measuring blood oxygen level,dependent (BOLD) weighted signal intensity at different times during the evolution of seizures. Results: Behavioral seizures were associated with electrographic seizures. Intracranial EEG obtained in the MR scanner was of high quality. Focal spiking and seizures were seen in all animals and developed 11.3 ± 11.2 s and 17.3 ± 12.1 min after penicillin administration, respectively. An average of 13 ± 4.8 seizures were seen per animal, each lasting 27.3 ± 12.3 s. Functional MR images with little parenchymal artefact were obtained. Regional BOLD signal-intensity changes were observed during seizures at the seizure focus and ipsilateral amygdala. Conclusions: We have developed an animal model of partial epilepsy in which seizures can be reliably elicited with concurrent fMRI and intracranial EEG. During unilateral electrographic seizures, focal BOLD signal changes occurred at the seizure focus and ipsilateral amygdala, suggesting the presence of a cortico,subcortical loop. This observation illustrates the potential of the model for understanding seizure generation, spread, and possibly the consequences of repeated seizures on the brain. [source] Once-weekly epoetin beta therapy in patients with solid tumours and chemotherapy-induced anaemia: a randomized, double-blind, dose-finding studyEUROPEAN JOURNAL OF CANCER CARE, Issue 6 2008P. HERAS md, phd Anaemia is common in patients receiving chemotherapy, causing symptoms that have a major impact on quality of life (QoL). Epoetin beta rapidly increases haemoglobin (Hb) levels and improves QoL in anaemic patients with a variety of tumours. This was a randomized, double-blind, parallel-group, dose-finding study assessing the efficacy and safety of once-weekly epoetin beta in patients with solid tumours receiving chemotherapy. Adult patients with anaemia (Hb < 11 g/dL) were randomized to receive epoetin beta 30 000 IU or 20 000 IU once weekly for 12 weeks. All patients received oral iron supplementation. Haemoglobin levels, transfusion need and QoL [Functional Assesment of Cancer Therapy-fatigue (FACT-F) subscale score] were assessed at regular intervals. Fifty patients were randomized; 30 patients received epoetin beta 30 000 IU once weekly and 20 received 20 000 IU once weekly. Mean (± SD) increase in Hb from baseline to week 12 was 1.75 ± 2.15 g/dL in the 30 000 IU group (P = 0.008 vs. baseline) and 1.04 ± 1.75 g/dL in the 20 000 IU group (non-significant). Haemoglobin response (increase in Hb ,2 g/dL from baseline) was observed in 78.3% of patients receiving epoetin beta 30 000 IU and 66.7% receiving epoetin beta 20 000 IU. Improvements in FACT-F subscale score were significantly (P < 0.001) correlated with increases in Hb level. Transfusion use was low during the study in both groups. Both epoetin beta regiments were well tolerated and there were no dose-dependant adverse events. Epoetin beta 30 000 IU once weekly is an effective and well-tolerated treatment of anaemia in patients with solid tumours. [source] Effect of oxytocin on nitric oxide activity controlling gonadotropin secretion in humansEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 5 2003P. Chiodera Abstract Background Previously described inhibitory effects of the nitric oxide synthase (NOS) inhibitor L-NAME on luteinizing hormone-releasing hormone (LH-RH)-induced LH and follicle stimulating hormone (FSH) secretion in humans suggested modulation by nitric oxide (NO) of the gonadotropin-releasing action of LH-RH. Design In order to establish whether oxytocin (OT) participates in this regulatory mechanism, 10 normal men were treated with LH-RH (100 µg as an i.v. bolus) given alone or in the presence of L-NAME (40 µg kg,1 injected plus 50 µg kg,1 infused i.v. for 60 min), OT (2 IU injected plus 4 IU infused i.v. for 60 min) or a combination of both drugs. Results The administration of OT was unable to change the gonadotropin responses to LH-RH. In contrast, L-NAME significantly reduced both FSH and LH increments induced by LH-RH. When L-NAME was given in the presence of OT, the LH and FSH responses to LH-RH were similar to those observed after the administration of LH-RH alone. Conclusion These data suggest antagonistic actions of OT and L-NAME in the control of NOS activity in regulation of gonadotropin secretion induced by LH-RH. [source] A pilot study on systemic thrombolysis followed by low molecular weight heparin in ischemic strokeEUROPEAN JOURNAL OF NEUROLOGY, Issue 10 2006R. Mikulík Low molecular weight heparin (LMWH) administered immediately after intravenous thrombolysis (IT) may reduce the risk of arterial re-occlusion. Its benefit, however, may not outweigh the risk of intracranial hemorrhage (ICH). We sought preliminary data regarding safety of this combined therapy in an open-label, non-randomized study. The patients received either a standard anticoagulation (AC) starting 24 h after IT (the standard AC group) or AC with 2850 IU of nadroparin, given every 12 h immediately after IT (the early AC group). Sixty patients received IT treatment: 25 in the standard AC group [mean age 66, median National Institutes of Health Stroke Scale (NIHSS) 13, 64% men] and 35 in the early AC group (mean age 68, median NIHSS 13, 69% men). Symptomatic ICH occurred in one patient (4%) in the standard AC group and three patients (8.6%) in the early AC group [odds ratio (OR) 1.8; 95%CI 0.2,12.8]. At 3 months, nine patients in the standard AC group (36%) and 16 patients in the early AC group (45.7%) achieved a modified Rankin scale 0 or 1 (OR 1.2; 95%CI 0.5,3.2). Our study suggests that treatment with LMWH could be associated with higher odds of ICH, although it may not necessarily lead to a worse outcome. This justifies larger clinical trials. [source] SEXUAL SELECTION AND IMMUNE FUNCTION IN DROSOPHILA MELANOGASTEREVOLUTION, Issue 2 2008Kurt A. McKean The evolution of immune function depends not only on variation in genes contributing directly to the immune response, but also on genetic variation in other traits indirectly affecting immunocompetence. In particular, sexual selection is predicted to trade-off with immunocompetence because the extra investment of resources needed to increase sexual competitiveness reduces investment in immune function. Additional possible immunological consequences of intensifying sexual selection include an exaggeration of immunological sexual dimorphism, and the reduction of condition-dependent immunological costs due to selection of ,good genes' (the immunocompetence handicap hypothesis, ICHH). We tested for these evolutionary possibilities by increasing sexual selection in laboratory populations of Drosophila melanogaster for 58 generations by reestablishing a male-biased sex ratio at the start of each generation. Sexually selected flies were larger, took longer to develop, and the males were more sexually competitive than males from control (equal sex ratio) lines. We found support for the trade-off hypothesis: sexually selected males were found to have reduced immune function compared to control males. However, we found no evidence that sexual selection promoted immunological sexual dimorphism because females showed a similar reduction in immune function. We found no evidence of evolutionary changes in the condition-dependent expression of immunocompetence contrary to the expectations of the ICHH. Lastly, we compared males from the unselected base population that were either successful (IS) or unsuccessful (IU) in a competitive mating experiment. IS males showed reduced immune function relative to IU males, suggesting that patterns of phenotypic correlation largely mirror patterns of genetic correlation revealed by the selection experiment. Our results suggest increased disease susceptibility could be an important cost limiting increases in sexual competitiveness in populations experiencing intense sexual selection. Such costs may be particularly important given the high intersex correlation, because this represents an apparent genetic conflict, preventing males from reaching their sexually selected optimum. [source] Reformulated BeneFix®: efficacy and safety in previously treated patients with moderately severe to severe haemophilia BHAEMOPHILIA, Issue 3 2007T. LAMBERT Summary. BeneFix®, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6,12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year,1; and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX. [source] Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate®): a prospective pharmacovigilance studyHAEMOPHILIA, Issue 5 2004B. M. Ewenstein Summary., Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate®, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1,50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 ×109 IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05,28.0%) for PUPs when compared with 0.123% (CI: 0.030,0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00,11.8%) for PUPs and 0.0554% (CI: 0.0113,0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent. [source] Treatment of gustatory sweating (Frey's syndrome) with botulinum toxin A,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 8 2003André Eckardt MD Abstract Background. Gustatory sweating is a common complication of parotid surgery. Injection of botulinum toxin A has been reported as a safe and effective treatment option for patients with Frey's syndrome. Patients and Methods. A total of 69 patients who had undergone superficial parotidectomy because of adenoma were evaluated with respect to the incidence of Frey's syndrome and treatment interest. Minor's iodine starch test was used to detect the affected skin area. Affected skin areas were documented using a digital camera; skin areas were evaluated morphometrically. A single injection of Botox per 1 cm2 skin field was administered to those patients interested in treatment. Results. Of 43 patients (62%) with gustatory sweating, 33 patients requested treatment. The affected skin area varied from 16 cm2 to 81 cm2. The individual Botox dosage ranged from 16 to 80 IU. All relevant clinical symptoms of sweating disappeared within 1 week after a single injection. Treatment was well tolerated with no side effects. Conclusion. Botox A injection is a safe and effective treatment with long-lasting effects for patients with extensive gustatory sweating. © 2003 Wiley Periodicals, Inc. Head Neck 25: 624,628, 2003 [source] Randomized, placebo-controlled trial of low molecular weight heparin in active ulcerative colitisINFLAMMATORY BOWEL DISEASES, Issue 6 2007M.A. de Bièvre MD Abstract Background: In several open and 1 controlled trial, unfractionated heparin was effective in the treatment of active ulcerative colitis (UC). Low molecular weight heparin (LMWH) had a similar effect in several open studies. Methods: We studied the efficacy, safety, and tolerability of LMWH in mild to moderately active UC in a randomized, double-blind, placebo-controlled trial. In all, 29 patients with a mild or moderate recurrence of UC during salicylate treatment were randomized to receive either reviparin 3,436 IU (n = 15) subcutaneously twice daily or placebo (n = 14). The study period was 8 weeks. Treatment was discontinued if there was no improvement at 4 weeks or at any disease progression. Primary outcome measure was clinical improvement at 8 weeks measured by the Colitis Activity Index (CAI) and the Clinical Symptoms Grading (CSG, based on the CAI). Endoscopic and histologic grading and quality of life as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) were secondary outcome measures. Patients were closely monitored for adverse events. Results: Twenty of 29 patients finished the 8-week treatment period (reviparin versus placebo: 11 versus 9; P = 0.70). There was no difference in CSG, CAI, endoscopic and histologic grading, or IBDQ. Treatment was well tolerated and no serious adverse events occurred. Conclusion: In this study, treatment with LMWH showed no significant clinical advantage compared to placebo in mild to moderately active UC. (Inflamm Bowel Dis 2007) [source] Establishment of the 1st World Health Organization international standards for human papillomavirus type 16 DNA and type 18 DNAINTERNATIONAL JOURNAL OF CANCER, Issue 12 2010Dianna E. Wilkinson Abstract A World Health Organization collaborative study was conducted to evaluate candidate international standards for human papillomavirus (HPV) Type 16 DNA (NIBSC code 06/202) and HPV Type 18 DNA (NIBSC code 06/206) for use in the amplification and detection steps of nucleic acid-based assays. The freeze-dried candidate international standards were prepared from bulk preparations of cloned plasmid containing full-length HPV-16 or HPV-18 genomic DNA. Nineteen laboratories from 13 countries participated in the study using a variety of commercial and in-house quantitative and qualitative assays. The data presented here indicate that, upon freeze-drying, there is no significant loss in potency for the candidate HPV-18 DNA and a slight loss in potency for the candidate HPV-16 DNA; although this is likely not scientifically relevant when assay precision is considered. In general, the individual laboratory mean estimates for each study sample were grouped ±,2 log10 around the theoretical HPV DNA concentration of the reconstituted ampoule (1 × 107 HPV genome equivalents/mL). The agreement between laboratories is improved when potencies are made relative to the candidate international standards, demonstrating their utility in harmonizing amplification and detection steps of HPV-16 and ,18 DNA assays. Degradation studies indicate that the candidate international standards are extremely stable and suitable for long-term use. Based on these findings, the candidate standards were established as the 1st WHO international standards for HPV-16 DNA and HPV-18 DNA, each with a potency of 5 × 106 international units (IU) per ampoule or 1 × 107 IU mL,1 when reconstituted as directed. [source] Venous thromboembolism in the medically ill patient: a call to actionINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 5 2005J.-F. Bergmann Summary The risk of venous thromboembolism (VTE) in medical patients is generally underestimated. However, recent studies including two large double-blind placebo-controlled trials, the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilised Patients trial (PREVENT) and prophylaxis in MEDical patients with ENOXaparin, study show that low-molecular-weight heparins (LMWHs) provide effective thromboprophylaxis for medical patients at risk from VTE without increasing the risk of bleeding. In PREVENT the significant 45%, reduction in VTE among patients receiving dalteparin 5000 IU once daily for 14 days was attributed entirely to a reduction in clinically relevant VTE. The recently published guidelines for the prevention and treatment of VTE, issued by the American College of Chest Physicians, recommend prophylaxis with LMWHs (or low-dose unfractionated heparin) in acutely ill medical patients with risk factors for VTE (grade 1A). Current evidence should encourage the more widespread adoption of thromboprophylaxis in at-risk medical patients, and thus reduce the number of preventable deaths and complications due to VTE. [source] Hereditary palmoplantar keratoderma (four cases in three generations)INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 2 2001Virendra N. Sehgal MD A 39-year-old man reported with progressive thickening of the skin of the hands and feet and an inability to flex his hand. It was largely asymptomatic; however, brisk walking caused excessive sweating, pain, and widening of the fissures on the soles of the feet. He was unable to walk barefooted. According to his mother, the first episode presented with blistering at 7 days of age. Ever since, the condition has steadily worsened to acquire the current status. He was married at the age of 18 years, and had a stillborn child 18 months afterwards. Presently, he has three children, two girls aged 14 and 12 years and a son aged 10 years. Both the daughters are similarly affected. While cataloguing the details of the pattern of inheritance, the mother of the index case was also found to be affected (Fig. 1). The natural history of the disease was identical. Figure 1. Palmoplantar keratoderma: pattern of inheritance; black indicates affected individuals Examination of the palms was marked by pronounced thickening of the skin resulting in the masking of palmar creases. The thickening was well demarcated and its margins were prominent and surrounded by an erythematous halo. The color of the skin was yellow and waxy (Fig. 2a). Contractures were present on all the fingers; nevertheless, the deformity of the middle and distal interphalangeal joints of the little finger was prominent. The soles of the feet had a similar morphology. In addition, marked fissuring was obvious (Fig. 2b). His daughters had an identical affliction of the palms and soles. The texture and morphology of the nails were normal. Light microscopy performed on scrapings from the fissures, mounted on 10% potassium hydroxide, revealed mycelia (hyphae) and spores. Figure 2. Well-demarcated hyperkeratosis depicting the yellow, waxy color of the palms, with masking of creases (a). Marked fissuring on the soles was prominent (b) Hematoxylin and eosin-stained microsections from the palms and soles showed exquisite changes in the epidermis characterized by considerable uniform orthohyperkeratosis. Hypergranulosis and acanthosis were other associated changes. In addition, perinuclear vacuolization and keratohyalin granules of varying sizes and shapes were located at the periphery of the cells. A sparse mononuclear infiltrate was located at the dermo-epidermal junction. Hyphae and spores of fungi were also identified in the stratum corneum (Fig. 3). Figure 3. Orthohyperkeratosis, hypergranulosis, and acanthosis. Perinuclear vacuolization and keratohyalin granules at the periphery of the cells; a sparse mononuclear infiltrate was also present (hematoxylin and eosin, ×,40 (a), ×,400 (b)) Itraconazole, 400 mg/day in two equally divided doses, was administered with major meals for 7 days. In addition, high doses of vitamin A (100,000 IU) were given daily for 2 weeks, supplemented by 12% salicylic acid (Salicylix SF12) ointment for daytime application and an ointment containing 6% coal tar and 3% salicylic acid (Salytar) for night-time application. This treatment is useful in recalcitrant cases. [source] Heterogeneity in Serum 25-Hydroxy-Vitamin D Response to Cholecalciferol in Elderly Women with Secondary Hyperparathyroidism and Vitamin D DeficiencyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 8 2010Andrea Giusti MD OBJECTIVES: To compare the effects on parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25(OH)D) of two dosing regimens of cholecalciferol in women with secondary hyperparathyroidism (sHPTH) and hypovitaminosis D and to investigate variables affecting 25(OH)D response to cholecalciferol. DESIGN: Randomized-controlled trial with 6-month follow-up. SETTING: Two osteoporosis centers in northern Italy. PARTICIPANTS: Sixty community-dwelling women aged 65 and older with sHPTH and hypovitaminosis D, creatinine clearance greater than 65 mL/min and without diseases or drugs known to influence bone and vitamin D metabolism. INTERVENTION: Cholecalciferol 300,000 IU every 3 months, once at baseline and once at 3 months (intermittent D3 group) or cholecalciferol 1,000 IU/day (daily D3 group). MEASUREMENTS: Serum PTH, 25(OH)D, calcium, bone-specific alkaline phosphatase, ,-C-terminal telopeptide of type I collagen, phosphate, 24-hour urinary calcium excretion. RESULTS: The two groups had similar baseline characteristics. All participants had vitamin D deficiency [25(OH)D<20 ng/mL)], and 36 subjects (60%) had severe deficiency (<10 ng/mL), with no difference between the groups (severe deficiency: intermittent D3 group, n=18; daily D3 group, n=18). After 3 and 6 months, both groups had a significant increase in 25(OH)D and a reduction in PTH. Mean absolute increase±standard deviation of 25(OH)D at 6 months was higher in the intermittent D3 group (22.7±11.8 ng/mL) than in the daily D3 group (13.7±6.7 ng/mL, P<.001), with a higher proportion of participants in the intermittent D3 group reaching desirable serum concentration of 25(OH)D , 30 ng/mL (55% in the intermittent D3 group vs 20% in the daily D3 group, P<.001). Mean percentage decrease of PTH in the two groups was comparable, and at 6 months, a similar proportion of participants reached normal PTH values. 25(OH)D response to cholecalciferol showed a wide variability. In a logistic regression analysis, body mass index and type of treatment appeared to be significantly associated with normalization of 25(OH)D values. CONCLUSION: Cholecalciferol 300,000 IU every 3 months was more effective than 1,000 IU daily in correcting vitamin D deficiency, although the two groups achieved similar effects on PTH at 6 months. Only 55% of the higher-dose intermittent group reached desirable concentrations of 25(OH)D, suggesting that yet-higher doses will be required for adequate vitamin D repletion. [source] Influence of high levels of vitamin E on semen parameters of cocksJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 11-12 2002S. Danikowski Summary This study was an attempt to find whether the reproductive performance of cocks would be influenced by oral administration of different amounts of dietary vitamin E over a long period of time. For that purpose 60 cocks were divided into five dietary groups of 12 animals each, and supplemented with 0 (control group), 100, 1000, 10 000 or 20 000 IU ,-tocopherol/kg diet, respectively, over a period of 12 months. The effect on semen parameters and biochemical parameters measured in pooled semen samples and the weight of the testes were determined. The weight of testes decreased with increasing amounts of supplemented vitamin E. Volume, pH, colour, consistency and motility were not influenced by the diets, but density of ejaculate (sperm/,l), total amount of spermatozoa and morphology of sperm were significantly lowered by increasing amounts of supplemented vitamin E. The ,-tocopherol concentration in ejaculates increased significantly in relation to the diet whereas phospholipid content and thiobarbituric acid-reactive substances (TBARS) of the semen samples decreased significantly with increasing vitamin E supplementation. The reproductive performance of cocks was negatively influenced by high doses of vitamin E although decreased TBARS indicated rising oxidative defence. [source] Wintertime Vitamin D Supplementation Inhibits Seasonal Variation of Calcitropic Hormones and Maintains Bone Turnover in Healthy Men,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2009Heli T Viljakainen Abstract Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21,49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 ± 5.1 (SD) ,g/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 ,g (800 IU), 10 ,g (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5,20 ,g (700,800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men. [source] Effect of Teriparatide {rhPTH(1-34)} on BMD When Given to Postmenopausal Women Receiving Hormone Replacement TherapyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2006Louis G Ste-Marie Abstract The effects of teriparatide when given in combination with HRT were studied in postmenopausal women with low bone mass or osteoporosis. The data provide evidence that the adverse event profile for combination therapy with teriparatide + HRT together is consistent with that expected for each treatment alone and that the BMD response is greater than for HRT alone. Introduction: Teriparatide {rhPTH(1-34)}, given as a once-daily injection, activates new bone formation in patients with osteoporosis. Hormone replacement therapy (HRT) prevents osteoporosis by reducing bone resorption and formation. Combination therapy with these two compounds, in small clinical trials, increased BMD and reduced vertebral fracture burden. The purpose of this study was to determine whether teriparatide provided additional effect on BMD when given in combination with HRT. Materials and Methods: A randomized, double-blind, placebo-controlled study was conducted in postmenopausal women with either low bone mass or osteoporosis. Patients were randomized to placebo subcutaneous plus HRT (n = 125) or teriparatide 40 ,g/day (SC) plus HRT (TPTD40 + HRT; n = 122) for a median treatment exposure of 13.8 months. Approximately one-half of the patients in each group were pretreated with HRT for at least 12 months before randomization. Patients received 1000 mg calcium and 400,1200 IU of vitamin D daily as oral supplementation. BMD was measured by DXA. Results: Compared with HRT alone, TPTD40 + HRT produced significant (p < 0.001) increases in spine BMD (14% versus 3%), total hip (5.2% versus 1.6%), and femoral neck (5.2% versus 2%) at study endpoint. BMD, in whole body and ultradistal radius, was higher, and in the one-third distal radius was lower, in the combination therapy but not in the HRT group. Serum bone-specific alkaline phosphatase and urinary N-telopeptide/Cr were increased significantly (p < 0.01) in the women receiving TPTD40 + HRT compared with HRT. A similar profile of BMD and bone markers was evident in both randomized patients as well as in subgroups of patients not pretreated or pretreated with HRT. Patients tolerated both the treatments well. Nausea and leg cramps were more frequently reported in the TPTD40 + HRT group. Conclusions: Adding teriparatide, a bone formation agent, to HRT, an antiresorptive agent, provides additional increases in BMD beyond that provided by HRT alone. The adverse effects of teriparatide when added to HRT were similar to the adverse effects described for teriparatide administered alone. Whether teriparatide was initiated at the same time as HRT or after at least 1 year on HRT, the incremental increases over HRT alone were similar. [source] Bioavailability and Biological Efficacy of a New Oral Formulation of Salmon Calcitonin in Healthy Volunteers,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2002Thierry Buclin Abstract Salmon calcitonin (SCT) is a well-tolerated peptide drug with a wide therapeutic margin and is administered parenterally for long-term treatments of bone diseases. Its clinical usefulness would be enhanced by the development of an orally active formulation. In this randomized crossover double-blinded phase I trial, controlled by both a placebo and a parenteral verum, we have tested a new oral formulation of SCT associated with a caprylic acid derivative as carrier. Eight healthy volunteers received single doses of 400, 800, and 1200 ,g of SCT orally, a placebo, and a 10-,g (50 IU) SCT intravenous infusion. SCT was reliably absorbed from the oral formulation, with an absolute bioavailability of 0.5,1.4%, depending on the dose. It induced a marked, dose-dependent drop in blood and urine C-terminal telopeptide of type I collagen (CTX), a sensitive and specific bone resorption marker, with the effects of 1200 ,g exceeding those of 10 ,g intravenously. It also decreased blood calcium and phosphate, and increased the circulating levels of parathyroid hormone (PTH) and, transiently, the urinary excretion of calcium. It was well-tolerated, with some subjects presenting mild and transient nausea, abdominal cramps, diarrheic stools, and headaches. This study shows that oral delivery of SCT is feasible with reproducible absorption and systemic biological efficacy. Such an oral formulation could facilitate the use of SCT in the treatment of osteoporosis and other bone diseases. [source] BEHAVIOR OF AVIRULENT YERSINIA PESTIS IN LIQUID WHOLE EGG AS AFFECTED BY STORAGE TEMPERATURE, ANTIMICROBIALS AND THERMAL PASTEURIZATIONJOURNAL OF FOOD SAFETY, Issue 3 2010JOSHUA B. GURTLER ABSTRACT Yersinia spp. are psychrotrophic bacteria capable of growth at temperatures as low as ,2C, known to contaminate shell eggs and liquid eggs in the U.S.A. and South America. A study was performed to determine the thermal sensitivity of avirulent Yersinia pestis in liquid whole egg (LWE), evaluate the growth pattern of the bacterium in LWE at temperatures of 4,22C and assess the ability of 10 antimicrobial compounds to inhibit the growth of attenuated Y. pestis in LWE. The estimated decimal reduction values of avirulent Y. pestis in LWE at 54C (D54) were 1.39,1.58 min, and D60 values were 13.8 and 11.4 s by the addition of 0 and 965 IU of nisin (MP Biomedicals, LLC, Solon, OH), respectively. Low molecular weight chitosan (0.5%) and an activated lactoperoxidase system (2.18 U/mL) were ineffective at inhibiting growth of Y. pestis, while 500 IU/mL of nisin inhibited populations by up to 1 log cfu/mL at 4, 10 and 15C when compared with the control. Allyl isothiocyanate, diacetyl, diethyl dicarbonate, ethylenediaminetetraacetic acid, methylparaben, monolaurin and benzoyl peroxide inhibited the growth of attenuated Y. pestis when added at high levels. PRACTICAL APPLICATIONS The genus Yersinia does not currently pose a problem in pasteurized liquid egg products, although it has been isolated from eggs in the U.S.A. and Argentina. Yersiniae, which are psychrotrophic bacteria, can grow at temperatures as low as ,2C; therefore, incidental or intentional contamination of liquid whole egg (LWE) with Yersinia spp. could result in multiplication to high populations, even when stored under refrigeration (ca. 4C). We have shown that avirulent Yersinia pestis is able to multiply to populations of >2, 5 and 8 log cfu/mL in LWE at 4C within 6, 14 and 26 days, respectively. This study provides information that will be helpful in determining thermal and nonthermal means of controlling yersiniae in LWE products. [source] Development of real-time detection direct test for hepatitis B virus and comparison with two commercial tests using the WHO international standardJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2003MOTOKAZU MUKAIDE Abstract Aims:, A highly reproducible and sensitive hepatitis B virus real-time detection direct (HBV RTD-direct) test using DNA extraction by magnetic beads coated with polyclonal anti-HBsAg, followed by the real-time detection polymerase chain reaction (PCR) method, was developed for the detection of HBV DNA. Methods:, The HBV DNA could be extracted from the HBsAg positive viral particles without resulting in viral DNA fragmentation. The HBV RTD-direct test was validated using a serial dilution panel of the WHO standard HBV DNA 97/746 I. Results:, The test had a dynamic range of 0.7,8.0 log10 international units (IU) per mL and the results were shown to be comparable to those obtained with two commercially available tests: the HBV DNA transcription-mediated amplification-hybridization protection assay and the Amplicor HBV Monitor test. In addition, the HBV RTD-direct test, based on magnetic extraction, successfully eliminated PCR inhibitors in clinical specimens. Conclusion:, We conclude that the HBV RTD-direct test is an excellent alternative for monitoring patients undergoing antiviral treatment or for screening various clinical specimens. [source] Prolonged activated partial thromboplastin time in thromboprophylaxis with unfractionated heparin in patients undergoing cesarean sectionJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 1 2010Shigeki Matsubara Abstract Aim:, Hemorrhage is an important complication of heparin-thromboprophylaxis after surgery. We attempted to clarify the incidence rate of prolonged activated partial thromboplastin time (APTT), representative of hemorrhagic tendency, in Japanese women who received thromboprophylaxis with unfractionated subcutaneous heparin administration after cesarean section (CS). We also determined factors which affected postoperative APTT. Methods:, We studied 280 women who were administered thromboprophylaxis with unfractionated subcutaneous heparin 5000 IU two times per day after CS. Postoperative APTT under heparin was measured and the incidence of its prolongation was determined. Preoperative APTT, blood loss during surgery, postoperative hematocrit, postoperative serum total protein level, and postpartum body weight were measured, and their correlation with postoperative APTT was determined. Results:, Preoperative and postoperative APTT values were 28.3 (26.7,30.3) and 33.8 (31.0,37.5) seconds for median (interquartile range), respectively. Overall, 7.1% of patients showed ,45 s postoperative APTT. Two patients (0.7%) showed ,60 s APTT, one of whom suffered subcutaneous hemorrhage around the abdominal incision with complete healing. There were no other hemorrhagic complications. Preoperative APTT positively, and postpartum body weight inversely, correlated with postoperative APTT. The amount of blood loss, postoperative hematocrit, and postoperative serum total protein level did not correlate with postoperative APTT. No discernible deep vein thrombosis or pulmonary embolism occurred. Conclusion:, Although 7.1% of women under heparin-thromboprophylaxis showed a prolonged APTT that was 150% of the preoperative APTT, serious side effects were not observed. Subcutaneous administration of unfractionated heparin, if checking APTT prolongation 1 day after surgery, may be safe method of thromboprophylaxis after CS. [source] Uterine preservation in a woman with spontaneous uterine rupture secondary to placenta percreta on the posterior wall: A case reportJOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH (ELECTRONIC), Issue 2 2009Le-Ming Wang Abstract Several cases in which uteruses have been preserved in women with placenta percreta have been reported. We herein report a 38-year-old woman with a history of previous cesarean section who was admitted with lower abdominal pain and vaginal bleeding at 31 weeks of gestation. An urgent exploratory laparotomy revealed active bleeding from the uterine rupture on the posterior uterine wall. A female infant weighing 1560 g, with Apgar scores of 1, 1, and 3 at 1, 5, and 10 min, respectively, was delivered, and the placenta was removed. We performed bilateral uterine vessel occlusion, followed by wedge resection of the ruptured uterine wall with the aid of an intrauterine muscle injection of 20 IU oxytocin, a local injection of diluted vasopressin (1:60) into the myometrium around and into the rupture site, and an intramuscular injection of 0.2 mg methylergonovine, primary repair of the defect, and an additional 24-h postoperative oxytocin infusion (30 IU in 5% dextrose 500 mL) to preserve the uterus successfully. Although the overall blood loss was 3700 mL, no disseminated intravascular coagulopathy occurred after the patient had received adequate blood transfusion. The postoperative pathological diagnosis was placenta percreta with uterine rupture. The patient and her baby were discharged uneventfully. In some cases of spontaneous uterine rupture secondary to placenta percreta, we can preserve the uterus by performing bilateral uterine vessel occlusion and wedge resection of the ruptured uterine wall. [source] Effect of chitosan on the intranasal absorption of salmon calcitonin in sheepJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2005Michael Hinchcliffe The effects of a chitosan-based delivery system on the pharmacokinetics of intranasally administered salmon calcitonin (sCT) were investigated in a sheep model. In particular, the feasibility of producing a formulation with a comparable or improved bioavailability and/or less variability than the currently marketed nasal product (Miacalcin nasal spray, Novartis Pharmaceuticals) was assessed. A comparator (control) formulation comprising sCT solution was also tested. Sheep (n = 6) were dosed intranasally according to a randomized crossover design. The intranasal sCT dose was 1100 IU (equivalent to approximately 17 IU kg,1). After completion of the nasal dosing legs, five of the sheep received 300 IU sCT (equivalent to approximately 5 IU kg,1) by subcutaneous injection to estimate relative bioavailability. After intranasal or subcutaneous dosing, serial blood samples were taken and plasma separated by centrifugation before measuring sCT concentrations by ELISA. Pharmacokinetic (non-compartmental) and statistical (analysis of variance or non-parametric alternative) analyses were performed. No systemic or local adverse effects were observed following intranasal or subcutaneous administration of sCT. The mean relative bioavailability of sCT from the chitosan solution was improved twofold compared with Miacalcin nasal spray and threefold compared with sCT control solution. Inter-animal variability in sCT absorption appeared to be lower with use of the chitosan-based solution compared with the control solution or commercial product. Based on the reported sheep data, a chitosan delivery system could offer the potential to significantly improve the intranasal absorption of sCT and reduce the variability in absorption. In the clinical setting, this may allow relatively lower doses of the drug to be given intranasally and/or lead to improvements in the efficacy or quality of intranasal therapy. [source] Evidence for lymphatic transport of insulin by topically applied biphasic vesiclesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2003Martin J. King ABSTRACT The cutaneous delivery pathway through the lymphatics of a novel transdermal lipid-based delivery system (biphasic vesicles), which was previously shown to deliver sustained physiological levels of basal insulin in a pain-free manner across the skin, was evaluated in a diabetic rat model. Transdermal patches (one per rat) containing insulin in biphasic vesicles (1,10 mg recombinant human insulin dose) were applied to the shaved abdominal skin of streptozotocin-induced diabetic rats for 73 h. Blood glucose was monitored approximately every 2,10 h using a Lifescan glucose meter. Inguinal lymph node insulin levels were analysed by ELISA. Insulin in the lymph nodes increased in a dose- and time-dependent manner. Maximal transdermal insulin concentrations in the lymph nodes were observed with both 140 IU (5 mg: 43.0 + 18.0 ,IU mg,1 (mean + s.e.m., n = 4)) and 280 IU (10 mg: 48.0 + 19.6 ,IU mg,1 (mean + s.e.m., n = 4)) doses of recombinant insulin at t = 73 h. The level of insulin in the lymph nodes after subcutaneous injection of 1 mg insulin at the peak blood glucose response was 35.8 ,IU mg,1 (n = 2), before falling to 0.35 ,IU mg,1 by t = 48 h (n = 2). The lymphatics is involved in the transdermal insulin delivery by biphasic vesicles. This is the first report on the lymphatic transport of a protein after non-invasive topical application on the skin. [source] A randomized, double-blind study of certoparin vs. unfractionated heparin to prevent venous thromboembolic events in acutely ill, non-surgical patients: CERTIFY StudyJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 6 2010H. RIESS Summary.,Background:,In medically ill patients, no contemporary double-blind head-to-head evaluation of low molecular weight heparin vs. unfractionated heparin (UFH) for the prevention of venous thromboembolic events is available. Objectives:,To compare the efficacy and safety of certoparin with those of UFH. Patients/Methods:,In this double-blind, randomized, controlled trial, acutely ill, non-surgical patients aged , 70 years were randomized to certoparin (3000 U of anti-factor Xa once daily) or to UFH (5000 IU t.i.d.). The primary endpoint was the composite of proximal deep vein thrombosis as assessed by bilateral compression ultrasonography, symptomatic non-fatal pulmonary embolism and venous thromboembolism-related death, and was assessed by a blinded central adjudication committee. Non-inferiority margins were set at 1.8 for the odds ratio (OR) and 3.45% for the absolute difference. Results:,Three thousand two hundred and thirty-nine patients aged 78.8 ± 6.3 years were treated for 9.1 ± 3.4 days. The incidence of the primary endpoint was 3.94% in the certoparin group and 4.52% in the UFH group, with a difference in proportions of , 0.59% [95% confidence interval (CI) ,2.09 to 0.92; P < 0.0001 for non-inferiority], and an OR of 0.87 (95% CI 0.60,1.26; P = 0.0001 for non-inferiority). Major bleeding occurred in 0.43% of certoparin-treated patients and 0.62% of UFH-treated patients (OR 0.69; 95% CI 0.26,1.83). Any bleeding occurred at 3.20% in certoparin-treated patients vs. 4.58% in UFH-treated patients (OR 0.69; 95% CI 0.48,0.99; P < 0.05), and 5.73% of certoparin-treated patients and 6.63% of UFH-treated patients experienced serious adverse events. All-cause mortality was 1.27% in certoparin-treated patients and 1.36% in UFH-treated patients. Conclusions:,In acutely ill, non-surgical elderly patients, thromboprophylaxis with certoparin (3000 U of anti-FXa once daily) was non-inferior to 5000 IU of UFH t.i.d., with a favorable safety profile. [source] | ||||||||||||||||||||||||||||||||||||||||