Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

Treatment of congenital extrahepatic portosystemic shunts in dogs : a systematic review and meta‐analysis

Background Several options have been proposed for the treatment of congenital extrahepatic portosystemic shunts (cEHPSS) in dogs, but formal comparisons among different treatment options are currently unavailable. A previous evidence-based review (2012) found low quality of evidence for papers assessing the treatment of cEHPSS in dogs. Objectives To assess the quality of evidence available in the treatment of cEHPSS, summarize the current state of knowledge with respect to outcome after cEHPSS management, and compare different treatment techniques. Animals Not used. Methods A bibliographic search was performed without date or language restrictions. Studies were assessed for quality of evidence (study design, study group sizes, subject enrollment quality, and overall risk of bias) and outcome measures reported (perioperative outcome, clinical outcome, and surgical or interventional outcome), all reported with 95% confidence intervals. A network meta-analysis was performed. Results Forty-eight studies were included. Six retrospective studies (grade 4b) compared 2 techniques and 7 were abstracts (grade 5). The quality of evidence was low and risk of bias high. Regarding surgical outcome, statistically significant superiority of ameroid constrictor over thin film band was observed (P = .003). No other comparisons were statistically significant. Conclusions and Clinical Importance The evidence base of choice of treatment of cEHPSS in dogs remains weak despite recent publications on the subject. Ameroid is superior to thin film band in causing EHPSS closure. Blinded randomized studies comparing different treatment modalities, which routinely include postoperative imaging to assess cEHPSS closure and acquired portosystemic shunt development are essential

The role of mothers-in-law in antenatal care decision-making in Nepal: a qualitative study

Background Antenatal care (ANC) has been recognised as a way to improve health outcomes for pregnant women and their babies. However, only 29% of pregnant women receive the recommended four antenatal visits in Nepal but reasons for such low utilisation are poorly understood. As in many countries of South Asia, mothers-in-law play a crucial role in the decisions around accessing health care facilities and providers. This paper aims to explore the mother-in-law’s role in (a) her daughter-in-law’s ANC uptake; and (b) the decision-making process about using ANC services in Nepal. Methods In-depth interviews were conducted with 30 purposively selected antenatal or postnatal mothers (half users, half non-users of ANC), 10 husbands and 10 mothers-in-law in two different (urban and rural) communities. Results Our findings suggest that mothers-in-law sometime have a positive influence, for example when encouraging women to seek ANC, but more often it is negative. Like many rural women of their generation, all mothers-in-law in this study were illiterate and most had not used ANC themselves. The main factors leading mothers-in-law not to support/ encourage ANC check ups were expectations regarding pregnant women fulfilling their household duties, perceptions that ANC was not beneficial based largely on their own past experiences, the scarcity of resources under their control and power relations between mothers-in-law and daughters-in-law. Individual knowledge and social class of the mothers-in-law of users and non-users differed significantly, which is likely to have had an effect on their perceptions of the benefits of ANC. Conclusion Mothers-in-law have a strong influence on the uptake of ANC in Nepal. Understanding their role is important if we are to design and target effective community-based health promotion interventions. Health promotion and educational interventions to improve the use of ANC should target women, husbands and family members, particularly mothers-in-law where they control access to family resources

What are we measuring? A critique of range of motion methods currently in use for Dupuytren's disease and recommendations for practice

Background: Range of motion is the most frequently reported measure used in practice to evaluate outcomes. A goniometer is the most reliable tool to assess range of motion yet, the lack of consistency in reporting prevents comparison between studies. The aim of this study is to identify how range of motion is currently assessed and reported in Dupuytren’s disease literature. Following analysis recommendations for practice will be made to enable consistency in future studies for comparability. This paper highlights the variation in range of motion reporting in Dupuytren’s disease. Methods: A Participants, Intervention, Comparison, Outcomes and Study design format was used for the search strategy and search terms. Surgery, needle fasciotomy or collagenase injection for primary or recurrent Dupuytren’s disease in adults were included if outcomes were monitored using range of motion to record change. A literature search was performed in May 2013 using subject heading and free-text terms to also capture electronic publications ahead of print. In total 638 publications were identified and following screening 90 articles met the inclusion criteria. Data was extracted and entered onto a spreadsheet for analysis. A thematic analysis was carried out to establish any duplication, resulting in the final range of motion measures identified. Results: Range of motion measurement lacked clarity, with goniometry reportedly used in only 43 of the 90 studies, 16 stated the use of a range of motion protocol. A total of 24 different descriptors were identified describing range of motion in the 90 studies. While some studies reported active range of motion, others reported passive or were unclear. Eight of the 24 categories were identified through thematic analysis as possibly describing the same measure, ‘lack of joint extension’ and accounted for the most frequently used. Conclusions: Published studies lacked clarity in reporting range of motion, preventing data comparison and meta-analysis. Percentage change lacks context and without access to raw data, does not allow direct comparison of baseline characteristics. A clear description of what is being measured within each study was required. It is recommended that range of motion measuring and reporting for Dupuytren’s disease requires consistency to address issues that fall into 3 main categories:- Definition of terms Protocol statement Outcome reportin

Back reaction, covariant anomaly and effective action

In the presence of back reaction, we first produce the one-loop corrections for the event horizon and Hawking temperature of the Reissner-Nordstr\"om black hole. Then, based on the covariant anomaly cancelation method and the effective action technique, the modified expressions for the fluxes of gauge current and energy momentum tensor, due to the effect of back reaction, are obtained. The results are consistent with the Hawking fluxes of a (1+1)-dimensional blackbody at the temperature with quantum corrections, thus confirming the robustness of the covariant anomaly cancelation method and the effective action technique for black holes with back reaction.Comment: 17 page

The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13 kb

Phase I study of dose-escalated paclitaxel, ifosfamide, and cisplatin (PIC) combination chemotherapy in advanced solid tumours

Based on the already known in vitro synergy between paclitaxel (taxol), cisplatin and oxazophosphorine cytostatics and the broad spectrum of activity of the above drugs we sought to evaluate the paclitaxel (taxol)-ifosfamide-cisplatin (PIC) combination in the outpatient setting in individuals with a variety of advanced solid tumours. Cohorts of patients were entered into six successive dose levels (DLs) with drug doses ranging as follows: paclitaxel 135–215 mg m−2day 1 – (1 h infusion), ifosfamide 4.5–6.0 g m−2(total dose) – divided over days 1 and 2, and cisplatin 80–100 mg m−2(total) – divided over days 1 and 2. Granulocyte colony-stimulating factor was given from day 5 to 14. Forty-two patients were entered. Eighteen patients had 2–8 cycles of prior chemotherapy with no taxanes or ifosfamide (cisplatin was allowed). The regimen was tolerated with outpatient administration in 36/42 patients. Toxicities included: grade 4 neutropenia for ≤ 5 days in 27% of cycles; 5 episodes of febrile neutropenia in three patients at DL-III, -V and -VI. Grade 3/4 thrombocytopenia and cumulative grade 3 anaemia were seen in 7% and 13% of cycles respectively. Three cases of severe grade 3 neuromotor/sensory neuropathy were recorded at DL-II, -III, and -V, all after cycle 3. The maximum tolerated dose was not formally reached at DL-V, but because of progressive anaemia and asthenia/fatigue, it was decided to test a new DL-VI with doses of paclitaxel 200 mg m−2, ifosfamide 5.0 g m−2and cisplatin 100 mg m−2; this appeared to be tolerable and is recommended for further phase II testing. The response rate was 47.5% (complete response + partial response: 20/42). The PIC regimen appears to be feasible and safe in the outpatient setting. Care should be paid to neurotoxicity. Phase II studies are starting in non-small-cell lung cancer, ovarian cancer and head and neck cancer at DL-VI. © 2000 Cancer Research Campaig

Profit and loss analysis for an intensive care unit (ICU) in Japan: a tool for strategic management

BACKGROUND: Accurate cost estimate and a profit and loss analysis are necessary for health care practice. We performed an actual financial analysis for an intensive care unit (ICU) of a university hospital in Japan, and tried to discuss the health care policy and resource allocation decisions that have an impact on critical intensive care. METHODS: The costs were estimated by a department level activity based costing method, and the profit and loss analysis was based on a break-even point analysis. The data used included the monthly number of patients, the revenue, and the direct and indirect costs of the ICU in 2003. RESULTS: The results of this analysis showed that the total costs of US$2,678,052 of the ICU were mainly incurred due to direct costs of 88.8$ 2,295,044. However, it was determined that the ICU required at least 1,986 patient days within one fiscal year based on a break-even point analysis. As a result, an annual deficit of US$ 383,008 has occurred in the ICU. CONCLUSION: These methods are useful for determining the profits or losses for the ICU practice, and how to evaluate and to improve it. In this study, the results indicate that most ICUs in Japanese hospitals may not be profitable at the present time. As a result, in order to increase the income to make up for this deficit, an increase of 437 patient days in the ICU in one fiscal year is needed, and the number of patients admitted to the ICU should thus be increased without increasing the number of beds or staff members. Increasing the number of patients referred from cooperating hospitals and clinics therefore appears to be the best strategy for achieving these goals

Electrocardiographic Left Ventricular Hypertrophy and Outcome in Hemodialysis Patients

BACKGROUND AND AIMS: Electrocardiography (ECG) is the most widely used initial screening test for the assessment of left ventricular hypertrophy (LVH), an independent predictor of cardiovascular mortality in patients with end-stage renal disease (ESRD). However, traditional ECG criteria based only on voltage to detect LVH have limited clinical utility for the detection of LVH because of their poor sensitivity. METHODS: This prospective observational study was undertaken to compare the prognostic significance of commonly used ECG criteria for LVH, namely Sokolow-Lyon voltage (SV) or voltage-duration product (SP) and Cornell voltage (CV) or voltage-duration product (CP) criteria, and to investigate the association between echocardiographic LV mass index (LVMI) and ECG-LVH criteria in ESRD patients, who consecutively started maintenance hemodialysis (HD) between January 2006 and December 2008. RESULTS: A total of 317 patients, who underwent both ECG and echocardiography, were included. Compared to SV and CV criteria, SP and CP criteria, respectively, correlated more closely with LVMI. In addition, CP criteria provided the highest positive predictive value for echocardiographic LVH. The 5-year cardiovascular survival rates were significantly lower in patients with ECG-LVH by each criterion. In multivariate analyses, echocardiographic LVH [adjusted hazard ratio (HR): 11.71; 95% confidence interval (CI): 1.57-87.18; P = 0.016] and ECG-LVH by SP (HR: 3.43; 95% CI: 1.32-8.92; P = 0.011) and CP (HR: 3.07; 95% CI: 1.16-8.11; P = 0.024) criteria, but not SV and CV criteria, were significantly associated with cardiovascular mortality. CONCLUSIONS: The product of QRS voltage and duration is helpful in identifying the presence of LVH and predicting cardiovascular mortality in incident HD patients