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Abstract: Oseltamivir phosphate (OP) is an antiviral drug that is used in the treatment and prophylaxis of both influenza A and influenza B. It is effective against all known influenza viruses than can infect humans, including pandemic influenza viruses and may be the most appropriate antiviral option against avian influenza caused by H5N1 virus. Tamiflu®, the registered trademark used under exclusive license by Roche laboratories with OP as active pharmaceutical ingredient, is considered the best treatment for the bird flu disease. A simple, selective, linear, accurate and precise HPLC method was developed and validated for rapid assay of OP aimed to the quality control of Tamiflu® capsules and generic versions. Isocratic elution at a flow rate of 1.2mL/min was employed on a Zorbax CN column (150mm×4.6mm; 5μm) at ambient temperature. The mobile phase consisted of methanol and 0.04M formic acid pH 3.0 (50:50, v/v). The UV detection wavelength was 226nm and 20μL of sample was injected. Sotalol hydrochloride was used as the internal standard (IS). The retention times for OP and IS were 3.40 and 2.25min, respectively. The method was successfully applied to commercial pharmaceuticals, Tamiflu® and generic versions. The proposed method could be applicable for routine analysis of OP and monitoring of the quality of marketed drugs as possibly counterfeit Tamiflu®. [Copyright &y& Elsevier]

Background: The relationship between depression and low blood pressure in unclear.Aims: To examine the temporal relation between low blood pressure and depression in a two-year follow-up.Method: The study group consisted of 1389 subjects aged 59-71 years; 1272 (92%) were examined after two years. Subjects completed the Center for Epidemiological Studies-Depression (CES-D) and the Spielberger inventory scales to assess depressive and anxiety symptoms respectively. Data were collected on socio-demographic characteristics, smoking and drinking habits, medical history, drug use and blood pressure measures.Results: Among 1112 subjects who were considered as non-depressed at baseline, logistic regression models showed that low diastolic blood pressure (DBP) and decrease of blood pressure were predictors of high depressive symptomatology at follow-up. Baseline high CES-D scores did not predict low blood pressure two years after.Conclusions: In our study, low blood pressure was a risk factor for, but not a consequence of, high depressive symptomatology. [ABSTRACT FROM AUTHOR]

Rationale & Objective: Outcomes of kidney transplantation for patients with renal AA amyloidosis are uncertain, with reports of poor survival and high rates of disease recurrence. However, the data are inconclusive and mostly based on studies from the early 2000s and earlier., Study Design: Retrospective multicenter cohort study., Setting & Participants: We searched the French national transplant database to identify all patients with renal AA amyloidosis who underwent kidney transplantation between 2008 and 2018., Exposures: Age, cause of amyloidosis, use of biotherapies, and C-reactive protein levels., Outcomes: Outcomes were all-cause mortality and allograft loss. We also reported amyloidosis allograft recurrence, occurrence of acute rejection episodes, as well as infectious, cardiovascular, and neoplastic disease events., Analytical Approach: Kaplan-Meier estimator for mortality and cumulative incidence function method for allograft loss. Factors associated with patient and allograft survival were investigated using a Cox proportional hazards model and a cause-specific hazards model, respectively., Results: 86 patients who received kidney transplants for AA amyloidosis at 26 French centers were included. The median age was 49.4 years (IQR, 39.7-61.1). The main cause of amyloidosis was familial Mediterranean fever (37 cases; 43%). 16 (18.6%) patients received biotherapy after transplantation. Patient survival rates were 94.0% (95% CI, 89.1-99.2) at 1 year and 85.5% (77.8-94.0) at 5 years after transplantation. Cumulative incidences of allograft loss were 10.5% (4.0-17.0) at 1 year and 13.0% (5.8-20.1) at 5 years after transplantation. Histologically proven AA amyloidosis recurrence occurred in 5 transplants (5.8%). An infection requiring hospitalization developed in 55.8% of cases, and there was a 27.9% incidence of acute allograft rejection. Multivariable analysis showed that C-reactive protein concentration at the time of transplantation was associated with patient survival (HR, 1.01; 95% CI, 1.00-1.02; P=0.01) and allograft survival (HR, 1.68; 95% CI, 1.10-2.57; P=0.02)., Limitations: The study lacked a control group, and the effect of biotherapies on transplantation outcomes could not be explored., Conclusions: This relatively contemporary cohort of patients who received a kidney transplant for AA amyloidosis experienced favorable rates of survival and lower recurrence rates than previously reported. These data support the practice of treating these patients with kidney transplantation for end-stage kidney disease., Plain-Language Summary: AA amyloidosis is a severe and rare disease. Kidney involvement is frequent and leads to end-stage kidney disease. Because of the involvement of other organs, these patients are often frail, which has raised concerns about their suitability for kidney transplantation. We reviewed all patients with AA amyloidosis nephropathy who underwent kidney transplantation in France in the recent era (2008-2018) and found that the outcomes after kidney transplantation were favorable, with 85.5% of patients still alive 5 years after transplantation, a survival rate that is comparable to the outcomes of patients receiving a transplant for other forms of kidney diseases. Recurrence of amyloidosis in the transplanted kidney was infrequent (5.8%). These data support the practice of kidney transplantation for patients with AA amyloidosis who experience kidney failure., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Analysing the nutritional and environmental impacts of our current diets and promoting sustainable dietary shifts require quantified data on the characteristics of foods. We have jointly studied environmental and nutritional performances of more than 200 generic foods consumed in France, by combining and completing different databases. Several environmental issues calculated by Life Cycle Assessment (LCA) were selected, including impacts on biodiversity. This required to (1) model diets for given subpopulations; (2) adapt the LCA database of food products, Agribalyse 3.0, to link selected food and environmental inventories (3) compile characterization factors to assess impacts on biodiversity. Additionally, modifying Agribalyse 3.0 required to also modify the characterization method on Land Competition. This data paper compiles all the data used to obtain the results presented in the companion article entitled: Environmental trade-offs of fulfilling nutritionally adequacy with reduced animal protein share for French adult populations [1] ; i.e. (i) the characterization methods used, (ii) the modifications made to Agribalyse 3.0 and (iii) the nutrient content and quantities consumed of generic foods (iv) the optimized quantities of simulated diets reaching nutrient recommendations with low share of animal-based proteins. It also comprises (iv) Life Cycle Impact Assessment for all Agribalyse 3.0 processes of food having a CIQUAL code (2,497 processes)., (© 2023 The Author(s).)

Notch signaling is a conserved signaling pathway that participates in many aspects of mammary gland development and homeostasis, and has extensively been associated with breast tumorigenesis. Here, to unravel the as yet debated role of Notch3 in breast cancer development, we investigated its expression in human breast cancer samples and effects of its loss in mice. Notch3 expression was very weak in breast cancer cells and was associated with good patient prognosis. Interestingly, its expression was very strong in stromal cells of these patients, though this had no prognostic value. Mechanistically, we demonstrated that Notch3 prevents tumor initiation via HeyL-mediated inhibition of Mybl2, an important regulator of cell cycle. In the mammary glands of Notch3-deficient mice, we observed accelerated tumor initiation and proliferation in a MMTV-Neu model. Notch3-null tumors were enriched in Mybl2 mRNA signature and protein expression. Hence, our study reinforces the anti-tumoral role of Notch3 in breast tumorigenesis., (© 2023. The Author(s).)

Primary membranous nephropathy (MN) is an autoimmune glomerular disease in which autoantibodies are directed against podocyte proteins. In about 80% of cases the main targeted antigen is the phospholipase A2 receptor 1 (PLA2R1). Anti-PLA2R1 antibodies are mainly immunoglobulin G type 4 (IgG4). However, the antigenic target remains to be defined in 20% of cases. MN can be associated with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system where a common antigenic target has yet to be identified. To ascertain a possible novel target antigen, we analyzed kidney biopsies from five patients positive for anti-contactin 1 antibodies and presenting with MN combined with chronic inflammatory demyelinating polyneuropathy. Eluted IgG from biopsy sections against contactin 1 and nerve tissue were screened. Western blot revealed contactin 1 expression in normal kidney glomeruli. Confocal microscopic analysis showed the presence and colocalization of contactin 1 and IgG4 on the glomerular basement membrane of these patients. Glomerular contactin 1 was absent in patients with anti-PLA2R1-associated MN or membranous lupus nephritis or a healthy control. The eluted IgG from contactin 1-positive biopsy sections but not the IgG eluted from patients with PLA2R1 MN bound contactin 1 with the main eluted subclass IgG4. Eluted IgG could bind paranodal tissue (myelinated axon) and colocalized with commercial anti-contactin 1 antibody. Thus, contactin 1 is a novel common antigenic target in MN associated with chronic inflammatory demyelinating polyneuropathy. However, the precise pathophysiology remains to be elucidated., (Copyright © 2021. Published by Elsevier Inc.)

Background and Objectives: Presymptomatic testing is available for early diagnosis of hereditary autosomal dominant polycystic kidney disease (ADPKD). However, the complex ethical and psychosocial implications can make decision-making challenging and require an understanding of patients' values, goals and priorities. This study aims to describe patient and caregiver beliefs and expectations regarding presymptomatic testing for ADPKD., Design, Setting and Participants: 154 participants (120 patients and 34 caregivers) aged 18 years and over from eight centres in Australia, France and Korea participated in 17 focus groups. Transcripts were analysed thematically., Results: We identified five themes: avoiding financial disadvantage (insecurity in the inability to obtain life insurance, limited work opportunities, financial burden); futility in uncertainty (erratic and diverse manifestations of disease limiting utility, taking preventive actions in vain, daunted by perplexity of results, unaware of risk of inheriting ADPKD); lacking autonomy and support in decisions (overwhelmed by ambiguous information, medicalising family planning, family pressures); seizing control of well-being (gaining confidence in early detection, allowing preparation for the future, reassurance in family resilience); and anticipating impact on quality of life (reassured by lack of symptoms, judging value of life with ADPKD)., Conclusions: For patients with ADPKD, presymptomatic testing provides an opportunity to take ownership of their health through family planning and preventive measures. However, these decisions can be wrought with tensions and uncertainty about prognostic implications, and the psychosocial and financial burden of testing. Healthcare professionals should focus on genetic counselling, mental health and providing education to patients' families to support informed decision-making. Policymakers should consider the cost burden and risk of discrimination when informing government policies. Finally, patients are recommended to focus on self-care from an early age., Competing Interests: Competing interests: GKR declares he is site investigator of clinical trials sponsored by Sanofi, Otsuka and Reata, principal investigator of the PREVENT-ADPKD clinical trial (funded in part by the NHMRC, Danone Nutricia—manufacturer of bottled water—PKD Australia, Westmead Medical Research Foundation) and Chair, Scientific Advisory Board, PKD Australia. RP declares he is site investigator of clinical trials sponsored by Sanofi, Kadmon, Reata, Otsuka and the US Department of Defense (TAME PKD), and section editor for Cystic Kidney Disease, UpToDate., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale & Objective: Trials in autosomal dominant polycystic kidney disease (ADPKD) have increased, but their impact on decision making has been limited. Because heterogeneity in reported outcomes may be responsible, we assessed their range and variability in ADPKD trials., Study Design: Systematic review., Setting & Study Population: Adult participants in clinical trials in ADPKD., Selection Criteria for Studies: We included trials that studied adults and were published in English. For trials that enrolled patients without ADPKD, only those enrolling ≥50% of participants with ADPKD were included., Data Extraction: We extracted information on all discrete outcome measures, grouped them into 97 domains, and classified them into clinical, surrogate, and patient-reported categories. For each category, we choose the 3 most frequently reported domains and performed a detailed analysis of outcome measures., Analytical Approach: Frequencies and characteristics of outcome measures were described., Results: Among 68 trials, 1,413 different outcome measures were reported. 97 domains were identified; 41 (42%) were surrogate, 30 (31%) were clinical, and 26 (27%) were patient reported. The 3 most frequently reported domains were in the surrogate category: kidney function (54; 79% of trials; using 46 measures), kidney and cyst volumes (43; 63% of trials; 52 measures), and blood pressure (27; 40% of trials, 30 measures); in the clinical category: infection (10; 15%; 21 measures), cardiovascular events (9; 13%; 6 measures), and kidney failure requiring kidney replacement therapy (8; 12%; 5 measures); and in the patient-reported category: pain related to ADPKD (16; 24%; 26 measures), pain for other reasons (11; 16%; 11 measures), and diarrhea/constipation/gas (10; 15%; 9 measures)., Limitations: Outcome measures were assessed for only the top 3 domains in each category., Conclusions: The outcomes in ADPKD trials are broad in scope and highly variable. Surrogate outcomes were most frequently reported. Patient-reported outcomes were uncommon. A consensus-based set of core outcomes meaningful to patients and clinicians is needed for future ADPKD trials., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Aim: Patients with autosomal dominant polycystic kidney disease (ADPKD) are at increased risk of premature mortality, morbidities and complications, which severely impair quality of life. However, patient-centered outcomes are not consistently reported in trials in ADPKD, which can limit shared decision-making. We aimed to identify outcomes important to patients and caregivers and the reasons for their priorities., Methods: Nominal group technique was adopted involving patients with ADPKD and caregivers who were purposively selected from eight centres across Australia, France and the Republic of Korea. Participants identified, ranked and discussed outcomes for trials in ADPKD. We calculated an importance score (0-1) for each outcome and conducted thematic analyses., Results: Across 17 groups, 154 participants (121 patients, 33 caregivers) aged 19 to 78 (mean 54.5 years) identified 55 outcomes. The 10 highest ranked outcomes were: kidney function (importance score 0.36), end-stage kidney disease (0.32), survival (0.21), cyst size/growth (0.20), cyst pain/bleeding (0.18), blood pressure (0.17), ability to work (0.16), cerebral aneurysm/stroke (0.14), mobility/physical function (0.12), and fatigue (0.12). Three themes were identified: threatening semblance of normality, inability to control and making sense of diverse risks., Conclusion: For patients with ADPKD and their caregivers, kidney function, delayed progression to end-stage kidney disease and survival were the highest priorities, and were focused on achieving normality, and maintaining control over health and lifestyle. Implementing these patient-important outcomes may improve the meaning and relevance of trials to inform clinical care in ADPKD., (© 2019 Asian Pacific Society of Nephrology.)

JIP1 was first identified as scaffold protein for the MAP kinase JNK and is a cargo protein for the kinesin1 molecular motor. JIP1 plays significant and broad roles in neurons, mainly as a regulator of kinesin1-dependent transport, and is associated with human pathologies such as cancer and Alzheimer disease. JIP1 is specifically recruited by the kinesin-light chain 1 (KLC1) of kinesin1, but the details of this interaction are not yet fully elucidated. Here, using calorimetry, we extensively biochemically characterized the interaction between KLC1 and JIP1. Using various truncated fragments of the tetratricopeptide repeat (TPR) domain of KLC1, we narrowed down its JIP1-binding region and identified seven KLC1 residues critical for JIP1 binding. These isothermal titration calorimetry (ITC)-based binding data enabled us to footprint the JIP1-binding site on KLC1-TPR. This footprint was used to uncover the structural basis for the marginal inhibition of JIP1 binding by the autoinhibitory LFP-acidic motif of KLC1, as well as for the competition between JIP1 and another cargo protein of kinesin1, the W-acidic motif-containing alcadein-α. Also, we examined the role of each of these critical residues of KLC1 for JIP1 binding in light of the previously reported crystal structure of the KLC1-TPR:JIP1 complex. Finally, sequence search in eukaryotic genomes identified several proteins, among which is SH2D6, that exhibit a motif similar to the KLC1-binding motif of JIP1. Overall, our extensive biochemical characterization of the KLC:JIP1 interaction, as well as identification of potential KLC1-binding partners, improves the understanding of how this growing family of cargos is recruited to kinesin1 by KLC1., (© 2018 Nguyen et al.)

The group specificity a of HBsAg is responsible for the induction of protective antibodies. Several synthetic peptides for vaccination are in preparation. It is not known if the structure of the epitope(s) implied in specificity a is continuous or discontinuous. For this analysis, we have prepared six monoclonal anti-a antibodies (all belonging to the IgG1 subclass) which precipitated native HBsAg and agglutinated sensitized red blood cells. The antibody affinities ranged from 1.2 X 10(9) to 10 X 10(10) 1/M. These monoclonal antibodies were comparatively tested against native radioiodinated HBsAg and polypeptides obtained from HBsAg after reduction and alkylation. Two antibodies with low affinity continued to bind about 40% of polypeptides (compared to 94% retained by polyclonal antibodies). Three antibodies with higher affinity did not bind any polypeptide under the same conditions. When an inhibition technique was used, the two antibodies binding the polypeptides could be inhibited by polypeptides in their reaction with HBsAg. For the other antibodies, polypeptides did not inhibit the reaction with HBsAg. These results show that continuous and discontinuous epitopes are implied in specificity a of HBsAg. Therefore, for effective synthetic vaccines, mere synthesis of peptides corresponding to selected sequences of the primary structure of the protein may not be sufficient and a sophisticated mimicking of a conformational epitope might also be necessary.

A simple method, allowing easy detection of abnormally increased sIgA levels is described. It consists in quantitation of combined SC by gel double diffusion, using appropriate anti-SC immune sera. The technical conditions, locating the threshold of sensitivity of precipitation at about 25 microgram/ml, a value higher than that found in normal sera, were established. Comparison with other classical methods (SRID, ELISA and IHA) emphasizes the validity and simplicity of the technique which has shown convenient whenever a large number of sera have to be tested.