Belatacept does not inhibit follicular T cell-dependent B-cell differentiation in kidney transplantation

Humoral alloreactivity has been recognized as a common cause of kidney transplant dysfunction. B-cell activation, differentiation, and antibody production are dependent on IL-21+CXCR5+ follicular T-helper (Tfh) cells. Here, we studied whether belatacept, an inhibitor of the costimulatory CD28-CD80/86-pathway, interrupts the crosstalk between Tfh- and B-cells more efficiently than the calcineurin inhibitor tacrolimus. The suppressive effects of belatacept and tacrolimus on donor antigen-driven Tfh-B-cell interaction were functionally studied in peripheral blood mononuclear cells from 40 kidney transplant patients randomized to a belatacept- or tacrolimus-based immunosuppressive regimen. No significant differences in uncultured cells or donor antigen-stimulated cells were found between belatacept- and tacrolimus-treated patients in the CXCR5+Tfh cell generation and activation (upregulation of PD-1). Belatacept and tacrolimus in vitro minimally inhibited Tfh-cell generation (by ~6-7%) and partially prevented Tfh-cell activation (by ~30-50%). The proportion of IL-21+-activated Tfh-cells was partially decreased by in vitro addition of belatacept or tacrolimus (by ~60%). Baseline expressions and proportions of activated CD86+ B-cells, plasmablasts, and transitional B-cells after donor antigen stimulation did not differ between belatacept- and tacrolimus-treated patients. Donor antigen-drive

A Randomized Controlled Clinical Trial Comparing Belatacept With Tacrolimus After De Novo Kidney Transplantation

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Burden of cardiovascular disease across 29 countries and GPs' decision to treat hypertension in oldest-old

OBJECTIVES: We previously found large variations in general practitioner (GP) hypertension treatment probability in oldest-old (>80 years) between countries. We wanted to explore whether differences in country-specific cardiovascular disease (CVD) burden and life expectancy could explain the differences. DESIGN: This is a survey study using case-vignettes of oldest-old patients with different comorbidities and blood pressure levels. An ecological multilevel model analysis was performed. SETTING: GP respondents from European General Practice Research Network (EGPRN) countries, Brazil and New Zeeland. SUBJECTS: This study included 2543 GPs from 29 countries. MAIN OUTCOME MEASURES: GP treatment probability to start or not start antihypertensive treatment based on responses to case-vignettes; either low (/=50% started treatment). CVD burden is defined as ratio of disability-adjusted life years (DALYs) lost due to ischemic heart disease and/or stroke and total DALYs lost per country; life expectancy at age 60 and prevalence of oldest-old per country. RESULTS: Of 1947 GPs (76%) responding to all vignettes, 787 (40%) scored high treatment probability and 1160 (60%) scored low. GPs in high CVD burden countries had higher odds of treatment probability (OR 3.70; 95% confidence interval (CI) 3.00-4.57); in countries with low life expectancy at 60, CVD was associated with high treatment probability (OR 2.18, 95% CI 1.12-4.25); but not in countries with high life expectancy (OR 1.06, 95% CI 0.56-1.98). CONCLUSIONS: GPs' choice to treat/not treat hypertension in oldest-old was explained by differences in country-specific health characteristics. GPs in countries with high CVD burden and low life expectancy at age 60 were most likely to treat hypertension in oldest-old. Key Points * General practitioners (GPs) are in a clinical dilemma when deciding whether (or not) to treat hypertension in the oldest-old (>80 years of age). * In this study including 1947 GPs from 29 countries, we found that a high country-specific cardiovascular disease (CVD) burden (i.e. myocardial infarction and/or stroke) was associated with a higher GP treatment probability in patients aged >80 years. * However, the association was modified by country-specific life expectancy at age 60. While there was a positive association for GPs in countries with a low life expectancy at age 60, there was no association in countries with a high life expectancy at age 60. * These findings help explaining some of the large variation seen in the decision as to whether or not to treat hypertension in the oldest-old

Variation in GP decisions on antihypertensive treatment in oldest-old and frail individuals across 29 countries

BACKGROUND: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision. METHODS: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP. RESULTS: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs' decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48-0.59; ORs per country 0.11-1.78). CONCLUSIONS: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making

Разработка и обоснование бизнес-плана на открытие фитнес - клуба «Эталон»

Survey. (DOCX 49 kb

Tomato Spotted Wilt Virus Glycoproteins Exhibit Trafficking and Localization Signals That Are Functional in Mammalian Cells

The glycoprotein precursor (G1/G2) gene of tomato spotted wilt virus (TSWV) was expressed in BHK cells using the Semliki Forest virus expression system. The results reveal that in this cell system, the precursor is efficiently cleaved and the resulting G1 and G2 glycoproteins are transported from the endoplasmic reticulum (ER) to the Golgi complex, where they are retained, a process that could be blocked by tunicamycin. Expression of G2 alone resulted in transport to and retention in the Golgi complex, albeit less efficient, suggesting that G2 contains a Golgi retention signal. G1 alone was retained in the ER, irrespective of whether it contained the precursor's signal sequence or its own N-terminal hydrophobic sequence. Coexpression of G1 and G2 from separate gene constructs resulted in rescue of efficient G1 transport, as the proteins coaccumulated in the Golgi complex, indicating that their interaction is essential for proper targeting to this organelle. The results demonstrate that transport and targeting of the plant TSWV glycoproteins in mammalian BHK cells are strikingly similar to those of animal-infecting bunyavirus glycoproteins in mammalian cells. The observations are likely to reflect the dual tropism of TSWV, which replicates both in its plant host and in its animal (thrips) vector

Vérnyomáscsökkentés nagyon idős és esendő állapotú betegeknél: az alapellátásbeli gyakorlat kérdései = Variation in GP decisions on antihypertensive treatment

A vérnyomáscsökkentő terápiában a családorvosi gyakorlatban megmutatkozó eltérések elemzése érdekében 2543 családorvos bevonásával online kérdőíves felmérést végeztünk különböző karakterisztikájú – esendőség, SBP és CVD tekintetében –, nagyon idős (80 évesnél idősebb) betegek körében. Arra is kerestük a választ, hogy mennyire befolyásolja a kezelési döntésüket az időskori esendőség. A tanulmányunk másik célkitűzése a magyar eredmények összehasonlítása volt a nemzetközi eredményekkel. Országonként összehasonlításra került azon esetek aránya, amelyekben a kezelés mellett döntöttek a családorvosok. A 29 országból 24 országban (83%) a beteg esendő állapotát a családorvosok azzal a döntéssel kapcsolták össze, hogy inkább nem indítanak kezelést. A legalacsonyabb kezelési arány Hollandiában volt, a legmagasabb arány pedig Ukrajnában. Magyarország azon országok közé tartozott, ahol a családorvosok inkább kezelik az esendő pácienseket (a kezelési arány 50–59% között volt). A páciens esendősége nem befolyásolta a terápia megkezdését, sokkal jobban a cardiovascularis megbetegedés és a 160 Hgmm feletti SBP. A vizsgálat fontos üzenete volt, hogy továbbra is szükséges a családorvosok és a családorvos-rezidensek oktatása az idős, esendő hypertoniás betegek kezelésével kapcsolatban. = We conducted an online questionnaire survey with 2543 family physicians to analyse the variation in antihypertensive therapy among very elderly primary care patients (over 80 years of age) with different characteristics in terms of prevalence, SBP and CVD. We also sought answers to our question of how much their treatment decisions are influenced by their elderly frailty. Another aim of our study was to compare Hungarian results with international results. We compared the proportion of cases in which family doctors decided in favour of treatment across countries. In 24 of the 29 countries (83%), family physicians associated the patient's frailty with the decision not to initiate treatment. The lowest treatment rate was in the Netherlands and the highest rate in Ukraine. Hungary was one of the countries where family physicians preferred to treat patients with frailty (treatment rates ranged from 50-59%). Patient’s frailty did not influence the initiation of therapy, cardiovascular disease and SBP above 160 mmHg were more important. The main message from the study was the need for continued education of family physicians and family medicine residents on the management of elderly, frail hypertensive patients

Additional file 3: of Variation in GP decisions on antihypertensive treatment in oldest-old and frail individuals across 29 countries

Participating countries: number of invited GPs and response rates per country. (DOCX 21 kb