Reduced Cardiovascular Reserve in Chronic Kidney Failure: A Matched Cohort Study

Background: Patients with chronic kidney failure (CKF) experience impaired functional cardiovascular reserve with reduced oxygen consumption at peak exercise (Vo2peak). No studies have examined whether this is related to impaired cardiovascular compliance as a consequence of loss of adaptive structural alterations, resulting from chronic uremia or hypertension. Study Design: Prospective matched-cohort study. Setting & Participants: We assessed CKF in parallel with patients with essential hypertension but without cardiovascular disease. Patients with CKF were either scheduled for kidney transplantation or transplant waitlisted. 80 patients with CKF and 80 with essential hypertension matched in age, sex, and body mass index were evaluated. 61 patients with CKF (76.3%) were dialysis dependent. Predictor: CKF versus essential hypertension without cardiovascular disease. Measurements & Outcomes: Vo2peak was measured during maximal exercise testing. 2-dimensional echocardiography and arterial applanation tonometry were performed prior to exercise testing. To evaluate for the difference in Vo2peak between study groups, statistically significant predictors of Vo2peak in multiple regression models were additionally assessed by fitting models comprising the interaction term of patient group with the predictor variable of interest. Results: Vo2peak was significantly lower in patients with CKF than those with essential hypertension (18.8 vs 24.5 mL/min·kg; P < 0.001). Independent predictors of Vo2peak for CKF included left ventricular (LV) filling pressure (E/mean e′; unstandardized regression coefficient: change in Vo2peak [in mL/min·kg] per 1-unit change of variable = −5.1) and pulse wave velocity (−4.0); in essential hypertension, these were LV mass index (0.2), LV end-diastolic volume index (0.4), peak heart rate (0.2), and pulse wave velocity (−8.8). The interaction effect of Vo2peak between patient groups with LV mass index (P < 0.001), LV end-diastolic volume index (P < 0.001), and peak heart rate (P < 0.01) were significantly stronger in the hypertension group, whereby higher values led to greater Vo2peak. Limitations: Skeletal muscle strength was not assessed. Conclusion: This study suggests that maladaptive LV changes, as well as blunted chronotropic response, are important mechanistic factors resulting in reduced cardiovascular reserve in patients with CKF, beyond predominantly vascular changes associated with hypertension

Mouse models for preeclampsia: disruption of redox-regulated signaling

The concept that oxidative stress contributes to the development of human preeclampsia has never been tested in genetically-defined animal models. Homozygous deletion of catechol-Omethyl transferase (Comt-/-) in pregnant mice leads to human preeclampsia-like symptoms (high blood pressure, albuminurea and preterm birth) resulting from extensive vasculo-endothelial pathology, primarily at the utero-fetal interface where maternal cardiac output is dramatically increased during pregnancy. Comt converts estradiol to 2-methoxyestradiol 2 (2ME2) which counters angiogenesis by depleting hypoxia inducible factor-1 alpha (HIF-1 alpha) at late pregnancy. We propose that in wild type (Comt++) pregnant mice, 2ME2 destabilizes HIF-1 alpha by inhibiting mitochondrial superoxide dismutase (MnSOD). Thus, 2ME2 acts as a pro-oxidant, disrupting redox-regulated signaling which blocks angiogenesis in wild type (WT) animals in physiological pregnancy. Further, we suggest that a lack of this inhibition under normoxic conditions in mutant animals (Comt-/-) stabilises HIF-1 alpha by inactivating prolyl hydroxlases (PHD). We predict that a lack of inhibition of MnSOD, leading to persistent accumulation of HIF-1 alpha, would trigger inflammatory infiltration and endothelial damage in mutant animals. Critical tests of this hypothesis would be to recreate preeclampsia symptoms by inducing oxidative stress in WT animals or to ameliorate by treating mutant mice with Mn-SOD-catalase mimetics or activators of PHD

T-Bet and Eomes Regulate the Balance between the Effector/Central Memory T Cells versus Memory Stem Like T Cells

Memory T cells are composed of effector, central, and memory stem cells. Previous studies have implicated that both T-bet and Eomes are involved in the generation of effector and central memory CD8 T cells. The exact role of these transcription factors in shaping the memory T cell pool is not well understood, particularly with memory stem T cells. Here, we demonstrate that both T-bet or Eomes are required for elimination of established tumors by adoptively transferred CD8 T cells. We also examined the role of T-bet and Eomes in the generation of tumor-specific memory T cell subsets upon adoptive transfer. We showed that combined T-bet and Eomes deficiency resulted in a severe reduction in the number of effector/central memory T cells but an increase in the percentage of CD62LhighCD44low Sca-1+ T cells which were similar to the phenotype of memory stem T cells. Despite preserving large numbers of phenotypic memory stem T cells, the lack of both of T-bet and Eomes resulted in a profound defect in antitumor memory responses, suggesting T-bet and Eomes are crucial for the antitumor function of these memory T cells. Our study establishes that T-bet and Eomes cooperate to promote the phenotype of effector/central memory CD8 T cell versus that of memory stem like T cells. © 2013 Li et al

Occupational correlates of smoking among urban transit operators: A prospective study

<p>Abstract</p> <p>Background</p> <p>Workers in blue-collar and service occupations smoke at higher rates than workers in white-collar and professional occupations. Occupational stress may explain some of the occupational class differences in smoking and quitting behavior. The purpose of this study is to investigate the contribution of occupational factors to smoking behavior over a ten year period among a multiethnic cohort of urban transit operators, while accounting for demographic factors and alcohol.</p> <p>Methods</p> <p>The sample consists of 654 San Francisco Municipal Railway (MUNI) transit operators who participated in two occupational health studies and biennial medical examinations during 1983–85 and 1993–95. Workers who had initiated, increased, or maintained their smoking over the ten year period were compared to workers who remained non-smokers. Occupational factors included self-rated frequency of job problems (e.g., difficulties with equipment, passengers, traffic), job burnout (i.e., the emotional exhaustion subscale of the Maslach Burnout Inventory), time needed to unwind after work, and years employed as a transit operator. A series of logistic regression models were developed to estimate the contribution of occupational factors to smoking behavior over time.</p> <p>Results</p> <p>Approximately 35% of the workers increased, initiated, or maintained their smoking over the ten-year period. Frequency of job problems was significantly associated with likelihood of smoking increase, initiation, or maintenance (OR = 1.30; 95% CI 1.09, 1.55). Black operators were significantly more likely to have smoked over the ten-year period compared to operators in other racial/ethnic groups.</p> <p>Conclusion</p> <p>Understanding the role of work-related stress vis-à-vis smoking behavior is of critical importance for crafting workplace smoking prevention and cessation interventions that are applicable to blue-collar work settings, and for developing policies that mitigate occupational stress.</p

Supportive interventions to improve physiological and psychological health outcomes among patients undergoing cystectomy: A systematic review

Background Our understanding of effective perioperative supportive interventions for patients undergoing cystectomy procedures and how these may affect short and long-term health outcomes is limited. Methods Randomised controlled trials involving any non-surgical, perioperative interventions designed to support or improve the patient experience for patients undergoing cystectomy procedures were reviewed. Comparison groups included those exposed to usual clinical care or standard procedure. Studies were excluded if they involved surgical procedure only, involved bowel preparation only or involved an alternative therapy such as aromatherapy. Any short and long-term outcomes reflecting the patient experience or related urological health outcomes were considered. Results 19 articles (representing 15 individual studies) were included for review. Heterogeneity in interventions and outcomes across studies meant meta-analyses were not possible. Participants were all patients with bladder cancer and interventions were delivered over different stages of the perioperative period. The overall quality of evidence and reporting was low and outcomes were predominantly measured in the short-term. However, the findings show potential for exercise therapy, pharmaceuticals, ERAS protocols, psychological/educational programmes, chewing gum and nutrition to benefit a broad range of physiological and psychological health outcomes. Conclusions Supportive interventions to date have taken many different forms with a range of potentially meaningful physiological and psychological health outcomes for cystectomy patients. Questions remain as to what magnitude of short-term health improvements would lead to clinically relevant changes in the overall patient experience of surgery and long-term recovery

Traditional knowledge on zootherapeutic uses by the Saharia tribe of Rajasthan, India

The present zootherapeutic study describes the traditional knowledge related to the use of different animals and animal-derived products as medicines by the Saharia tribe reside in the Shahabad and Kishanganj Panchayat Samiti's of Baran district of Rajasthan, India. A field survey was conducted from April to June 2006 by performing interview through structured questionnaire with 21 selected respondents, who provided information regarding use of animals and their products in folk medicine. A total of 15 animal species were recorded and they are used for different ethnomedical purposes, including cough, asthma, tuberculosis, paralysis, earache, herpes, weakness, muscular pain etc. The zootherapeutic knowledge was mostly based on domestic animals, but some protected species like the peacock (Pavo cristatus,), hard shelled turtle (Kachuga tentoria), sambhar (Cervus unicolor) were also mentioned as medicinal resources. We would suggest that this kind of neglected traditional knowledge should be included into the strategies of conservation and management of faunistic resources. Further studies are required for experimental validation to confirm the presence of bioactive compounds in these traditional remedies and also to emphasize more sustainable use of these resources

Cardiovascular Functional Reserve Before and After Kidney Transplant.

Importance: Restitution of kidney function by transplant confers a survival benefit in patients with end-stage renal disease. Investigations of mechanisms involved in improved cardiovascular survival have relied heavily on static measures from echocardiography or cardiac magnetic resonance imaging and have provided conflicting results to date. Objectives: To evaluate cardiovascular functional reserve in patients with end-stage renal disease before and after kidney transplant and to assess functional and morphologic alterations of structural-functional dynamics in this population. Design, Setting, and Participants: This prospective, nonrandomized, single-center, 3-arm, controlled cohort study, the Cardiopulmonary Exercise Testing in Renal Failure and After Kidney Transplantation (CAPER) study, included patients with stage 5 chronic kidney disease (CKD) who underwent kidney transplant (KTR group), patients with stage 5 CKD who were wait-listed and had not undergone transplant (NTWC group), and patients with hypertension only (HTC group) seen at a single center from April 1, 2010, to January 1, 2013. Patients were followed up longitudinally for up to 1 year after kidney transplant. Clinical data collection was completed February 2014. Data analysis was performed from June 1, 2014, to March 5, 2015. Further analysis on baseline and prospective data was performed from June 1, 2017, to July 31, 2019. Main Outcomes and Measures: Cardiovascular functional reserve was objectively quantified using state-of-the-art cardiopulmonary exercise testing in parallel with transthoracic echocardiography. Results: Of the 253 study participants (mean [SD] age, 48.5 [12.7] years; 141 [55.7%] male), 81 were in the KTR group, 85 in the NTWC group, and 87 in the HTC group. At baseline, mean (SD) maximum oxygen consumption (V̇O2max) was significantly lower in the CKD groups (KTR, 20.7 [5.8] mL · min-1 · kg-1; NTWC, 18.9 [4.7] mL · min-1 · kg-1) compared with the HTC group (24.9 [7.1] mL · min-1 · kg-1) (P < .001). Mean (SD) cardiac left ventricular mass index was higher in patients with CKD (KTR group, 104.9 [36.1] g/m2; NTWC group, 113.8 [37.7] g/m2) compared with the HTC group (87.8 [16.9] g/m2), (P < .001). Mean (SD) left ventricular ejection fraction was significantly lower in the patients with CKD (KTR group, 60.1% [8.6%]; NTWC group, 61.4% [8.9%]) compared with the HTC group (66.1% [5.9%]) (P < .001). Kidney transplant was associated with a significant improvement in V̇O2max in the KTR group at 12 months (22.5 [6.3] mL · min-1 · kg-1; P < .001), but the value did not reach the V̇O2max in the HTC group (26.0 [7.1] mL · min-1 · kg-1) at 12 months. V̇O2max decreased in the NTWC group at 12 months compared with baseline (17.7 [4.1] mL · min-1 · kg-1, P < .001). Compared with the KTR group (63.2% [6.8%], P = .02) or the NTWC group (59.3% [7.6%], P = .003) at baseline, transplant was significantly associated with improved left ventricular ejection fraction at 12 months but not with left ventricular mass index. Conclusions and Relevance: The findings suggest that kidney transplant is associated with improved cardiovascular functional reserve after 1 year. In addition, cardiopulmonary exercise testing was sensitive enough to detect a decline in cardiovascular functional reserve in wait-listed patients with CKD. Improved V̇O2max may in part be independent from structural alterations of the heart and depend more on ultrastructural changes after reversal of uremia

Traditional zootherapeutic studies in India: a review

The present study aims to review the zootherapeutic practices of the different ethnic communities of India. This work is also an attempt to present a list of animals' use for medicinal purposes by different communities of India. Data were gathered from 15 published research papers of various authors on zootherapeutic studies in India from 2000 to 2007. Approximately 109 animals and their 270 uses are reported in traditional medicine in different parts of India. Of these, the highest numbers of animal species (42, 38.5%) with 50 (18.5%) uses have been reported for the treatment of Respiratory system related problems. Rheumatic and other pains are treated with 32 species (29.4%) in 34 (12.9%) uses. Gastric problems are reported to be treated with 22 (20.2%) species in 26 (9.9%) uses. The mammals constitute the highest number of animals used for medicinal purposes. 44 (40%) mammals, 24 (22%) invertebrates, 18 (17%) birds, 12 (11%) reptiles, nine (8%) fishes and two (2%) amphibians have been reported for medicinal purposes. Of the total 109 animal species reported, 76(70%) are included in IUCN red data list and 36 (33%) animal species are listed in CITES appendix I, II, and III. This work will be helpful in biodiversity conservation in India and also give a clue to investigate bio-active compound in these animal raw materials

CD40-Activated B Cells Can Efficiently Prime Antigen-Specific Naïve CD8+ T Cells to Generate Effector but Not Memory T cells

Background: The identification of the signals that should be provided by antigen-presenting cells (APCs) to induce a CD8 + T cell response in vivo is essential to improve vaccination strategies using antigen-loaded APCs. Although dendritic cells have been extensively studied, the ability of other APC types, such as B cells, to induce a CD8 + T cell response have not been thoroughly evaluated. Methodology/Principal Findings: In this manuscript, we have characterized the ability of CD40-activated B cells, stimulated or not with Toll-like receptor (TLR) agonists (CpG or lipopolysaccharide) to induce the response of mouse naïve CD8 + T cells in vivo. Our results show that CD40-activated B cells can directly present antigen to naïve CD8 + T cells to induce the generation of potent effectors able to secrete cytokines, kill target cells and control a Listeria monocytogenes infection. However, CD40-activated B cell immunization did not lead to the proper formation of CD8 + memory T cells and further maturation of CD40-activated B cells with TLR agonists did not promote the development of CD8 + memory T cells. Our results also suggest that inefficient generation of CD8 + memory T cells with CD40-activated B cell immunization is a consequence of reduced Bcl-6 expression by effectors and enhanced contraction of the CD8 + T cell response. Conclusions: Understanding why CD40-activated B cell immunization is defective for the generation of memory T cells and gaining new insights about signals that should be provided by APCs are key steps before translating the use of CD40-B cel

External validation and calibration of IVFpredict:A national prospective cohort study of 130,960 in vitro fertilisation Cycles

© 2015 Smith et al. Background Accurately predicting the probability of a live birth after in vitro fertilisation (IVF) is important for patients, healthcare providers and policy makers. Two prediction models (Templeton and IVFpredict) have been previously developed from UK data and are widely used internationally. The more recent of these, IVFpredict, was shown to have greater predictive power in the development dataset. The aim of this study was external validation of the two models and comparison of their predictive ability. Methods and Findings 130,960 IVF cycles undertaken in the UK in 2008-2010 were used to validate and compare the Templeton and IVFpredict models. Discriminatory power was calculated using the area under the receiver-operator curve and calibration assessed using a calibration plot and Hosmer-Lemeshow statistic. The scaled modified Brier score, with measures of reliability and resolution, were calculated to assess overall accuracy. Both models were compared after updating for current live birth rates to ensure that the average observed and predicted live birth rates were equal. The discriminative power of both methods was comparable: the area under the receiver-operator curve was 0.628 (95% confidence interval (CI): 0.625-0.631) for IVFpredict and 0.616 (95% CI: 0.613-0.620) for the Templeton model. IVFpredict had markedly better calibration and higher diagnostic accuracy, with calibration plot intercept of 0.040 (95% CI: 0.017-0.063) and slope of 0.932 (95% CI: 0.839 - 1.025) compared with 0.080 (95% CI: 0.044-0.117) and 1.419 (95% CI: 1.149-1.690) for the Templeton model. Both models underestimated the live birth rate, but this was particularly marked in the Templeton model. Updating the models to reflect improvements in live birth rates since the models were developed enhanced their performance, but IVFpredict remained superior. Conclusion External validation in a large population cohort confirms IVFpredict has superior discrimination and calibration for informing patients, clinicians and healthcare policy makers of the probability of live birth following IVF