Ultrafiltration is better than diuretic therapy for volume-overloaded acute heart failure patients: a meta-analysis.

Studies on the effectiveness of ultrafiltration (UF) in patients hospitalized with acute decompensated heart failure (ADHF) have led to heterogeneous study outcomes. This meta-analysis aimed to assess the impact of UF therapy in ADHF patients. We searched the medical literature to identify well-designed studies comparing UF with the usual diuretic therapy in this setting. Systematic evaluation of 8 randomized controlled trials enrolling 801 participants showed greater fluid removal (difference in means 1372.5 mL, 95% CI 849.6 to 1895.4 mL; p < 0.001), weight loss (difference in means 1.592 kg, 95% CI 1.039 to 2.144 kg; p < 0.001) and lower incidences of worsening heart failure (OR 0.63, 95% CI 0.43 to 0.94, p = 0.022) and rehospitalization for heart failure (OR 0.54, 95% CI 0.36 to 0.82, p = 0.003) without a difference in renal impairment (OR 1.386, 95% CI 0.870 to 2.209; p = 0.169) or all-cause mortality (OR 1.13, 95% CI 0.75 to 1.71, p = 0.546). UF increases fluid removal and weight loss and reduces rehospitalization and the risk of worsening heart failure in congestive patients, suggesting ultrafiltration as a safe and effective treatment option for volume-overloaded heart failure patients.

Endoscopic and surgical drainage for pancreatic fluid collections are better than percutaneous drainage: Meta-analysis.

BACKGROUND: Pancreatic pseudocyst (PP) and walled-off necrosis can be managed endoscopically, percutaneously or surgically, but with diverse efficacy. AIMS & METHODS: A comprehensive literature search was carried out from inception to December 2018, to identify articles which compared at least two of the three kinds of treatment modalities, regarding the mortality, clinical success, recurrence, complications, cost and length of hospitalisation (LOH). RESULTS: The outcomes of endoscopic (ED) and percutaneous drainage (PD) were comparable in six articles. The clinical success of endoscopic intervention was better considering any types of fluid collections (OR = 3.36; 95% confidence interval (CI) 1.48, 7.63; p = 0.004). ED was preferable regarding recurrence of PP (OR = 0.23; 95% CI 0.08, 0.66; p = 0.006). Fifteen articles compared surgical intervention with ED. Significant difference was found in postoperative LOH (WMD (days) = -4.61; 95%CI -7.89, -1.33; p = 0.006) and total LOH (WMD (days) = -3.67; 95%CI -5.00, -2.34; p < 0.001) which favored endoscopy, but ED had lower rate of clinical success (OR = 0.54; 95% CI 0.35, 0.85; p = 0.007) and higher rate of recurrence (OR = 1.80; 95% CI 1.16, 2.79; p = 0.009) in the treatment of PP. Eleven studies compared surgical and percutaneous intervention. PD resulted in higher rate of recurrence (OR = 4.91; 95% CI 1.82, 13.22; p = 0.002) and lower rate of clinical success (OR = 0.13; 95% CI 0.07, 0.22, p < 0.001). CONCLUSION: Both endoscopy and surgery are preferable over percutaneous intervention, furthermore endoscopic treatment is associated with shorter hospitalisation than surgery.

Capsaicin and capsiate could be appropriate agents for treatment of obesity: A meta-analysis of human studies.

Consumption of capsaicin or its nonpungent analogues, capsinoids has been reported to affect energy expenditure and fat oxidation, although available data are still controversial. The aim of the present study was to conduct a meta-analysis regarding the effects of these substances on energy expenditure and respiratory quotient, with special emphasis on the role of body mass index (BMI) of the participants. Medical databases were systematically searched for papers. Of the 627 trials identified, 9 provided results suitable to be included in analysis. Data analysis showed that after ingestion of capsaicin or capsinoids the energy expenditure increased (245 kJ/day, 58.56 kcal/day, p = 0.030) and the respiratory quotient decreased (by 0.216; p = 0.031) indicating a rise in fat oxidation. Studies with mean BMI of the participants below 25 kg/m2 failed to report any effect of capsaicin or capsinoids on the energy expenditure (p = 0.718) or on the respiratory quotient (p = 0.444), but studies with mean BMI exceeding 25 kg/m2 demonstrated an increase in energy expenditure (292 kJ/day, 69.79 kcal/day, p = 0.023) and a marked decrease in respiratory quotient (-0.257, p = 0.036). Our data clearly suggest that capsaicin or capsiate could be a new therapeutic approach in obesity promoting a negative energy balance and increased fat oxidation.

Gender difference in the effects of interleukin-6 on grip strength - a systematic review and meta-analysis.

BACKGROUND: Aging sarcopenia characterized by low muscle mass with low muscle strength affects men and women differently. The contribution of interleukin-6 (IL-6) to sarcopenia has been suggested based on a negative correlation between plasma IL-6 and muscle function described by some studies. However, no consensus regarding clinically relevant cut-off criteria has been reached. Another question arises whether pooling male and female data is an accurate way to determine the predictive value of IL-6 in sarcopenia. The present meta-analysis was designed to assess: (1) whether plasma IL-6 in aged populations in fact correlates negatively to muscle strength; (2) whether such a correlation exists both in men and in women; and (3) whether plasma IL-6 shows a gender difference in old age. METHODS: We applied the preferred reporting items for systematic review and meta-analysis protocols (PRISMA). We searched PubMed and Embase for papers that reported data on individuals over 65 without inflammatory diseases. We extracted either separate male and female data on plasma IL-6 along with at least one muscle parameter or correlation coefficient between plasma IL-6 and these parameters. Random effect models calculated with DerSimonian and Laird weighting methods were applied to analyze correlation coefficients and gender difference in plasma IL-6. Egger's test was used to assess the small study effect. RESULTS: Twenty articles out of 468 records identified were suitable for analyses. Plasma IL-6 correlates negatively with grip strength in mixed populations and also separately in men [- 0.25 with 95% confidence interval (CI): - 0.48, - 0.02] and in women (- 0.14 with 95% CI: - 0.24, - 0.03). However, contrary to expectations, men with better muscle condition have higher plasma IL-6 than women of similar age with worse muscle condition (plasma IL-6 male-female difference: 0.25 pg/mL with 95% CI: 0.15, 0.35). CONCLUSION: This is the first study to demonstrate that a higher predictive IL-6 cut-off level should be determined for aging sarcopenia in men than in women.

Uninterrupted or Minimally Interrupted Direct Oral Anticoagulant Therapy is a Safe Alternative to Vitamin K Antagonists in Patients Undergoing Catheter Ablation for Atrial Fibrillation: An Updated Meta-Analysis.

Adequate anticoagulation during catheter ablation (CA) for atrial fibrillation (AF) is crucial for the prevention of both thromboembolic events and life-threatening bleeding. The purpose of this updated meta-analysis is to compare the safety and efficacy of uninterrupted and minimally interrupted periprocedural direct oral anticoagulant (DOAC) protocols and uninterrupted vitamin K antagonist (VKA) therapy in patients undergoing CA for AF based on the latest evidence. Randomized controlled trials, prospective observational studies, and retrospective registries comparing DOACs to VKAs were identified in multiple databases (Embase, MEDLINE via PubMed, CENTRAL, and Scopus). The primary outcomes were stroke or transient ischemic attack (TIA), major bleeding, and net clinical benefit. Forty-two studies with a total of 22,715 patients were included in the final analysis. The occurrence of major bleeding was significantly lower in patients assigned to uninterrupted DOAC treatment compared to VKAs (pooled odds ratio (POR): 0.71, confidence interval (CI): 0.51-0.99). The pooled analysis of both uninterrupted and minimally interrupted DOAC groups also showed significant reduction in major bleeding events (POR: 0.70, CI: 0.53-0.93). The incidence of thromboembolic events was low, with no significant difference between groups. This updated meta-analysis showed that DOAC therapy is as effective as VKA in preventing stroke and TIA. Minimally interrupted DOAC therapy is a non-inferior periprocedural anticoagulation strategy; however, uninterrupted DOAC therapy showed superiority compared to VKA with regard to major, life-threatening bleeding. Based on our in-depth analysis, we conclude that both DOAC strategies are equally safe and preferable alternatives to VKAs in patients undergoing CA for AF.

Computed Tomography Severity Index vs. Other Indices in the Prediction of Severity and Mortality in Acute Pancreatitis: A Predictive Accuracy Meta-analysis.

Background: The management of the moderate and severe forms of acute pancreatitis (AP) with necrosis and multiorgan failure remains a challenge. To predict the severity and mortality of AP multiple clinical, laboratory-, and imaging-based scoring systems are available. Aim: To investigate, if the computed tomography severity index (CTSI) can predict the outcomes of AP better than other scoring systems. Methods: A systematic search was performed in three databases: Pubmed, Embase, and the Cochrane Library. Eligible records provided data from consecutive AP cases and used CTSI or modified CTSI (mCTSI) alone or in combination with other prognostic scores [Ranson, bedside index of severity in acute pancreatitis (BISAP), Acute Physiology, and Chronic Health Examination II (APACHE II), C-reactive protein (CRP)] for the evaluation of severity or mortality of AP. Area under the curves (AUCs) with 95% confidence intervals (CIs) were calculated and aggregated with STATA 14 software using the metandi module. Results: Altogether, 30 studies were included in our meta-analysis, which contained the data of 5,988 AP cases. The pooled AUC for the prediction of mortality was 0.79 (CI 0.73-0.86) for CTSI; 0.87 (CI 0.83-0.90) for BISAP; 0.80 (CI 0.72-0.89) for mCTSI; 0.73 (CI 0.66-0.81) for CRP level; 0.87 (CI 0.81-0.92) for the Ranson score; and 0.91 (CI 0.88-0.93) for the APACHE II score. The APACHE II scoring system had significantly higher predictive value for mortality than CTSI and CRP (p = 0.001 and p < 0.001, respectively), while the predictive value of CTSI was not statistically different from that of BISAP, mCTSI, CRP, or Ranson criteria. The AUC for the prediction of severity of AP were 0.80 (CI 0.76-0.85) for CTSI; 0.79, (CI 0.72-0.86) for BISAP; 0.83 (CI 0.75-0.91) for mCTSI; 0.73 (CI 0.64-0.83) for CRP level; 0.81 (CI 0.75-0.87) for Ranson score and 0.80 (CI 0.77-0.83) for APACHE II score. Regarding severity, all tools performed equally. Conclusion: Though APACHE II is the most accurate predictor of mortality, CTSI is a good predictor of both mortality and AP severity. When the CT scan has been performed, CTSI is an easily calculable and informative tool, which should be used more often in routine clinical practice.

Vitex agnus-castus in premenstrual syndrome: A meta-analysis of double-blind randomised controlled trials.

Although chasteberry (Vitex agnus-castus, VAC) has been studied in several clinical trials and available as medicine for the alleviation of premenstrual syndrome (PMS) symptoms, the efficacy of properly characterised preparations has not been assessed in meta-analyses. The aim of our work was to evaluate the efficacy of VAC in PMS. The meta-analysis was performed following the PRISMA guidelines using the PICOS format, taking into account the CONSORT recommendations. PubMed, Embase, the Cochrane Central Register of Controlled Trials and Web of Science were searched for studies on VAC. The analysis assessed the efficacy of properly characterised products VAC compared to a placebo for the alleviation of PMS symptoms in terms of responder rate, considering the decrease of Total Symptom Score or PMS Diary score. The random effects model was used to calculate summary relative risk (RR) and 95% confidence interval (CI). Only those randomised, double-blind, placebo-controlled trials were included that fulfilled the criteria of the CONSORT recommendations aiming at the proper characterization of herbal products. Out of the 21 clinical trials, three studies (520 females) fulfilled the inclusion criteria, comparing the efficacy of special extracts Ze 440 and BNO 1095 to a placebo for the treatment of PMS. VAC preparations were confirmed to be effective in the reduction of PMS symptoms: women taking VAC were 2.57 (95% CI 1.52-4.35) times more likely to experience a remission in their symptoms compared to those taking the placebo. Although several clinical trials have been carried out with VAC, the majority of the studies cannot be used as evidence for efficacy due to incomplete reporting, especially concerning the description of the used medication. More trials following the CONSORT recommendations are needed to assess the efficacy of VAC extracts.

Activity of the Hypothalamic Melanocortin System Decreases in Middle-Aged and Increases in Old Rats.

Appearance of middle-aged obesity and aging anorexia both in humans and rodents suggests a role for regulatory alterations. Hypothalamic melanocortin agonist, α-melanocyte-stimulating hormone (α-MSH) produced in the arcuate nucleus (ARC), reduces body weight via inducing hypermetabolism and anorexia mainly through melanocortin 4 receptors (MC4Rs) in the paraventricular nucleus (PVN). Orexigenic ARC-derived agouti-related protein (AgRP) is an inverse agonist on MC4R in the PVN. Previously, we demonstrated that characteristic age-related shifts in the catabolic effects of α-MSH may contribute both to middle-aged obesity and aging anorexia. Responsiveness to α-MSH decreases in middle-aged rats compared with young adults, whereas in old age it rises again significantly. We hypothesized corresponding age-related dynamics of endogenous melanocortins. Therefore, we quantified mRNA gene expression and peptide or protein level of α-MSH, AgRP, and MC4R in the ARC and PVN of male Wistar rats of five age groups (from young to old). Immunofluorescence and quantitative reverse transcriptase polymerase chain reaction were applied. α-MSH and MC4R immunoreactivities in the ARC and PVN declined in middle-aged and increased together with their expressions in aging rats. AgRP gene expression but not its immunoreactivity increased in aging rats. Our results demonstrate that age-dependent changes of endogenous melanocortins contribute to middle-aged obesity and aging anorexia.

Body fat of rats of different age groups and nutritional states: assessment by micro-CT and skinfold thickness.

Obesity presents a growing public health problem. Therefore the analysis of body composition is important in clinical practice as well as in animal research models of obesity; hence precise methods for the assessment of body fat would be essential. We aimed to evaluate in vivo abdominal microcomputed tomography scan restricted to the L1-L3 region [micro-CT(L1-L3)], a skinfold thickness-based method (STM), and postmortem body composition analysis (PMA) with regard to whole body micro-CT scan in rats. Male Wistar rats of different age groups (from 3 to 24 mo) and nutritional states (normally fed, high-fat diet-induced obese, and calorie-restricted) were used. The fat percentage was determined with micro-CT(L1-L3) and whole body scan in anesthetized rats. Their skinfold thickness was measured in five locations with a Lange caliper. Wet weights of epididymal and retroperitoneal fat pads were determined via PMA. With regard to fat mass, the strongest correlation was observed between abdominal and whole body micro-CT. The other methods showed weaker associations with whole body micro-CT and with each other. Micro-CT(L1-L3) and PMA showed similar age-associated increase in fat mass between 3 and 18 mo. Micro-CT(L1-L3), STM, and PMA were efficient to detect differences in fat mass values in groups of different nutritional states. Micro-CT(L1-L3) appears to be a useful method for body fat assessment in rats with reduced scanning time. In rats, STM may also be a useful, low priced, noninvasive, and simple in vivo technique to assess obesity. NEW & NOTEWORTHY Body fat of rats assessed by in vivo abdominal microcomputed tomography of the L1-L3 region strongly correlates with values determined by whole body scan. Therefore, it is a useful method for fat assessment with reduced scanning time. Skinfold thickness measurement is an in vivo technique to assess progression of obesity in rats.

Perceived stress correlates with visceral obesity and lipid parameters of the metabolic syndrome: A systematic review and meta-analysis.

BACKGROUND: Perceived stress has been proposed as a risk factor of metabolic syndrome. However, correlations between perceived stress and parameters of the metabolic syndrome have not been properly analyzed despite extensive research data on the topic. Our current meta-analysis aimed to examine the mutual association between perceived stress of patients and parameters of metabolic syndrome. METHODS: This systematic review has been registered on the PROSPERO database (registration number CRD42017055293). Eligible studies divided participants based on their stress level or on the presence of metabolic syndrome. They reported at least one parameter of the metabolic syndrome or the stress level of the participants measured with some stress scale. Data from 17 articles met the eligibility criteria and were included. Random effects model with the DerSimonian and Laird weighting methods was applied. I-squared indicator and Q test were performed to assess heterogeneity. RESULTS: Although the majority of individual studies failed to demonstrate correlations between stress and their analyzed parameters of metabolic syndrome, our meta-analysis showed a significant association between stress and BMI [average effect size (ES) with 95% confidence interval (95%CI), ES = 0.65, 95%CI 0.16, 1.14), waist circumference (ES = 1.84 cm, 95%CI 0.79, 2.89) and serum triglyceride level (ES = 7.52 mg/dl, 95%CI 0.07, 14.96). Additional analysis confirmed effects of stress on serum HDL (ES = - 1.699 mg/dl, 95%CI -2.966, -0.432) and diastolic blood pressure (ES = 1.04 mmHg, 95%CI 0.18, 1.89). No correlations were found for fasting glucose or systolic blood pressure. No association between metabolic syndrome and stress level of patients was detected either. CONCLUSION: The potentially key role of visceral obesity in the association between perceived stress and dyslipidemia or diastolic blood pressure are discussed together with potential moderators (e.g. gender-differences, variations in stress assessment and metabolic syndrome criteria) that may explain the inconsistent, contradictory results of the individual studies.

Therapeutic Whole-Body Hypothermia Reduces Death in Severe Traumatic Brain Injury if the Cooling Index Is Sufficiently High: Meta-Analyses of the Effect of Single Cooling Parameters and Their Integrated Measure.

Therapeutic hypothermia was investigated repeatedly as a tool to improve the outcome of severe traumatic brain injury (TBI), but previous clinical trials and meta-analyses found contradictory results. We aimed to determine the effectiveness of therapeutic whole-body hypothermia on the deaths of adult patients with severe TBI by using a novel approach of meta-analysis. We searched the PubMed, EMBASE, and Cochrane Library databases from inception to February 2017. The identified human studies were evaluated regarding statistical, clinical, and methodological designs to ensure interstudy homogeneity. We extracted data on TBI severity, body temperature, death, and cooling parameters; then we calculated the cooling index, an integrated measure of therapeutic hypothermia. Forest plot of all identified studies showed no difference in the outcome of TBI between cooled and not cooled patients, but interstudy heterogeneity was high. On the contrary, by meta-analysis of randomized clinical trials that were homogenous with regard to statistical, clinical designs, and precisely reported the cooling protocol, we showed decreased odds ratio for death in therapeutic hypothermia compared with no cooling. As independent factors, milder and longer cooling, and rewarming at <0.25°C/h were associated with better outcome. Therapeutic hypothermia was beneficial only if the cooling index (measure of combination of cooling parameters) was sufficiently high. We conclude that high methodological and statistical interstudy heterogeneity could underlie the contradictory results obtained in previous studies. By analyzing methodologically homogenous studies, we show that cooling improves the outcome of severe TBI, and this beneficial effect depends on certain cooling parameters and on their integrated measure, the cooling index.

Age-related changes in central effects of corticotropin-releasing factor (CRF) suggest a role for this mediator in aging anorexia and cachexia.

Hypothalamic corticotropin-releasing factor (CRF) lays downstream to catabolic melanocortins and at least partly mediates their catabolic effects. Age-related changes in the melanocortin system (weak responsiveness in middle-aged and a strong one in old rats) have been shown to contribute to middle-aged obesity and later to aging anorexia and cachexia of old age groups. We hypothesized that catabolic (anorexigenic and hypermetabolic) CRF effects vary with aging similarly to those of melanocortins. Thus, we aimed to test whether age-related variations of CRF effects may also contribute to middle-aged obesity and aging anorexia leading to weight loss of old age groups. Food intake, body weight, core temperature, heart rate, and activity were recorded in male Wistar rats of young, middle-aged, aging, and old age groups (from 3 to 24 months) during a 7-day intracerebroventricular CRF infusion (0.2 µg/µl/h) in a biotelemetric system. In addition, CRF gene expression was also assessed by quantitative RT-PCR in the paraventricular nucleus (PVN) of intact animals of the same age groups. The infusion suppressed body weight in the young, aging, and old rats, but not in middle-aged animals. Weak anorexigenic and hypermetabolic effects were detected in the young, whereas strong anorexia (without hypermetabolism) developed in the oldest age groups in which post mortem analysis showed also a reduction of retroperitoneal fat mass. CRF gene expression in the PVN increased with aging. Our results support the potential contribution of age-related changes in CRF effects to aging anorexia and cachexia. The role of the peptide in middle-aged obesity cannot be confirmed.

Acute central effects of alarin on the regulation on energy homeostasis.

Hypothalamic neuropeptides influence the main components of energy balance: metabolic rate, food intake, body weight as well as body temperature, by exerting either an overall anabolic or catabolic effect. The contribution of alarin, the most recently discovered member of the galanin peptide family to the regulation of energy metabolism has been suggested. Our aim was to analyze the complex thermoregulatory and food intake-related effects of alarin in rats. Adult male Wistar rats received different doses of alarin (0.3; 1; 3 and 15µg corresponding approximately to 0.1, 0.33, 1, and 5 nmol, respectively) intracerebroventricularly. Regarding thermoregulatory analysis, oxygen consumption (indicating metabolic rate), core temperature and heat loss (assessed by tail skin temperature) were recorded in an Oxymax indirect calorimeter system complemented with thermocouples and Benchtop thermometer. In order to investigate potential prostaglandin-mediated mechanisms of the hyperthermic effect of alarin, effects of intraperitoneally applied non-selective (indomethacin, 2mg/kg) or selective cyclooxygenase inhibitor (COX-2 inhibitor meloxicam, 1; 2mg/kg) were tested. Effects of alarin on daytime and nighttime spontaneous food intake, as well as, 24-h fasting-induced re-feeding were recorded in an automated FeedScale system. Alarin increased oxygen consumption with simultaneous suppression of heat loss leading to a slow coordinated rise in core temperature. Both applied COX-inhibitors suppressed this action. Alarin failed to induce daytime food intake, but suppressed spontaneous nighttime and also fasting-induced re-feeding food intake. Alarin appears to elicit a slow anorexigenic and prostaglandin-mediated, fever-like hyperthermic response in rats. Such a combination would characterize a catabolic mediator. The potential involvement of alarin in sickness behavior may be assumed.

In middle-aged and old obese patients, training intervention reduces leptin level: A meta-analysis.

BACKGROUND: Leptin is one of the major adipokines in obesity that indicates the severity of fat accumulation. It is also an important etiological factor of consequent cardiometabolic and autoimmune disorders. Aging has been demonstrated to aggravate obesity and to induce leptin resistance and hyperleptinemia. Hyperleptinemia, on the other hand, may promote the development of age-related abnormalities. While major weight loss has been demonstrated to ameliorate hyperleptinemia, obese people show a poor tendency to achieve lasting success in this field. The question arises whether training intervention per se is able to reduce the level of this adipokine. OBJECTIVES: We aimed to review the literature on the effects of training intervention on peripheral leptin level in obesity during aging, in order to evaluate the independent efficacy of this method. In the studies that were included in our analysis, changes of adiponectin levels (when present) were also evaluated. DATA SOURCES: 3481 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 19 articles were suitable for analyses. STUDY ELIGIBILITY CRITERIA: Empirical research papers were eligible provided that they reported data of middle-aged or older (above 45 years of age) overweight or obese (body mass index above 25) individuals and included physical training intervention or at least fitness status of groups together with corresponding blood leptin values. STATISTICAL METHODS: We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. To assess publication bias Egger's test was applied. In case of significant publication bias, the Duval and Tweedie's trim and fill algorithm was used. RESULTS: Training intervention leads to a decrease in leptin level of middle-aged or older, overweight or obese male and female groups, even without major weight loss, indicated by unchanged serum adiponectin levels. Resistance training appears to be more efficient in reducing blood leptin level than aerobic training alone. CONCLUSIONS: Physical training, especially resistance training successfully reduces hyperleptinemia even without diet or major weight loss.

Fever Is Associated with Reduced, Hypothermia with Increased Mortality in Septic Patients: A Meta-Analysis of Clinical Trials.

BACKGROUND: Sepsis is usually accompanied by changes of body temperature (Tb), but whether fever and hypothermia predict mortality equally or differently is not fully clarified. We aimed to find an association between Tb and mortality in septic patients with meta-analysis of clinical trials. METHODS: We searched the PubMed, EMBASE, and Cochrane Controlled Trials Registry databases (from inception to February 2016). Human studies reporting Tb and mortality of patients with sepsis were included in the analyses. Average Tb with SEM and mortality rate of septic patient groups were extracted by two authors independently. RESULTS: Forty-two studies reported Tb and mortality ratios in septic patients (n = 10,834). Pearson correlation analysis revealed weak negative linear correlation (R2 = 0.2794) between Tb and mortality. With forest plot analysis, we found a 22.2% (CI, 19.2-25.5) mortality rate in septic patients with fever (Tb > 38.0°C), which was higher, 31.2% (CI, 25.7-37.3), in normothermic patients, and it was the highest, 47.3% (CI, 38.9-55.7), in hypothermic patients (Tb < 36.0°C). Meta-regression analysis showed strong negative linear correlation between Tb and mortality rate (regression coefficient: -0.4318; P < 0.001). Mean Tb of the patients was higher in the lowest mortality quartile than in the highest: 38.1°C (CI, 37.9-38.4) vs 37.1°C (CI, 36.7-37.4). CONCLUSIONS: Deep Tb shows negative correlation with the clinical outcome in sepsis. Fever predicts lower, while hypothermia higher mortality rates compared with normal Tb. Septic patients with the lowest (< 25%) chance of mortality have higher Tb than those with the highest chance (> 75%).

Regulatory Alterations of Energy Homeostasis in Spontaneously Hypertensive Rats (SHR).

Spontaneously hypertensive rats (SHR) have high sympathetic tone and progressive hypertension. Chronic calorie-restriction prevents hypertension. Their food intake (FI) and body weight are lower than in normotensive (NT) controls, even on a high-fat diet, suggesting a dysregulation of energy homeostasis. We assumed enhanced activity of hypothalamic anorexigenic melanocortins and diminished tone of orexigenic neuropeptide Y (NPY) in the background. FI of male SHR and NT Wistar rats was recorded in a FeedScale system upon intracerebroventricular injection of NPY, melanocortin ligands alpha-melanocyte-stimulating hormone (alpha-MSH), and agouti-related peptide (AgRP) or during a 7-day intracerebroventricular infusion of melanocortin antagonist HS024. Alpha-MSH, NPY, and AgRP immunoreactivities were semi-quantified in the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus in NT vs. SHR. Proopiomelanocortin gene expression was also assessed by quantitative RT-PCR in the ARC. Melanocortin-induced anorexia was stronger, FI induced by NPY or HS024 was smaller and delayed in SHR. Cellular alpha-MSH-specific signal density was higher in the ARC of SHR as evaluated by immunofluerescence, which was supported by PCR data. In the PVN, no differences in alpha-MSH-, NPY-, or AgRP-immunosignal were observed. Our results suggest that a higher melanocortin production/responsiveness and lower NPY responsiveness may contribute to the body weight dysregulation of SHR.

Acute central effects of corticotropin-releasing factor (CRF) on energy balance: Effects of age and gender.

Previously demonstrated age-related changes in the catabolic melanocortin system that may contribute to middle-aged obesity and aging anorexia, raise the question of the potential involvement of corticotropin-releasing factor (CRF) in these phenomena, as this catabolic hypothalamic mediator acts downstream to melanocortins. Catabolic effects of CRF were shown to be mediated by both CRF1 (hypermetabolism) and CRF2 (anorexia) receptors. To test the potential role of CRF in age-related obesity and aging anorexia, we investigated acute central effects of the peptide on energy balance in male and female rats during the course of aging. Effects of an intracerebroventricular CRF injection on food intake (FI), oxygen-consumption (VO2), core- and tail skin temperatures (Tc and Ts) were studied in male and female Wistar rats of five different age-groups (from 3- to 24-month). Anorexigenic responsiveness was tested during 180-min re-feeding (FeedScale) following 24-h fasting. Thermoregulatory analysis was performed by indirect calorimetry (Oxymax) complemented by thermocouples recording Tc and Ts (indicating heat loss). CRF suppressed FI in 3-month male and female animals. In males, CRF-induced anorexia declined with aging, whereas in females it was maintained in all groups. The peptide increased VO2 and Tc in all male age-groups, while the weaker hypermetabolic response characterizing 3-month females declined rapidly with aging. Thus, age-related alterations in acute central anorexigenic and hypermetabolic effects of CRF show different non-parallel patterns in males and females. Our findings underline the importance of gender differences. They also call the attention to the differential age-related changes in the CRF1 and CRF2 receptor systems.

In Obesity, HPA Axis Activity Does Not Increase with BMI, but Declines with Aging: A Meta-Analysis of Clinical Studies.

BACKGROUND: Obesity is one of the major public health challenges worldwide. It involves numerous endocrine disorders as etiological factors or as complications. Previous studies strongly suggested the involvement of the hypothalamic-pituitary-adrenal (HPA) axis activity in obesity, however, to date, no consistent trend in obesity-associated alterations of the HPA axis has been identified. Aging has been demonstrated to aggravate obesity and to induce abnormalities of the HPA axis. Thus, the question arises whether obesity is correlated with peripheral indicators of HPA function in adult populations. OBJECTIVES: We aimed to meta-analyze literature data on peripheral cortisol levels as indicators of HPA activity in obesity during aging, in order to identify possible explanations for previous contradictory findings and to suggest new approaches for future clinical studies. DATA SOURCES: 3,596 records were identified through searching of PubMed, Embase and Cochrane Library Database. Altogether 26 articles were suitable for analyses. STUDY ELIGIBILITY CRITERIA: Empirical research papers were eligible provided that they reported data of healthy adult individuals, included body mass index (BMI) and measured at least one relevant peripheral cortisol parameter (i.e., either morning blood cortisol or 24-h urinary free cortisol). STATISTICAL METHODS: We used random effect models in each of the meta-analyses calculating with the DerSimonian and Laird weighting methods. I-squared indicator and Q test were performed to assess heterogeneity. Meta-regression was applied to explore the effect of BMI and age on morning blood and urinary free cortisol levels. To assess publication bias Egger's test was used. RESULTS: Obesity did not show any correlation with the studied peripheral cortisol values. On the other hand, peripheral cortisol levels declined with aging within the obese, but not in the non-obese groups. CONCLUSIONS: Our analysis demonstrated that obesity or healthy aging does not lead to enhanced HPA axis activity, peripheral cortisol levels rather decline with aging.

Age versus nutritional state in the development of central leptin resistance.

Leptin, a catabolic adiposity signal acts in the hypothalamus via suppressing food intake and inducing hypermetabolism. Age and obesity are accompanied by leptin resistance. The present study aimed to clarify which components of the catabolic leptin effects are influenced most strongly by aging and which ones by nutritional state-induced alterations in body composition. In our biotelemetric study the effects of a 7-day intracerebroventricular leptin infusion on various parameters of energy balance (food intake, body weight, oxygen consumption, heart rate and body temperature) were analyzed in male Wistar rats of different age-groups (from 3 to 24 months) and nutritional states (normally fed, diet-induced obese and calorie-restricted). Leptin resistance of older animals affected hypermetabolic actions, whereas leptin induced anorexia in all age-groups. Weight reducing effect of leptin diminished in middle-aged and aging animals to become significant again in the oldest group. In diet-induced obese rats leptin-induced hypermetabolism of the young rats and hypermetabolism plus anorexia of the aging ones were suppressed. Calorie-restriction reduced body weight and fat mass to a similar extent in all age-groups. It strongly enhanced leptin-induced hypermetabolism at all ages and prevented the manifestation of anorexigenic actions of leptin with the exception of the oldest group. This latter finding suggests an unexpected increase of responsiveness to anorexigenic leptin actions in old rats. Accordingly, anorexia and hypermetabolism change in disparate ways with aging. Nutritional state predominantly influences hypermetabolic leptin actions. Resistance to both hypermetabolic and anorexigenic actions were promoted by obesity, while calorie-restriction enhanced responsiveness to leptin, especially in old rats.