Effect of Rosuvastatin on Acute Kidney Injury in Sepsis-Associated Acute Respiratory Distress Syndrome.

Background:Acute kidney injury (AKI) commonly occurs in patients with sepsis and acute respiratory distress syndrome (ARDS). Objective:To investigate whether statin treatment is protective against AKI in sepsis-associated ARDS. Design:Secondary analysis of data from Statins for Acutely Injured Lungs in Sepsis (SAILS), a randomized controlled trial that tested the impact of rosuvastatin therapy on mortality in patients with sepsis-associated ARDS. Setting:44 hospitals in the National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Patients:644 of 745 participants in SAILS who had available baseline serum creatinine data and who were not on chronic dialysis. Measurements:Our primary outcome was AKI defined using the Kidney Disease Improving Global Outcomes creatinine criteria. Randomization to rosuvastatin vs placebo was the primary predictor. Additional covariates include demographics, ARDS etiology, and severity of illness. Methods:We used multivariable logistic regression to analyze AKI outcomes in 511 individuals without AKI at randomization, and 93 with stage 1 AKI at randomization. Results:Among individuals without AKI at randomization, rosuvastatin treatment did not change the risk of AKI (adjusted odds ratio: 0.99, 95% confidence interval [CI]: 0.67-1.44). Among those with preexisting stage 1 AKI, rosuvastatin treatment was associated with an increased risk of worsening AKI (adjusted odds ratio: 3.06, 95% CI: 1.14-8.22). When serum creatinine was adjusted for cumulative fluid balance among those with preexisting stage 1 AKI, rosuvastatin was no longer associated worsening AKI (adjusted odds ratio: 1.85, 95% CI: 0.70-4.84). Limitations:Sample size, lack of urine output data, and prehospitalization baseline creatinine. Conclusion:Treatment with rosuvastatin in patients with sepsis-associated ARDS did not protect against de novo AKI or worsening of preexisting AKI

Acute and Chronic Effects of 12 Weeks of Combined Exercise Training on Plasma IL-6 in Post-Menopausal Women

Post-menopausal women exhibit higher levels of IL-6, a pro-inflammatory cytokine and anti-inflammatory myokine, and up-regulation of cellular receptors and cofactors for IL-6. Exercise is associated with an acute elevation of IL-6, but consistent exercise training diminishes this response. PURPOSE: to analyze the acute and chronic effects of 12 weeks of combined resistance and aerobic exercise training on plasma IL-6 in overweight or obese, post-menopausal women (55-75 years). METHODS: Forty-three women were randomly assigned to an exercise (EX, n=22) or an education (ED, n=21) group. EX completed resistance training (2 sets of 8 resistance exercises at 80% of 1RM) followed by aerobic training (25-minute treadmill walk at 70-80% of HRR) three times per week for 12 weeks. ED attended classes and activities two times per week for 12 weeks to control for seasonal variation and social interaction. Blood samples were collected a total of 8 times: 4 times before training (BT) (before the acute exercise bout (PRE), immediately after exercise (PO), 1 hour after exercise (1HR), and 2 hours after exercise (2HR)) and 4 times after training (AT). Lean, post-menopausal, and age-matched women were recruited for collection of one resting blood sample to serve as healthy controls (LN, n=11). Plasma IL-6 was determined using an ELISA kit according to manufacturer instructions. RESULTS: Baseline IL-6 concentration was significantly lower in the LN group compared to the EX (LN BT PRE: 1.0 ± 0.5; EX BT PRE: 2.8 ± 1.3 pg/mL; p\u3c0.001) and ED (LN BT PRE: 1.0 ± 0.5; ED BT PRE: 3.8 ± 1.7 pg/mL; p\u3c0.001) groups. No statistically significant BT/AT x group interaction was observed (p\u3e0.05) when the BT and AT PRE time points of the EX and ED groups were compared. In the EX group, PO was significantly higher than PRE (PRE 2.6 ± 1.2; PO 4.3 ± 1.8 pg/mL; p\u3c0.001), and PO was significantly higher than 1 HR (PO 4.3 ± 1.8; 1HR 3.4 ± 1.2 pg/mL; p=0.038) and 2HR (PO 4.3 ± 1.8; 2 HR 3.9 ± 1.6 pg/mL; p=0.005). No statistically significant differences were observed when corresponding time points before and after the intervention within a group were compared (i.e., EX BT PRE to EX AT PRE) (p\u3e0.05). CONCLUSION:The training intervention may not have been long enough and/or intense enough to observe a chronic effect of combined exercise training on plasma IL-6. Significant elevation of IL-6 immediately post-exercise was observed in the EX group, but this response was not blunted by consistent exercise training

The Influence of Physical Activity on Monocyte Phenotype on Circulating Platelet-Monocyte Complexes in Overweight/Obese Persons

Elevated platelet-monocyte complexes (PMC) promote atherosclerosis and are associated with cardiovascular disease. It is unknown whether consistent physical activity (PA) decreases circulating PMCs. Additionally, no one has determined the monocyte phenotype most associated with PMCs. Purposes: 1) to examine the influence of PA on PMCs and their association with inflammatory /prothrombotic markers such as C-reactive protein (CRP), L-selectin (LS), platelet factor 4 (PF4), von Willebrand Factor (vWF), and hemoglobin A1C (HbA1c) and 2) to determine the monocyte phenotype most likely to form PMCs. Methods: Thirty-one overweight/obese subjects (44±5yr, BMI 34.2±5 kg×m2) were divided into two groups: sedentary (SED, n=17) and physically active (PA, n=14) based on physical activity logs. SED participated in \u3c 1 h of formal exercise while PA participated in moderate-high intensity exercise at least 3 h per week. Flow cytometry was used to identify PMCs on the monocyte phenotypes: classical (CD14+CD16-), intermediate (CD14+CD16+), and non-classical (CD14+CD16++). Platelets were identified using the marker CD42a. Results: Percentage of circulating PMCs and median fluorescence intensity of CD42a (MedFI; marker of platelet density per monocyte) were not different between groups; however, monocyte phenotype significantly impacted PMC percentage and MedFI where the lower the CD16 expression, the greater the adhesion of platelets. Classical monocytes (CD16-) had the highest % of PMC, etc. (Fig 1). HbA1c was greater (p=0.031) and LS (p=0.019) was lower in SED compared to PA (Fig. 2). There were no significant associations between any blood marker and PMC percentage, but PF4 was correlated with percent of CD16 -(r= -0.482, p=0.031) and CD16+(r= 0.473, p=0.035) monocytes. Conclusions: The absence of a separation between groups in VO2max may partially explain the lack of a difference in PMCs between groups. Regarding our second aim, classical monocytes appear to be more involved in PMC formation than do CD16+ monocytes with CD16++ having the lowest percentage of cells with platelets adhered (PMC). This observation may be due to the shedding of adhesion molecules from platelets and monocytes during activation from classical (CD16-) to a more inflammatory state (ie. CD16+)

HIT vs. LSD: Four Days of Intensive Training does not Influence Lactoferrin, but LSD Increases Resting IL-6 while Attenuating the Acute Exercise Response, yet HIT Elevates Salivary Cortisol Levels

High intensity training programs (HIT) induce comparable endurance performance adaptations to those of continuous long slow distance training (LSD). HIT has increased, as athletes are able to maintain their VO2 max or performance with less time, and reduced training volume. High training volume may be immunosuppressive. PURPOSE: To examine a major mucosal immune component (salivary lactoferrin), the circulating cytokines (IL-6, IL-8, TNF-α), and cortisol response to HIT and LSD during 4 days of intensified training (IT). METHODS: Eight endurance-trained males (23.1±2.0yr,VO2 max 53.9±5.3 ml×kg-1×min-1) performed two, 4-day IT protocols: HIT and LSD conditions (separated by ³ 21 days). Both conditions included 2 exercise sessions / day (morning (AM) and late afternoon (PM)). LSD consisted of 50 min cycle ergometery in the AM (70% VO2max) and 90 min running in the PM (70% VO2max). The AM HIT session included 8 all-out, 30 sec cycling sprints (resistance=0.075kg×kg-1 body mass) with 4.5-8.5 min active recovery. The PM HIT session was the same as that for LSD. Blood and saliva samples were obtained at various time points based on the dependent variable. Plasma cytokines and creatine kinase (CK) activity were assessed both before and after the AM exercise sessions (pre-(PR), post(PO)-exercise) in both conditions on the first (before training; BT) and fourth (after training; AT) day of IT. Creatine kinase activity and cytokines were assessed in plasma. Salivary lactoferrin, and cortisol were assessed at 3 time points on days 1, 2 and 4 (PR and PO for AM, and PR for PM) in UHIT and LSD. Additionally, saliva was also collected at one time point (PR for the AM session) on the third and fifth day. RESULTS: Values above are listed as IL-6 (pg·mL-1), CK (U/L). BT= Day 1, AT= Day 4. Same letters indicate differences between time points for IL-6 serum levels (p\u3c0.05). Same numbers indicate differences between time points for CK activity (p\u3c0.05). Additionally, a significant time x day interaction occurred for lactoferrin secretion rate (PO\u3ePR on days 1 and 4, 1735\u3e5639 and 2290\u3e5663 ng·min-1, respectively; p=0.032). Moreover, a significant condition x time interaction occurred for lactoferrin secretion rate (p=0.047). A main effect for condition revealed that salivary cortisol was greater in HIT vs. LSD (p=0.028). CONCLUSION: Four days of IT did not attenuate the lactoferrin response to acute exercisese. LSD resulted in elevated resting IL-6, which may be responsible for the attenuation of the IL-6 response to acute exercise in this condition due to a feedback inhibition mechanism. Cortisol response is frequently linked to that of Il-6. Il-6 response to acute exercise was maintained in HIT, which may explain the elevated cortisol levels

Application of DEN refinement and automated model building to a difficult case of molecular-replacement phasing: the structure of a putative succinyl-diaminopimelate desuccinylase from Corynebacterium glutamicum.

Phasing by molecular replacement remains difficult for targets that are far from the search model or in situations where the crystal diffracts only weakly or to low resolution. Here, the process of determining and refining the structure of Cgl1109, a putative succinyl-diaminopimelate desuccinylase from Corynebacterium glutamicum, at ∼3 Å resolution is described using a combination of homology modeling with MODELLER, molecular-replacement phasing with Phaser, deformable elastic network (DEN) refinement and automated model building using AutoBuild in a semi-automated fashion, followed by final refinement cycles with phenix.refine and Coot. This difficult molecular-replacement case illustrates the power of including DEN restraints derived from a starting model to guide the movements of the model during refinement. The resulting improved model phases provide better starting points for automated model building and produce more significant difference peaks in anomalous difference Fourier maps to locate anomalous scatterers than does standard refinement. This example also illustrates a current limitation of automated procedures that require manual adjustment of local sequence misalignments between the homology model and the target sequence

The organization of the transcriptional network in specific neuronal classes

Genome-wide expression profiling has aided the understanding of the molecular basis of neuronal diversity, but achieving broad functional insight remains a considerable challenge. Here, we perform the first systems-level analysis of microarray data from single neuronal populations using weighted gene co-expression network analysis to examine how neuronal transcriptome organization relates to neuronal function and diversity. We systematically validate network predictions using published proteomic and genomic data. Several network modules of co-expressed genes correspond to interneuron development programs, in which the hub genes are known to be critical for interneuron specification. Other co-expression modules relate to fundamental cellular functions, such as energy production, firing rate, trafficking, and synapses, suggesting that fundamental aspects of neuronal diversity are produced by quantitative variation in basic metabolic processes. We identify two transcriptionally distinct mitochondrial modules and demonstrate that one corresponds to mitochondria enriched in neuronal processes and synapses, whereas the other represents a population restricted to the soma. Finally, we show that galectin-1 is a new interneuron marker, and we validate network predictions in vivo using Rgs4 and Dlx1/2 knockout mice. These analyses provide a basis for understanding how specific aspects of neuronal phenotypic diversity are organized at the transcriptional level

Exercise-Induced Th17 Lymphocyte Response and Their Relationship to Cardiovascular Disease Risk Factors in Obese, Post-Menopausal Women

Obesity-induced inflammation promotes type 2 diabetes and cardiovascular disease (CVD). A causative link between adaptive immunity and pathogenesis of obesity-associated diseases has been established. PURPOSE: To examine the effects of exercise on circulating T-helper (Th) 17 lymphocytes in overweight/obese post-menopausal women. METHODS: Twenty-seven overweight/obese women (BMI 32.7 ± 5.1 kg×m-2, 55-75 yr) were randomly assigned to the exercise (EX, n=14) or education (ED, n=13) groups. EX performed a 25-min walk (75-80% HRR) and 2 sets of 8 resistance exercises (70-80% 1RM) with blood samples obtained at: pre-exercise, post-exercise, one-hour and two-hour post-exercise. Blood samples were obtained at the same time points in resting ED. Whole blood was stained using the extracellular markers CD4, CD196, CD194, CD26, and CD161 to identify Th17 lymphocytes via flow cytometry. RESULTS: Acute exercise increased lymphocyte number (p = 0.0001), but decreased percent of CD4+ cells (p = 0.019) at PO. We observed a diurnal response (main effect) where CD26 expression was significantly lower by 2H compared to PRE (PR: 10631 ± 208; 2H: 9961 ± 271 MFI). There was a main effect (p=0.024) of group for CD26 expression (EX: 10745 ± 251; ED 9880 ± 260 MFI). The difference may have been driven by the apparent exercise-induced plateau of CD26 expression at 2H, which minimized the diurnal reduction observed in ED (p \u3e 0.05). There was a tendency (p = 0.09) for a group x time interaction in Th17 cell number at 1HR (EX = 25.3 ± 4.8; ED =37.2 ± 5.2 x 103 cells×ml-1). BMI was significantly correlated with Th17% (r = 0.5, p = 0.008). HbA1c was positively correlated with Th17 number and percentage (r = 0.598, p = 0.003; r = 0.614, p = 0.001, respectively), as well as CCR4+ Th17 cells (r = 0.421, p = 0.036). Multiple regression analysis revealed that BMI, fat percentage, and HbA1c were significant predictors (69%, r2 = 0.685) of Th17 cell %. CONCLUSION: Exercise reduced CD26 expression, the receptor responsible for Th17 cell migration, but did not significantly alter Th17 concentration (p = 0.09). CD26 upregulation may indicate that Th17 cells, via chemokine release, promote the stress-dependent migratory response of T-helper cells (CD4+). Obese individuals may experience a preferential differentiation of Th17 cells, based on their association with adiposity (BMI and %fat) and HbA1c

Acute Exercise-Induced Response of Platelet-Monocyte Complexes in Obese, Postmenopausal Women

Inactivity-related diseases such as cardiovascular disease (CVD) are linked to chronic low-grade, systemic inflammation. Platelet-monocyte complexes (PMCs) are markers of in vivo platelet activation and atherosclerosis, and may be early indicators of subclinical inflammation. PURPOSE: To examine the effects of an exercise bout on PMCs in those at risk for CVD. METHODS: Twenty-five overweight-obese (BMI 32.7 ± 5.2 kg×m-2, 55-75 yr) women were randomly assigned to either the exercise (EX, n=13) or non-exercise control (CON, n=12) group. EX performed 2 sets of 8 resistance exercises and a 25-min treadmill walk at 70-80% HRR. Blood was obtained pre-exercise (PR), post- (PO), 1-hour and 2 hours post-exercise (1HR and 2HR). Blood was obtained at the same time points in CON. PMCs were identified via flow cytometry and analyzed in each monocyte phenotype. Monocyte phenotypes were defined as: Mon1 (CD14+CD16−CCR2+), Mon2 (CD14+CD16+CCR2+), and Mon3 (CD14+CD16+CCR2−). All events positive for both CD14 and CD42a (marker for platelets) were considered PMCs. RESULTS: A main effect for time revealed an increase in PMC number at PO (p=0.036) which appears to have been driven by EX (EX = 61.5%; CON = 33.8% increase). PMCs formed with Mon1 and Mon2 followed a similar response. A significant group x time interaction for Mon3 PMC number (p=0.002) indicated an increase from PR to PO (PR = 5218±1170, PO = 8195±1152 cells·ml-1), and a decrease from PO to 1HR and 2HR (1HR = 3767±820 cells·ml-1 2HR = 3818±814 cells·ml-1) in EX. PMC number remained constant for CON at all timepoints. Estimated VO2max was negatively correlated with CD42a MFI (a marker of platelet density per monocyte) (r = -0.583, p = 0.003). Systolic blood pressure (SBP) positively correlated with percent PMC (% CD42a positive monocytes; r = 0.458, p = 0.042). CONCLUSION: Aerobic fitness appears to reduce platelet activation indicated by the negative relationship between VO2max and CD42a MFI. Chronic elevations in resting SBP are linked to PMC percentage, possibly due to sheer stress-induced platelet activation. It is possible that PMC elevation at PO is at least partially driven by exercise-induced increases in BP. These results support previous literature, indicating that PMCs are a CVD risk marker and may elucidate one mechanism by which physical fitness reduces risk for CVD