Bcl-xL-mediated remodeling of rod and cone synaptic mitochondria after postnatal lead exposure: electron microscopy, tomography and oxygen consumption.

PurposePostnatal lead exposure produces rod-selective and Bax-mediated apoptosis, decreased scotopic electroretinograms (ERGs), and scotopic and mesopic vision deficits in humans and/or experimental animals. Rod, but not cone, inner segment mitochondria were considered the primary site of action. However, photoreceptor synaptic mitochondria were not examined. Thus, our experiments investigated the structural and functional effects of environmentally relevant postnatal lead exposure on rod spherule and cone pedicle mitochondria and whether Bcl-xL overexpression provided neuroprotection.MethodsC57BL/6N mice pups were exposed to lead only during lactation via dams drinking water containing lead acetate. The blood [Pb] at weaning was 20.6±4.7 µg/dl, which decreased to the control value by 2 months. To assess synaptic mitochondrial structural differences and vulnerability to lead exposure, wild-type and transgenic mice overexpressing Bcl-xL in photoreceptors were used. Electron microscopy, three-dimensional electron tomography, and retinal and photoreceptor synaptic terminal oxygen consumption (QO(2)) studies were conducted in adult control, Bcl-xL, lead, and Bcl-xL/lead mice.ResultsThe spherule and pedicle mitochondria in lead-treated mice were swollen, and the cristae structure was markedly changed. In the lead-treated mice, the mitochondrial cristae surface area and volume (abundance: measure correlated with ATP (ATP) synthesis) were decreased in the spherules and increased in the pedicles. Pedicles also had an increased number of crista segments per volume. In the lead-treated mice, the number of segments/crista and fraction of cristae with multiple segments (branching) similarly increased in spherule and pedicle mitochondria. Lead-induced remodeling of spherule mitochondria produced smaller cristae with more branching, whereas pedicle mitochondria had larger cristae with more branching and increased crista junction (CJ) diameter. Lead decreased dark- and light-adapted photoreceptor and dark-adapted photoreceptor synaptic terminal QO(2). Bcl-xL partially blocked many of the lead-induced alterations relative to controls. However, spherules still had partially decreased abundance, whereas pedicles still had increased branching, increased crista segments per volume, and increased crista junction diameter. Moreover, photoreceptor and synaptic QO(2) were only partially recovered.ConclusionsThese findings reveal cellular and compartmental specific differences in the structure and vulnerability of rod and cone inner segment and synaptic mitochondria to postnatal lead exposure. Spherule and pedicle mitochondria in lead-exposed mice displayed complex and distinguishing patterns of cristae and matrix damage and remodeling consistent with studies showing that synaptic mitochondria are more sensitive to Ca(2+) overload, oxidative stress, and ATP loss than non-synaptic mitochondria. The lead-induced decreases in QO(2) likely resulted from the decreased spherule cristae abundance and smaller cristae, perhaps due to Bax-mediated effects as they occurred in apoptotic rod inner segments. The increase in pedicle cristae abundance and CJ diameter could have resulted from increased Drp1-mediated fission, as small mitochondrial fragments were observed. The mechanisms of Bcl-xL-mediated remodeling might occur via interaction with formation of CJ protein 1 (Fcj1), whereas the partial protection of synaptic QO(2) might result from the enhanced efficiency of energy metabolism via Bcl-xL's direct interaction with the F1F0 ATP synthase and/or regulation of cellular redox status. These lead-induced alterations in photoreceptor synaptic terminal mitochondria likely underlie the persistent scotopic and mesopic deficits in lead-exposed children, workers, and experimental animals. Our findings stress the clinical and scientific importance of examining synaptic dysfunction following injury or disease during development, and developing therapeutic treatments that prevent synaptic degeneration in retinal and neurodegenerative disorders even when apoptosis is blocked

New Zealand blackcurrant extract improves high-intensity intermittent running performance.

New Zealand blackcurrant (BC) intake showed reduced blood lactate during low and moderate intensity cycling and improved 16.1 km cycling time trial performance. We examined the effect of BC on high-intensity intermittent treadmill running and post-running lactate clearance. Thirteen active males (age: 25±4 yrs, stature: 1.82±0.07 m, body mass: 81±14 kg, V̇O2max: 56±4 mL∙kg-1∙min-1, velocity at V̇O2max: 17.6±0.8 km∙h-1, mean±SD) visited the laboratory three times. In the 1st visit, a ramp protocol (0.1 km∙h-1 every 5 sec) was completed to establish V̇O2max and velocity at V̇O2max, and subjects were familiarised with the protocols. In visits 2 and 3, subjects completed an high intensity intermittent running capability test which consisted of six 19 s high-intensity running bouts, each interspersed by 15 s of low-intensity running, followed by 1 minute of rest, this was repeated at increasing speeds, until exhaustion. Prior to visits 2 and 3, subjects consumed either New Zealand BC extract (300 mg∙day-1 CurraNZ™; containing 105 mg anthocyanin) or placebo (P) (300 mg∙day-1 microcrystalline cellulose M102) for 7 days in capsules (double blind, randomised, cross-over design, wash-out at least 14 days). Blood lactate was collected for 30 min post-exhaustion. Two-tailed paired t-tests were used and significance accepted at p< .05. BC increased total running distance by 10.6% (BC: 4282±833 m, P: 3871±622 m, p = .023, 10 out of 13 subjects improved), with the distance during the high-intensity running bouts by 10.8% (p= .024). Heart rate, rating of perceived exertion and oxygen uptake were not different between conditions for each stage. At exhaustion, lactate tended to be higher for BC (BC: 6.01±1.07 mmol∙L-1, P: 5.22±1.52 mmol∙L-1, p = .066, 9 out of 13 subjects). There was a trend towards improved lactate clearance following 15 min (BC: -2.89±0.51 mmol∙L-1, P: -2.46±0.39 mmol∙L-1, p = .07) and 30 minutes of passive recovery (BC: -4.12±0.73 mmol∙L-1, P: -3.66±1.01 mmol∙L-1, p = 0.11). It is concluded that New Zealand blackcurrant extract (CurraNZ™) may enhance performance in team sports characterised by high-intensity intermittent exercise as with BC intake greater distances were covered during high-intensity running, there was higher lactate tolerance, and increased lactate clearance after high-intensity exercise

The impact of asking intention or self-prediction questions on subsequent behavior: a meta-analysis

The current meta-analysis estimated the magnitude of the impact of asking intention and self-prediction questions on rates of subsequent behavior, and examined mediators and moderators of this question–behavior effect (QBE). Random-effects meta-analysis on 116 published tests of the effect indicated that intention/prediction questions have a small positive effect on behavior (d+ = 0.24). Little support was observed for attitude accessibility, cognitive dissonance, behavioral simulation, or processing fluency explanations of the QBE. Multivariate analyses indicated significant effects of social desirability of behavior/behavior domain (larger effects for more desirable and less risky behaviors), difficulty of behavior (larger effects for easy-to-perform behaviors), and sample type (larger effects among student samples). Although this review controls for co-occurrence of moderators in multivariate analyses, future primary research should systematically vary moderators in fully factorial designs. Further primary research is also needed to unravel the mechanisms underlying different variants of the QBE

Effect of New Zealand Blackcurrant Extract on Isometric Contraction-Induced Fatigue and Recovery: Potential Muscle-Fiber Specific Effects

New Zealand blackcurrant (NZBC) extract has shown performance-enhancing effects during cycling, running and sport climbing. We examined effects of NZBC extract on (1) voluntary and twitch force of the quadriceps femoris muscles during repeated isometric contraction-induced fatigue, (2) twitch force during recovery and (3) muscle fiber-specific effects. Familiarized recreationally active males (n = 12, age: 24 ± 5 yrs; height: 180 ± 5 cm; body mass: 89 ± 11 kg) performed sixteen, 5-s voluntary maximal isometric contractions (iMVC) separated by 3-s rest. Twitch force was recorded before, during the 3-s rests and 5-min recovery. Supplementation consisted of 7-days intake of NZBC extract (600 mg∙day−1 containing 210 mg anthocyanin) in a double-blind, randomized, placebo-controlled crossover design with a 14-days washout. NZBC extract allowed for greater force in the first quartile of the iMVCs. Twitch force at baseline was 12% higher with NZBC extract (p = 0.05). However, there was no effect of NZBC for twitch force during the 16-iMVCs and recovery. Based on the maximum post-activation potentiation during the placebo 16-iMVCs, four subjects were classified of having a predominant type I or II muscle fiber typology. In type II, NZBC extract provided a trend for increased MVC force (~14%) in the first quartile and for type I in the fourth quartile (~10%). In type I, NZBC extract seemed to have higher twitch forces during the fatiguing exercise protocol and recovery, indicating increased fatigue resistance. New Zealand blackcurrant extract affects force during repeated maximal isometric contractions. Future work on mechanisms by NZBC extract for muscle fiber-specific fatigue-induced force responses is warranted

Using integrated growth to delineate debris-flow inundation

Debris-flow volume is fundamental to mobility, yet many debris flows change volume as they travel. Growth can occur through diverse processes such as channel-bed entrainment, bank failures, aggregation of landslides, and coalescence of multiple flows. Integrating growth, either over upslope area or stream length, combines the effects of these growth processes and requires specification of only the growth zone extent and a growth factor. To delineate potential debris-flow inundation, we implement integrated growth factors and simple volume-area relations in a new USGS software package, Grfin Tools. We present two examples of forecasting debris-flow inundation – one using an area growth factor in Puerto Rico and another using a channel-length growth factor in Oregon, USA. The use of growth zones and growth factors enables scenario-based hazard assessments for geomorphic settings with debris-flow growth

The acute kidney outreach to prevent deterioration and death – a large pilot study for a cluster randomised trial

Background and objectives: The Acute Kidney Outreach to Reduce Deterioration and Death (AKORDD) trial was a large pilot study for a cluster randomised trial of AKI Outreach. Design, Setting, Participants, and Measurements: An observational Control (Before) phase was conducted in two teaching hospitals (9 miles apart) and their respective catchment areas. In the Intervention (After) phase, a working hours AKI outreach service operated for the intervention hospital/area for 20 weeks, with the other site acting as a control. All AKI alerts in both hospital and community patients were screened for inclusion. Major exclusion criteria were patients who were end of life, or unlikely to benefit from Outreach, or lacking mental capacity, or already referred to the Renal team. The intervention arm included a model of escalation of renal care to AKI patients, depending on AKI stage. The 30-day primary outcome was a combination of death, or deterioration, as shown by any need for dialysis or progression in AKI stage. 1762 adult patients were recruited; 744 at the Intervention site during the After phase. Results: A median of 3.0 non-medication recommendations and 0.5 medication related recommendations per patient were made by the Outreach team, a median of 15.7 hours after the AKI alert. Relatively low rates of the primary outcomes of death within 30 days (11-15%), or requirement for dialysis (0.4 – 3.7%) were seen across all four groups. In an exploratory analysis, at the Intervention hospital during the After phase the was an odds ratio for the combined primary outcome of 0.73 (95% CI 0.42, 1.26, p = 0.26). Conclusions: An AKI outreach service can provide standardised specialist care to those with AKI across a healthcare economy. Trials assessing AKI outreach may benefit from focusing on those patients with "mid-range" prognosis, where nephrological intervention could have the most impact

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

Aims/hypothesis Sodium glucose cotransporter 2 (SGLT2) inhibition lowers HbA(1c), systolic BP (SBP) and weight in patients with type 2 diabetes and reduces renal hyperfiltration associated with type 1 diabetes, suggesting decreased intraglomerular hypertension. As lowering HbA(1c), SBP, weight and intraglomerular pressure is associated with antialbuminuric effects in diabetes, we hypothesised that SGLT2 inhibition would reduce the urine albumin-to-creatinine ratio (UACR) to a clinically meaningful extent. Methods We examined the effect of the SGLT2 inhibitor empagliflozin on UACR by pooling data from patients with type 2 diabetes and prevalent microalbuminuria (UACR=30-300 mg/g; n = 636) or macroalbuminuria (UACR>300 mg/g; n=215) who participated in one of five phase III randomised clinical trials. Primary assessment was defined as percentage change in geometric mean UACR from baseline to week 24. Results After controlling for clinical confounders including baseline log-transformed UACR, HbA(1c), SBP and estimated GFR (according to the Modification of Diet in Renal Disease [MDRD] formula), treatment with empagliflozin significantly reduced UACR in patients with microalbuminuria (-32% vs placebo; p Conclusions/interpretation In patients with type 2 diabetes and either micro-or macroalbuminuria, empagliflozin reduced UACR by a clinically meaningful amount. This effect was largely independent of the known metabolic or systemic haemodynamic effects of this drug class. Our results further support a direct renal effect of SGLT2 inhibitors. Prospective studies are needed to explore the potential of this intervention to alter the course of kidney disease in high-risk patients with diabetes. Trial registration: Clinicaltrials.gov NCT01177813 (study 1); NCT01159600 (study 2); NCT01159600 (study 3); NCT01210001 (study 4); and NCT01164501 (study 5).Peer reviewe