Nuclear expression of PG-21, SRC-1, and pCREB in regions of the lumbosacral spinal cord involved in pelvic innervation in young adult and aged rats

In rats, ageing results in dysfunctional patterns of micturition and diminished sexual reflexes that may reflect degenerative changes within spinal circuitry. In both sexes the dorsal lateral nucleus and the spinal nucleus of the bulbospongiosus, which lie in the L5-S1 spinal segments, contain motor neurons that innervate perineal muscles, and the external anal and urethral sphincters. Neurons in the sacral parasympathetic nucleus of these segments provide autonomic control of the bladder, cervix and penis and other lower urinary tract structures. Interneurons in the dorsal gray commissure and dorsal horn have also been implicated in lower urinary tract function. This study investigates the cellular localisation of PG-21 androgen receptors, steroid receptor co-activator one (SRC-1) and the phosphorylated form of c-AMP response element binding protein (pCREB) within these spinal nuclei. These are components of signalling pathways that mediate cellular responses to steroid hormones and neurotrophins. Nuclear expression of PG-21 androgen receptors, SRC-1 and pCREB in young and aged rats was quantified using immunohistochemistry. There was a reduction in the number of spinal neurons expressing these molecules in the aged males while in aged females, SRC-1 and pCREB expression was largely unchanged. This suggests that the observed age-related changes may be linked to declining testosterone levels. Acute testosterone therapy restored expression of PG-21 androgen receptor in aged and orchidectomised male rats, however levels of re-expression varied within different nuclei suggesting a more prolonged period of hormone replacement may be required for full restoratio

Piperonyl butoxide (PBO) combined with pyrethroids in insecticide-treated nets to prevent malaria in Africa.

BackgroundPublic health strategies that target mosquito vectors, particularly pyrethroid long-lasting insecticidal nets (LLINs), have been largely responsible for the substantial reduction in the number of people in Africa developing malaria. The spread of insecticide resistance in Anopheles mosquitoes threatens these impacts. One way to control insecticide-resistant populations is by using insecticide synergists. Piperonyl butoxide (PBO) is a synergist that inhibits specific metabolic enzymes within mosquitoes and has been incorporated into pyrethroid-LLINs to form pyrethroid-PBO nets. Pyrethroid-PBO nets are currently produced by four LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns in countries. This review examines epidemiological and entomological evidence on whether the addition of PBO to LLINs improves their efficacy.Objectives1. Evaluate whether adding PBO to pyrethroid LLINs increases the epidemiological and entomological effectiveness of the nets.2. Compare the effects of pyrethroid-PBO nets currently in commercial development or on the market with their non-PBO equivalent in relation to:a. malaria infection (prevalence or incidence);b. entomological outcomes.Search methodsWe searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; CENTRAL, MEDLINE, Embase, Web of Science, CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 24 August 2018. We contacted organizations for unpublished data. We checked the reference lists of trials identified by the above methods.Selection criteriaWe included laboratory trials, experimental hut trials, village trials, and randomized clinical trials with mosquitoes from the Anopheles gambiae complex or Anopheles funestus group.Data collection and analysisTwo review authors assessed each trial for eligibility, extracted data, and determined the risk of bias for included trials. We resolved disagreements through discussion with a third review author. We analysed the data using Review Manager 5 and assessed the certainty of the evidence using the GRADE approach.Main resultsFifteen trials met the inclusion criteria: two laboratory trials, eight experimental hut trials, and five cluster-randomized controlled village trials.One village trial examined the effect of pyrethroid-PBO nets on malaria infection prevalence in an area with highly pyrethroid-resistant mosquitoes. The latest endpoint at 21 months post-intervention showed that malaria prevalence probably decreased in the intervention arm (OR 0.40, 95% CI 0.20 to 0.80; 1 trial, 1 comparison, moderate-certainty evidence).In highly pyrethroid-resistant areas ( 90% mosquito mortality), there may be little or no difference in the effect of unwashed pyrethroid-PBO nets compared to unwashed standard-LLINs on mosquito mortality (RR 1.20, 95% CI 0.64 to 2.26; 2791 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). This is similar for washed nets (RR 1.07, 95% CI 0.92 to 1.25; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence). We do not know if unwashed pyrethroid-PBO nets have any effect on blood feeding success of susceptible mosquitoes (RR 0.50, 95% CI 0.11 to 2.32; 2791 mosquitoes, 2 trials, 2 comparisons, very low-certainty evidence). The same applies to washed nets (RR 1.28, 95% CI 0.81 to 2.04; 2644 mosquitoes, 2 trials, 2 comparisons, low-certainty evidence).In village trials comparing pyrethroid-PBO nets to LLINs, there was no difference in sporozoite rate (4 trials, 5 comparison) and mosquito parity (3 trials, 4 comparisons).Authors' conclusionsIn areas of high insecticide resistance, pyrethroid-PBO nets reduce mosquito mortality and blood feeding rates, and results from a single clinical trial demonstrate that this leads to lower malaria prevalence. Questions remain about the durability of PBO on nets, as the impact of pyrethroid-PBO LLINs on mosquito mortality was not sustained over 20 washes in experimental hut trials. There is little evidence to support higher entomological efficacy of pyrethroid-PBO nets in areas where the mosquitoes show lower levels of resistance to pyrethroids

Piperonyl butoxide (PBO) combined with pyrethroids in insecticide‐treated nets to prevent malaria in Africa

Background: Public health strategies that target mosquito vectors, particularly pyrethroid long-lasting insecticidal nets (LLINs), have been largely responsible for the substantial reduction in the number of people in Africa developing malaria. The spread of insecticide resistance in Anopheles mosquitoes threatens these impacts. One way to control insecticide-resistant populations is by using insecticide synergists. Piperonyl butoxide (PBO) is a synergist that inhibits specific metabolic enzymes within mosquitoes and has been incorporated into pyrethroid-LLINs to form pyrethroid-PBO nets. Pyrethroid-PBO nets are currently produced by four LLIN manufacturers and,following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns incountries. This review examines epidemiological and entomological evidence on whether the addition of PBO to LLINs improves theirefficacy. Objectives1. Evaluate whether adding PBO to pyrethroid LLINs increasesthe epidemiological and entomological effectiveness of the nets.2. Compare the effects of pyrethroid-PBO nets currently in commercial development or on the market with their non-PBO equivalentin relation to:a. malaria infection (prevalence or incidence);b. entomological outcomes. Search methods . We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register; CENTRAL, MEDLINE, Embase, Web of Science,CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 24August 2018. We contacted organizations for unpublished data. We checked the reference lists of trials identified by the above methods

Structural Plasticity and Noncovalent Substrate Binding in the GroEL Apical Domain. A study using electrospray ionization mass spectrometry and fluorescence binding studies

Advances in understanding how GroEL binds to non-native proteins are reported. Conformational flexibility in the GroEL apical domain, which could account for the variety of substrates that GroEL binds, is illustrated by comparison of several independent crystallographic structures of apical domain constructs that show conformational plasticity in helices H and I. Additionally, ESI-MS indicates that apical domain constructs have co-populated conformations at neutral pH. To assess the ability of different apical domain conformers to bind co-chaperone and substrate, model peptides corresponding to the mobile loop of GroES and to helix D from rhodanese were studied. Analysis of apical domain-peptide complexes by ESI-MS indicates that only the folded or partially folded apical domain conformations form complexes that survive gas phase conditions. Fluorescence binding studies show that the apical domain can fully bind both peptides independently. No competition for binding was observed, suggesting the peptides have distinct apical domain-binding sites. Blocking the GroES-apical domain-binding site in GroEL rendered the chaperonin inactive in binding GroES and in assisting the folding of denatured rhodanese, but still capable of binding non-native proteins, supporting the conclusion that GroES and substrate proteins have, at least partially, distinct binding sites even in the intact GroEL tetradecamer

Some practical studies with flames used in analytical atomic spectroscopy

Imperial Users onl

Piperonyl butoxide (PBO) combined with pyrethroids in insecticide-treated nets to prevent malaria in Africa

Background Pyrethroid long‐lasting insecticidal nets (LLINs) have been important in the large reductions in malaria cases in Africa, but insecticide resistance in Anopheles mosquitoes threatens their impact. Insecticide synergists may help control insecticide‐resistant populations. Piperonyl butoxide (PBO) is such a synergist; it has been incorporated into pyrethroid‐LLINs to form pyrethroid‐PBO nets, which are currently produced by five LLIN manufacturers and, following a recommendation from the World Health Organization (WHO) in 2017, are being included in distribution campaigns. This review examines epidemiological and entomological evidence on the addition of PBO to pyrethroid nets on their efficacy. Objectives To compare effects of pyrethroid‐PBO nets currently in commercial development or on the market with effects of their non‐PBO equivalent in relation to: 1. malaria parasite infection (prevalence or incidence); and 2. entomological outcomes. Search methods We searched the Cochrane Infectious Diseases Group (CIDG) Specialized Register, CENTRAL, MEDLINE, Embase, Web of Science, CAB Abstracts, and two clinical trial registers (ClinicalTrials.gov and WHO International Clinical Trials Registry Platform) up to 25 September 2020. We contacted organizations for unpublished data. We checked the reference lists of trials identified by these methods. Selection criteria We included experimental hut trials, village trials, and randomized controlled trials (RCTs) with mosquitoes from the Anopheles gambiae complex or the Anopheles funestus group. Data collection and analysis Two review authors assessed each trial for eligibility, extracted data, and determined the risk of bias for included trials. We resolved disagreements through discussion with a third review author. We analysed data using Review Manager 5 and assessed the certainty of evidence using the GRADE approach. Main results Sixteen trials met the inclusion criteria: 10 experimental hut trials, four village trials, and two cluster‐RCTs (cRCTs). Three trials are awaiting classification, and four trials are ongoing. Two cRCTs examined the effects of pyrethroid‐PBO nets on parasite prevalence in people living in areas with highly pyrethroid‐resistant mosquitoes (< 30% mosquito mortality in discriminating dose assays). At 21 to 25 months post intervention, parasite prevalence was lower in the intervention arm (odds ratio (OR) 0.79, 95% confidence interval (CI) 0.67 to 0.95; 2 trials, 2 comparisons; moderate‐certainty evidence). In highly pyrethroid‐resistant areas, unwashed pyrethroid‐PBO nets led to higher mosquito mortality compared to unwashed standard‐LLINs (risk ratio (RR) 1.84, 95% CI 1.60 to 2.11; 14,620 mosquitoes, 5 trials, 9 comparisons; high‐certainty evidence) and lower blood feeding success (RR 0.60, 95% CI 0.50 to 0.71; 14,000 mosquitoes, 4 trials, 8 comparisons; high‐certainty evidence). However, in comparisons of washed pyrethroid‐PBO nets to washed LLINs, we do not know if PBO nets had a greater effect on mosquito mortality (RR 1.20, 95% CI 0.88 to 1.63; 10,268 mosquitoes, 4 trials, 5 comparisons; very low‐certainty evidence), although the washed pyrethroid‐PBO nets did decrease blood‐feeding success compared to standard‐LLINs (RR 0.81, 95% CI 0.72 to 0.92; 9674 mosquitoes, 3 trials, 4 comparisons; high‐certainty evidence). In areas where pyrethroid resistance is moderate (31% to 60% mosquito mortality), mosquito mortality was higher with unwashed pyrethroid‐PBO nets compared to unwashed standard‐LLINs (RR 1.68, 95% CI 1.33 to 2.11; 751 mosquitoes, 2 trials, 3 comparisons; moderate‐certainty evidence), but there was little to no difference in effects on blood‐feeding success (RR 0.90, 95% CI 0.72 to 1.11; 652 mosquitoes, 2 trials, 3 comparisons; moderate‐certainty evidence). For washed pyrethroid‐PBO nets compared to washed standard‐LLINs, we found little to no evidence for higher mosquito mortality or reduced blood feeding (mortality: RR 1.07, 95% CI 0.74 to 1.54; 329 mosquitoes, 1 trial, 1 comparison, low‐certainty evidence; blood feeding success: RR 0.91, 95% CI 0.74 to 1.13; 329 mosquitoes, 1 trial, 1 comparison; low‐certainty evidence). In areas where pyrethroid resistance is low (61% to 90% mosquito mortality), studies reported little to no difference in the effects of unwashed pyrethroid‐PBO nets compared to unwashed standard‐LLINs on mosquito mortality (RR 1.25, 95% CI 0.99 to 1.57; 948 mosquitoes, 2 trials, 3 comparisons; moderate‐certainty evidence), and we do not know if there was any effect on blood‐feeding success (RR 0.75, 95% CI 0.27 to 2.11; 948 mosquitoes, 2 trials, 3 comparisons; very low‐certainty evidence). For washed pyrethroid‐PBO nets compared to washed standard‐LLINs, we do not know if there was any difference in mosquito mortality (RR 1.39, 95% CI 0.95 to 2.04; 1022 mosquitoes, 2 trials, 3 comparisons; very low‐certainty evidence) or on blood feeding (RR 1.07, 95% CI 0.49 to 2.33; 1022 mosquitoes, 2 trials, 3 comparisons; low‐certainty evidence). In areas where mosquito populations are susceptible to insecticides (> 90% mosquito mortality), there may be little to no difference in the effects of unwashed pyrethroid‐PBO nets compared to unwashed standard‐LLINs on mosquito mortality (RR 1.20, 95% CI 0.64 to 2.26; 2791 mosquitoes, 2 trials, 2 comparisons; low‐certainty evidence). This is similar for washed nets (RR 1.07, 95% CI 0.92 to 1.25; 2644 mosquitoes, 2 trials, 2 comparisons; low‐certainty evidence). We do not know if unwashed pyrethroid‐PBO nets had any effect on the blood‐feeding success of susceptible mosquitoes (RR 0.52, 95% CI 0.12 to 2.22; 2791 mosquitoes, 2 trials, 2 comparisons; very low‐certainty evidence). The same applies to washed nets (RR 1.25, 95% CI 0.82 to 1.91; 2644 mosquitoes, 2 trials, 2 comparisons; low‐certainty evidence). In village trials comparing pyrethroid‐PBO nets to LLINs, there was no difference in sporozoite rate (4 trials, 5 comparisons) nor in mosquito parity (3 trials, 4 comparisons). Authors' conclusions In areas of high insecticide resistance, pyrethroid‐PBO nets have greater entomological and epidemiological efficacy compared to standard LLINs, with sustained reduction in parasite prevalence, higher mosquito mortality and reduction in mosquito blood feeding rates 21 to 25 months post intervention. Questions remain about the durability of PBO on nets, as the impact of pyrethroid‐PBO nets on mosquito mortality was not sustained over 20 washes in experimental hut trials, and epidemiological data on pyrethroid‐PBO nets for the full intended three‐year life span of the nets is not available. Little evidence is available to support greater entomological efficacy of pyrethroid‐PBO nets in areas where mosquitoes show lower levels of resistance to pyrethroids