Raloxifene blocks estradiol induction of the serotonin transporter and 5-hydroxytryptamine2A receptor in female rat brain

Sex steroids have potent effects on mood, mental state and cognition. Our previous findings and those of others suggest that these effects may be due at least in part to estradiol actions on central serotonergic mechanisms. Specifically, estradiol-17beta in its acute positive feedback mode for gonadotropin release in the female rat induces expression of the genes for the 5-hydroxytryptamine(2A) receptor (5-HT(2A)R) and the serotonin transporter (SERT) in the dorsal raphe nucleus (DRN). This is accompanied by an increase in the densities of 5-HT(2A)R and the SERT in forebrain regions which in the human are concerned with the control of mood, mental state, cognition and emotion. Here we report that raloxifene, a benzothiophene and selective estrogen receptor modulator (SERM), completely blocked estradiol stimulation of brain 5-HT(2A)R and SERT expression in acutely ovariectomized rats. Raloxifene also blocked the estrogen-induced surge of luteinizing hormone. Treatment of acutely ovariectomized rats with raloxifene alone increased the density of SERT sites in the mid-frontal cortex and decreased the density of 5-HT(2A)R in the posterior olfactory tubercle. The inhibitory effects of raloxifene on acute estrogen-induction of central serotonergic mechanisms were similar to those of tamoxifen even though there are major differences between the two SERMs in their affinity for the two estrogen receptor subtypes and their actions on the uterus. These findings provide robust evidence that estradiol induction of the 5-HT(2A)R and the SERT in brain is mediated by nuclear estrogen receptors. Our data may provide the basis for obtaining a better understanding of the effects of sex steroids on mood and mental state in the human and the possible rational development of congeners of sex steroids for the treatment of mental disorders.     

Diabetes and peripheral neuropathy: keeping people on their own two feet

Peripheral neuropathy is one of the most common forms of diabetes-related neuropathy, and most commonly affects the feet. Loss of sensation leaves the feet at risk of damage--from environmental hazards, incorrectly fitting footwear or un-felt pressure damage--which can lead to the need for amputations. This article discusses how to reduce the risk of peripheral neuropathy through glycaemic control, and the steps that need to be taken to reduce the risk of injury on the neuropathic foot.     

The impact of religiously tailored and ethically balanced education on intention for living organ donation among Muslim Americans

We tested the efficacy of religiously tailored and ethically balanced education upon living kidney organ donation intent among Muslim Americans. Pre-post changes in participant stage of change, preparedness, and likelihood judged efficacy. Among 137 participants, mean stage of change toward donation appeared to improve (0.59; SD ± 1.07, P < .0001), as did the group's preparedness to make a donation decision (0.55; SD ± 0.86, P < .0001), and likelihood to donate a kidney (0.39; SD ± 0.85, P < .0001). Mean change in likelihood to encourage a loved one, a co-worker, or a mosque community member with ESRD to seek a living donor also increased (0.22; SD ± 0.84, P = .0035, 0.23; SD ± 0.82, P = .0021, 0.33; SD ± 0.79, P < .0001 respectively). Multivariate ordered logistic regression models revealed that gains in biomedical knowledge regarding organ donation increased odds for positive change in preparedness (OR = 1.20; 95% CI 1.01-1.41, P = .03), while increasing age associated with lower odds of positive change in stage of change (OR = 0.98, 95% CI 0.96-0.998, P = .03), and prior registration as an organ donor lowered odds for an increase in likelihood to donate a kidney (OR = 0.22; 95% CI 0.08-0.60, P = .003). Our intervention appears to enhance living kidney donation-related intent among Muslim Americans [Clinicaltrials.gov number: NCT04443114].     

NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists

Spinal NMDA receptors (NMDA R) are important in neuropathic sensitisation and acute administration of antagonists can provide temporary attenuation of sensitisation. If establishment of the chronic pain state could be prevented by brief administration of such agents at or around the time of nerve injury (pre-emptive analgesia) it might be possible to avoid many of the unacceptable side effects associated with repeated administration of these or other antagonists. Several reports describe aspects of effective pre-emptive analgesia from NMDA R antagonists in animal models of neuropathic pain. The first aim of the present study was to make a direct comparison of changes in mechanical allodynia, cold allodynia and thermal hyperalgesia following nerve injury, demonstrating their increasing degree of susceptibility to pre-emptive NMDA R antagonist treatment. Secondly, we used immunoblotting and immunohistochemistry to investigate the effects of nerve injury on NMDA receptor subunit expression, revealing increased expression of NR2B, but not NR2A and reduced NR1 in the superficial dorsal horn. These changes were attenuated following NMDA receptor antagonist pre-treatment. Thirdly, we investigated the pharmacological properties of residual mechanical allodynia and cold allodynia that remained after pre-emptive treatment and revealed a greater sensitivity to NMDA R antagonists. These findings indicate that in addition to a marked suppression of thermal hyperalgesia and cold allodynia, pre-emptive treatment with NMDA R antagonist causes a lasting change in spinal NMDA R complexes such that remaining mechanical allodynia should be more effectively targeted by NMDA R antagonists.     

Badger responses to small-scale culling may compromise targeted control of bovine tuberculosis

Where wildlife disease requires management, culling is frequently considered but not always effective. In the British Isles, control of cattle tuberculosis (TB) is hindered by infection in wild badger (Meles meles) populations. Large-scale badger culling can reduce the incidence of confirmed cattle TB, but these benefits are undermined by culling-induced changes in badger behavior (termed perturbation), which can increase transmission among badgers and from badgers to cattle. Test–vaccinate/remove (TVR) is a novel approach that entails testing individual badgers for infection, vaccinating test-negative animals, and killing test-positive animals. Imperfect capture success, diagnostic sensitivity, and vaccine effectiveness mean that TVR would be expected to leave some infected and some susceptible badgers in the population. Existing simulation models predict that TVR could reduce cattle TB if such small-scale culling causes no perturbation, but could increase cattle TB if considerable perturbation occurs. Using data from a long-term study, we show that past small-scale culling was significantly associated with four metrics of perturbation in badgers: expanded ranging, more frequent immigration, lower genetic relatedness, and elevated prevalence of Mycobacterium bovis, the causative agent of TB. Though we could not reject the hypothesis that culling up to three badgers per social group might avoid perturbation, we also could not reject the hypothesis that killing a single badger prompted detectable perturbation. When considered alongside existing model predictions, our findings suggest that implementation of TVR, scheduled for 2014, risks exacerbating the TB problem rather than controlling it. Ongoing illegal badger culling is likewise expected to increase cattle TB risks.Infectious diseases are often difficult to control where wildlife hosts contribute to pathogen persistence. Wildlife culling is a frequently considered control option, which is sometimes effective (1, 2), but often ineffective (3–6).In the United Kingdom, the cattle farming industry is seriously affected by bovine tuberculosis (TB) caused by Mycobacterium bovis (7). Selective culling of test-positive cattle has helped to eradicate TB across much of the developed world, but eradication from the United Kingdom is impeded by M. bovis infection in European badgers (Meles meles) (8), as well as by continued transmission among cattle (9–11). Transmission has also been documented among badgers (12), from cattle to badgers (13), and from badgers to cattle (14, 15). Because badgers are clearly a contributing factor to the UK’s TB problem, successive TB control policies have included culling of badgers (7, 8). To date, cattle controls have emphasized selective slaughter of test-positive animals, whereas badger culls have typically been nonselective, with no testing of live animals before culling (but see ref. 16).The impacts of nonselective badger culling on M. bovis transmission are well established. Such culling reduces badger density (17), but also promotes dispersal into the culled area (18) as well as expanding badger ranging in and around the areas where culls occurred (19). In Britain these behavioral changes—termed social perturbation—have been linked to increases in the proportion of badgers infected with M. bovis (13, 20), and reductions in the spatial clustering of infection (21). In cattle, the incidence of confirmed TB was reduced inside large culling areas where badger numbers were substantially suppressed by annual “proactive” culling. However, on adjoining unculled lands, and in areas receiving localized “reactive” culling, reductions in badger numbers were smaller, the incidence of confirmed cattle TB was elevated (14, 15, 22–24), and spatial clustering of cattle infection was reduced (21).This propensity of nonselective badger culling to prompt social perturbation and hence increase disease transmission is a major constraint on its utility as a tool for controlling cattle TB. An alternative approach, first proposed in the 1980s, would be to target culling at test-positive badgers, just as current controls target test-positive cattle (16, 25). A further elaboration, termed test–vaccinate/remove (TVR), involves killing test-positive badgers while vaccinating test-negative badgers. A pilot TVR program is scheduled to take place across 100 sq km in Northern Ireland in 2014 (26).Selective culling approaches (such as TVR) are likely to remove relatively small numbers of badgers. First, constraints on capture success limit testing to 56–85% of the badger population (27, 28). Second, not all captured badgers will be infected with M. bovis: in the 10 initial proactive culls of the Randomized Badger Culling Trial (RBCT), 2–38% of badgers had infection detectable by bacterial culture at standard necropsy (29). Third, not all infected badgers are detectable by available live tests: the only available trap-side test detected 49% of badgers that were culture-positive at necropsy (30), and standard necropsy itself detected only 55% of infected badgers (31). This combination of imperfect capture success, low average infection prevalence, and imperfect test sensitivity means that the numbers of badgers to be killed by selective culling would probably be low, usually just one or two badgers within a social group (32). The same factors, combined with incomplete vaccine efficacy (33), mean that some infected and some susceptible badgers would be expected to remain despite implementation of TVR.Simulations indicate that the likely consequences of TVR for cattle TB control are highly sensitive to assumptions about whether culling small numbers of badgers prompts social perturbation (34, 35). Neither cage trapping for testing nor vaccination has been found to cause behavioral change. If the culling component of TVR likewise causes no perturbation, then TVR is predicted to reduce the prevalence of M. bovis infection in badgers and hence the incidence of cattle TB (34, 35). However, if TVR causes perturbation similar to that associated with past large- and small-scale culling, then it is projected to prompt sustained (34) or transient (35) increases in cattle TB. Unfortunately, it is not known which of these scenarios is more likely. Although the behavioral and epidemiological consequences of nonselective culling are relatively well understood, there have been no empirical studies of badgers’ behavioral responses to killing small numbers of animals per social group, as would occur under TVR and other forms of selective culling.In this paper, we use data from a large-scale study to assess whether killing small numbers of badgers would be expected to prompt social perturbation. We compare patterns of badger movement and M. bovis infection at the start of the RBCT (conducted 1998–2005) (14) with two indices of badger mortality. Our first measure, road density, provides an index of the numbers of badgers killed in road accidents (36), an important cause of badger mortality in Britain (37, 38). Our second measure is prior nonselective culling, conducted during the period 1986–1998 as small-scale badger removal operations (BROs), which typically targeted single farms (8). We hypothesized that high road densities and intense prior culling would each lead to expanded badger movement and elevated M. bovis prevalence. Further, we hypothesized that perturbation might be avoided if the number of badgers killed remained below a certain threshold, and sought to estimate this threshold.     

Prefrontal Cortex Activity and Gait in Parkinson's Disease With Cholinergic and Dopaminergic Therapy

Degradation of striatal dopamine in Parkinson's disease (PD) may initially be supplemented by increased cognitive control mediated by cholinergic mechanisms. Shift to cognitive control of walking can be quantified by prefrontal cortex activation. Levodopa improves certain aspects of gait and worsens others, and cholinergic augmentation influence on gait and prefrontal cortex activity remains unclear. This study examined dopaminergic and cholinergic influence on gait and prefrontal cortex activity while walking in PD. A single-site, randomized, double-blind crossover trial examined effects of levodopa and donepezil in PD. Twenty PD participants were randomized, and 19 completed the trial. Participants were randomized to either levodopa + donepezil (5 mg) or levodopa + placebo treatments, with 2 weeks with treatment and a 2-week washout. The primary outcome was change in prefrontal cortex activity while walking, and secondary outcomes were change in gait and dual-task performance and attention. Levodopa decreased prefrontal cortex activity compared with off medication (effect size, −0.51), whereas the addition of donepezil reversed this decrease. Gait speed and stride length under single- and dual-task conditions improved with combined donepezil and levodopa compared with off medication (effect size, 1 for gait speed and 0.75 for stride length). Dual-task reaction time was quicker with levodopa compared with off medication (effect size, −0.87), and accuracy improved with combined donepezil and levodopa (effect size, 0.47). Cholinergic therapy, specifically donepezil 5 mg/day for 2 weeks, can alter prefrontal cortex activity when walking and improve secondary cognitive task accuracy and gait in PD. Further studies will investigate whether higher prefrontal cortex activity while walking is associated with gait changes. © 2020 International Parkinson and Movement Disorder Society     

A Scoping Review of School-Based Efforts to Support Students Who Have Experienced Trauma

School Mental Health - The current review sought to describe the published literature relative to addressing trauma in schools. Through a systematic review of peer-reviewed publications as well as...     

Determination of arylglycerol-beta-aryl ether linkages in enzymatic mild acidolysis lignins (EMAL): comparison of DFRC/(31)P NMR with thioacidolysis

Enzymatic mild acidolysis lignins (EMAL) isolated from different species of softwood and Eucalyptus globulus were submitted to comparative analysis that included thioacidolysis, derivatization followed by reductive cleavage (DFRC), and DFRC followed by quantitative (31)P NMR (DFRC/(31)P NMR). While gas chromatography (GC) was used to determine the monomer yields from both thioacidolysis and DFRC, (31)P NMR studies quantified the various phenolic hydroxy groups released by DFRC. The monomer yields from thioacidolysis and DFRC were substantially different, with thioacidolysis resulting in higher yields. In contrast, an excellent agreement was obtained in the total number of beta-aryl ether structures determined by thioacidolysis and DFRC/(31)P NMR, indicating that the combination of DFRC with quantitative (31)P NMR overcomes, at least in part, the limitations presented by the DFRC method. Both thioacidolysis and DFRC/(31)P NMR were further used to better understand the lignin isolation process from wood. The results show that mild rotary ball milling minimizes, but does not prevent, the degradation of beta-O-4 structures during the early stages of wood pulverization. The extent of such degradation was found to be higher for E. globulus than for a variety of softwoods examined. Furthermore, the structures of the EMALs isolated at yields ranging from 20% to 62% were very similar, indicating structural homogeneity in the lignin biopolymer within the secondary wall.     

Comparison of changes in abdominal muscle thickness between standing and crook lying during active abdominal hollowing using ultrasound imaging

To determine if transversus abdominis (TrA) demonstrates a greater increase in thickness on lower abdominal hollowing (LAH) in standing compared to crook lying.Muscle thickness measurements of TrA, addition of internal obliques (IO) and external obliques (EO) were measured using ultrasound imaging at rest and during LAH on 28 healthy controls (14 female, 14 male) in crook lying and standing.TrA demonstrated greater thickness changes on LAH in standing (+0.88 mm ± 0.12 mm). IO and EO demonstrated greater thickness changes on LAH in crook lying (+0.59 mm ± 0.08 mm and ?0.87 mm ± 0.12 mm, respectively). These differences were all significant (p < 0.001). Increased resting thickness was noted in standing in TrA (20.7%), IO (10.3%) and EO (1.2%). This increase was only significantly different between TrA and EO (P = 0.004).TrA showed significantly greater increases in thickness on LAH in standing compared to crook lying, and with greater specificity in relation to IO and maybe EO. If muscle thickness can be an indicator of muscle function or activity, then this suggests that TrA rehabilitation should be facilitated in positions of greater function, such as standing.