Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.

/pdf/leuprorelin-rescues-polyglutamine-dependent-phenotypes-in-a-2p1o3srj96.pdf

Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy

Sex hormones, central nervous system and pain.

Background Sex differences in the response threshold to painful stimuli and the higher number of chronic pain syndromes in women than in men have prompted a series of studies on lower animals and humans aimed at clarifying the role of gonadal hormones in pain. Objective This article examines the morphologic and functional aspects of gonadal hormone systems and the relations between gonadal hormones and pain circuits, to identify areas deserving of increased attention in elucidating the endocrine mechanisms that contribute to abnormal pain states.

Gonadal hormones and sex differences in pain reactivity.

The male aging process brings about declines in hormonal function including a gradual decline in bioavailable testosterone levels. Animal studies suggest that testosterone modulates cognitive function through enhancing acetylcholine release and up-modulation of nicotinic receptors. Tau protein deposition is also affected by androgen supplementation in animals. We hypothesize that testosterone replacement in elderly hypogonadal males may improve cognition, in particular the visual-spatial domain. Thirty-six male patients with a new diagnosis of Alzheimer's disease had their total and bioavailable testosterone levels measured. None of the patients had been on acetylcholinesterase inhibitors. Ten of the 36 patients (28%) were deemed biochemically hypogonadal (total testosterone < 240 ng/dl or 7 nmol/l). Five of the hypogonadal patients were randomized to testosterone and five to placebo. Initial Alzheimer's Disease Assessment Scale cognitive subscale (ADAScog) and Mini Mental Status Examination (MMSE) ranged from 31 to 19 and from 17 to 22, respectively. The clock drawing test (CDT) and the pentagon-tracing portion of the MMSE were used as measures of visual-spatial abilities. Normal prostate-specific antigen (PSA) levels were essential before treatment with intramuscular testosterone, 200 mg every 2 weeks. Measurement of testosterone, complete blood count, lipids, PSA and neuropsychological cognitive tests were repeated at 3, 6, 9 and 12 months of treatment. In the testosterone-treated group, levels of total testosterone increased from a mean of 126.4 ng/dl to 341 ng/dl or 3.6 nmol/l to 9.7 nmol/l (p = 0.11). Bioavailable testosterone also increased from a mean of 48.7 ng/dl to 142 ng/dl or 1.39 nmol/l to 4.05 nmol/l (p = 0.10). PSA levels were also elevated from a mean of 0.98 to 1.37 ng/ml (p = 0.07). ADAScog improved from a mean of 25 to 16.3 (p = 0.02); MMSE improved from a mean of 19.4 to 23.2 (p = 0.02), CDT also improved from 2.2 to 3.2 (p = 0.07). One patient stopped treatment because of hypersexual behavior. The placebo-treated group deteriorated gradually. This small pilot study performed in aging male patients suggests that testosterone could indeed improve cognition, including visual-spatial skills in mild to moderate Alzheimer's disease.

https://www.hormonebalance.org/images/documents/Tan%2003%20Test%20Rx%20%20Alzeheimer%20TAM.pdf

A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer's disease

Sex steroid hormones and the neural control of breathing.

Androgens exert profound effects on the organization and function of the central nervous system. These effects are mediated by the androgen receptor (AR), a ligand-dependent transcription factor. The mechanisms of AR regulation in neural tissue, however, remain to be fully elucidated. Characterizing this process can provide important information regarding receptor function and AR gene regulation in the brain. Previously, it was shown that testosterone (T) up-regulated neural AR in a dose-dependent manner in both male and female mice. In the present study, whether AR was differentially regulated by the natural agonists T and dihydrotestosterone (DHT) or the nonsteroidal antagonist flutamide (FLU) was assessed. Males were gonadectomized and AR levels were allowed to decline to baseline 3 days after surgery. Changes in AR protein content produced by the various treatments were measured by semiquantitative Western blot of limbic system extracts. Treatment with T or DHT significantly augmented AR 3 and 7 h after hormone administration, but only DHT sustained this increase for 21 h. This difference also was observed when males were given T plus finasteride (FIN, a 5alpha reductase inhibitor). The findings demonstrate that the two endogenous ligands have differential time course effects on neural AR. The antiandrogen FLU failed to up-regulate AR at doses up to 100 times higher than T or DHT. When administered concomitantly with T or DHT, it effectively inhibited the augmentation of AR normally seen 3 h after androgen treatment. While immunohistochemical studies showed that FLU was able to promote nuclear translocation of AR, Western analysis revealed that FLU, in contrast to T and DHT, failed to maintain the integrity of AR. The results demonstrate that (a) the endogenous androgens T and DHT regulate AR differently, suggesting a potential cellular mechanism that may contribute to the difference in neural target gene sensitivity to these androgens; (b) up-regulation of AR occurs only in the presence of agonists; (c) the mechanism of action of FLU in the brain involves inhibition of AR protein up-regulation normally seen in response to androgen; and (d) FLU promotes AR nuclear translocation but not augmentation of cellular AR populations. These findings demonstrate that in vivo AR regulation in the brain basically parallels mechanisms proposed from results obtained with transfected cells and cell lines.

Neural androgen receptor regulation: Effects of androgen and antiandrogen

118 Single-cell transcriptomics links cellular origins of malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma

Functional dysregulations in multiple regions are caused by excessive copper deposition in the brain for Wilson disease (WD). While the biological mechanism of these dysregulations was thought to be the absent or reduced expression of the ATP7B protein in the liver, mechanisms for such gene impacting brain function remain unexplored. Here, we used a large cohort of resting-state fMRI data (105 WD patients and 93 healthy controls) to derive the functional connectome gradient, and its WD-related alterations were further evaluated. Then, we used Neurosynth, clinical data, and whole-brain gene expression to examine the meta-analytic cognitive function, clinical phenotypes, and transcriptional specializations related to WD gradient alterations. In parallel, spatial correlation between gradient and gray matter volume was accessed for both WD patients and healthy controls. Compared to controls, WD patients exhibited principal gradient alterations in both global and system levels and regional alterations mainly distributed in the sensorimotor, visual, ventral attention, subcortical, and default mode networks. Meta-analytic terms and clinical characters showed the correlations of these gradient alterations in motor-related processing, higher-order cognition, neurological symptom, and age. Results of spatial correlation revealed structure-function decoupling in multiple networks, especially in subcortical and visual networks. Within the cortex, the gradient alterations derived transcriptional specializations of WD that mainly display properties indicative of ion homeostasis, neural development, and motor controls. Within the subcortical regions, we for the first time characterized the role of the ATP7B gene impacting subcortical function. Transcriptional specializations of WD within both cortex and subcortical regions were also associated with neurological and psychiatric disorders, explaining the mechanism underlying complex clinical symptoms from the biological level for WD. In addition, we further illustrated that structural lesion and gradient perturbation shared similar transcriptional specializations in both cortex and subcortical regions for WD. These findings bridged functional gradient perturbation to structural lesions and transcriptional profiles in WD, possibly promoting our understanding of the neurobiological underpinnings underlying the emergence of complex neurological and psychiatric phenotypes.

/pdf/functional-gradient-perturbation-in-wilson-disease-2qm1wg2m.pdf

Functional gradient perturbation in Wilson disease correlates with structural lesions and transcriptomic specializations

Candida auris is a highly lethal, multidrug-resistant, invasive fungus. However, conventional methods of C. auris identification are time-consuming and laborious and have low sensitivity and high error rates. ABSTRACT Outbreaks of multidrug-resistant Candida auris infections, associated with a mortality rate of 30% to 60%, are of serious global concern. Candida auris demonstrates high transmission rates in hospital settings; however, its rapid and accurate identification using currently available clinical identification techniques is challenging. In this study, we developed a rapid and effective method for detecting C. auris based on recombinase-aided amplification combined with lateral flow strips (RAA-LFS). We also screened the appropriate reaction conditions. Furthermore, we investigated the specificity and sensitivity of the detection system and its ability to distinguish other fungal strains. Candida auris was accurately identified and differentiated from related species at 37°C within 15 min. The minimum detection limit was 1 CFU (or 10 fg/reaction) and was not affected by high concentrations of related species or host DNA. The simple and cost-efficient detection method established in this study exhibited high specificity and sensitivity and successfully detected C. auris in simulated clinical samples. Compared with other traditional detection methods, this method greatly reduces the time and cost of testing and is thus suitable for hospitals or clinics in remote underfunded areas for screening C. auris infection and colonization. IMPORTANCE Candida auris is a highly lethal, multidrug-resistant, invasive fungus. However, conventional methods of C. auris identification are time-consuming and laborious and have low sensitivity and high error rates. In this study, a new molecular diagnostic method based on recombinase-aided amplification combined with lateral flow strips (RAA-LFS) was developed, and accurate results could be obtained by catalyzing the reaction at body temperature for 15 min. This method can be used for rapid clinical detection of C. auris, consequently saving valuable treatment time for patients.

https://doi.org/10.1128/spectrum.04912-22

Development of a Novel Method for the Clinical Visualization and Rapid Identification of Multidrug-Resistant Candida auris

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Papers

Neural androgen receptor regulation: Effects of androgen and antiandrogen

118 Single-cell transcriptomics links cellular origins of malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma

Functional gradient perturbation in Wilson disease correlates with structural lesions and transcriptomic specializations

Development of a Novel Method for the Clinical Visualization and Rapid Identification of Multidrug-Resistant Candida auris