New insight into active muscarinic receptors with the novel radioagonist [H]iperoxo

Activation of G protein-coupled receptors involves major conformational changes of the receptor protein ranging from the extracellular transmitter binding site to the intracellular G protein binding surface. GPCRs such as the muscarinic acetylcholine receptors are commonly probed with radioantagonists rather than radioagonists due to better physicochemical stability, higher affinity, and indifference towards receptor coupling states of the former. Here we introduce tritiated iperoxo, a superagonist at muscarinic M₂ receptors with very high affinity. In membrane suspensions of transfected CHO-cells, [³H]iperoxo – unlike the common radioagonists [³H]acetylcholine and [³H]oxotremorine M – allowed labelling of each of the five muscarinic receptor subtypes in radioagonist displacement and saturation binding studies. [³H]iperoxo revealed considerable differences in affinity between the even- and the odd-numbered muscarinic receptor subtypes with affinities for the M₂ and M₄ receptor in the picomolar range. Probing ternary complex formation on the M₂ receptor, [³H]iperoxo dissociation was not influenced by an archetypal allosteric inverse agonist, reflecting activation-related rearrangement of the extracellular loop region. At the inner side of M₂, the preferred G_i protein acted as a positive allosteric modulator of [³H]iperoxo binding, whereas G_s and G_q were neutral in spite of their robust coupling to the activated receptor. In intact CHO-hM₂ cells, endogenous guanylnucleotides promoted receptor/G protein-dissociation resulting in low-affinity agonist binding which, nevertheless, was still reported by [³H]iperoxo. Taken together, the muscarinic superagonist [³H]iperoxo is the best tool currently available for direct probing activation-related conformational transitions of muscarinic receptors.     

A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH)

Purpose Tumor necrosis factor-α (TNF-α) is implicated in non-alcoholic steatohepatitis (NASH). Pentoxifylline inhibits TNF-α. We wanted to evaluate the efficacy of Pentoxifylline on NASH patients. Methods Patients with biopsy proven NASH and persistently elevated alanine aminotransferase (ALT) greater than 1.5 times the upper limit of normal were randomized to 3 months of treatment with a step 1 American Heart Association diet and daily exercise with Pentoxifylline or placebo. Liver function tests, serum lipids and TNF-α, Interleukin 6 (IL-6), and plasma hyaluronic acid were measured at baseline, at weeks 6 and 12. Categorical data were analyzed by Fisher’s exact test while independent sample t-test and Mann–Whitney test were used for continuous data. Results Eleven patients were randomized into the Pentoxifylline and nine to the placebo group. After 3 months of treatment body mass index (BMI), ALT and aspartate aminotransferase (AST) decreased significantly in both groups. There was no difference between the two groups in reduction of BMI (P = 0.897). There was significantly greater reduction in AST in the Pentoxifylline group (P = 0.038). There was a trend toward lower ALT level (P = 0.065) in the Pentoxifylline group. TNF-α and IL-6 decreased significantly in both groups after treatment, but there was no significant difference between the two groups. Conclusion Three months of Pentoxifylline treatment in combination with diet and exercise results in significantly greater reduction in AST levels in patients with NASH as compared with controls. This study was funded by the National Healthcare Group Small Innovative Grant NHG-grant number. RPR/04029. It received ethics approval by the National Healthcare Group Domain Specific Research Board D-registration number DSRB-D/04/083.     

Genetic polymorphisms and traumatic brain injury: the contribution of individual differences to recovery

Recovery after Traumatic Brain Injury (TBI) is variable, even for patients with similar severity of brain injury. Recent research has highlighted the contribution that genetic predisposition plays in determining TBI outcome. This review considers the potential for genetic polymorphisms to influence recovery of cognitive and social processes following TBI. Limitations and considerations that researchers should make when assessing the potential impact of polymorphisms on TBI outcome are also discussed. Understanding the genetic factors that support neuroplasticity will contribute to an understanding of the variation in outcome following injury and help to identify potential targets for rehabilitation.     

Original research: Widespread gaps in the quality of care for primary biliary cholangitis in UK

ObjectivePrimary biliary cholangitis (PBC) is a progressive, autoimmune, cholestatic liver disease affecting approximately 15 000 individuals in the UK. Updated guidelines for the management of PBC were published by The European Association for the Study of the Liver (EASL) in 2017. We report on the first national, pilot audit that assesses the quality of care and adherence to guidelines.DesignData were collected from 11 National Health Service hospitals in England, Wales and Scotland between 2017 and 2020. Data on patient demographics, ursodeoxycholic acid (UDCA) dosing and key guideline recommendations were captured from medical records. Results from each hospital were evaluated for target achievement and underwent χ² analysis for variation in performance between trusts.Results790 patients’ medical records were reviewed. The data demonstrated that the majority of hospitals did not meet all of the recommended EASL standards. Standards with the lowest likelihood of being met were identified as optimal UDCA dosing, assessment of bone density and assessment of clinical symptoms (pruritus and fatigue). Significant variations in meeting these three standards were observed across UK, in addition to assessment of biochemical response to UDCA (all p<0.0001) and assessment of transplant eligibility in high-risk patients (p=0.0297).ConclusionOur findings identify a broad-based deficiency in ‘real-world’ PBC care, suggesting the need for an intervention to improve guideline adherence, ultimately improving patient outcomes. We developed the PBC Review tool and recommend its incorporation into clinical practice. As the first audit of its kind, it will be used to inform a future wide-scale reaudit.     

Skin diseases in displaced populations: a review of contributing factors,challenges, and approaches to care

There are 70.8 million persons displaced worldwide due to war, persecution, and violence. Eighty percent of displaced persons reside in low- and middle-income countries with limited healthcare resources. Cutaneous diseases are commonly reported among displaced persons owing to numerous interrelated factors such as inadequate housing, overcrowding, food insecurity, environmental exposures, violence including torture, and breakdown of healthcare infrastructure. Diagnosis and management of these conditions, as well as an understanding of the context in which they present, is crucial to providing dermatologic care for displaced populations worldwide. Herein, we define displaced populations and, within this context, review the epidemiology of skin diseases, discuss pertinent skin conditions, examine challenges to care provision, and present approaches for improving dermatologic care. Inflammatory and communicable infectious disorders are the most common skin diseases seen in displaced populations. Other relevant conditions include skin manifestations of heat injuries, cold injuries, immersion foot syndromes, macronutrient and micronutrient deficiencies, torture, and sexual and gender-based violence. Provision of dermatologic care to displaced populations is hampered by limited diagnostic and therapeutic resources and specialist expertise. Medical screening for cutaneous disorders, context-relevant dermatology training, and telemedicine are potential tools to improve diagnosis and management of skin diseases in displaced populations.     

Transient cortico-cortical disconnection during psychogenic nonepileptic seizures (PNES)

Psychogenic nonepileptic seizures (PNES) are paroxysmal clinical events that are often misdiagnosed as epileptic seizures, but which are not associated with electrographic discharge. Brain connectivity changes occurring during PNES are not known. We studied functional connectivity (Fc) in two patients with drug-resistant epilepsy, explored by stereotactic electroencephalography (EEG), in whom we recorded both epileptic seizures (ES) and PNES. Functional connectivity using pair-wise nonlinear correlation was computed between signals from seven brain areas: amygdala, hippocampus, lateral temporal cortex, anterior insula, orbitofrontal cortex, prefrontal cortex, and lateral parietal cortex. We assessed changes in global Fc during PNES in comparison with a background period. During PNES, a global decrease of Fc occurred between the different brain regions studied, compared with the interictal period. In both patients, decreased Fc was prominent in connections involving the anterior insula and parietal cortex. In conclusion, some PNES are associated with ictal functional disconnection between brain areas, particularly involving the parietal cortices and the anterior insula.