Neurodegenerative Disease and the NLRP3 Inflammasome.

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by a progressive neuronal loss in the brain or peripheral nervous system, and generally involve protein aggregation, as well as metabolic abnormalities and immune dysregulation. Although the vast majority of neurodegeneration is idiopathic, there are many known genetic and environmental triggers. In the past decade, research exploring low-grade systemic inflammation and its impact on the development and progression of neurodegenerative disease has increased. A particular research focus has been whether systemic inflammation arises only as a secondary effect of disease or is also a cause of pathology. The inflammasomes, and more specifically the NLRP3 inflammasome, a crucial component of the innate immune system, is usually activated in response to infection or tissue damage. Dysregulation of the NLRP3 inflammasome has been implicated in the progression of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion diseases. This review aims to summarise current literature on the role of the NLRP3 inflammasome in the pathogenesis of neurodegenerative diseases, and recent work investigating NLRP3 inflammasome inhibition as a potential future therapy

Service evaluation of weight outcomes as a function of initial BMI in 34,271 adults referred to a primary care/commercial weight management partnership scheme

Peer reviewedPublisher PD

Osteoprotegerin reduces the development of pain behaviour and joint pathology in a model of osteoarthritis

Acknowledgements: OPG-Fc was a kind gift from Amgen Ltd. Funding: This work was supported by Arthritis Research UK, grant number 18769Peer reviewedPublisher PD

Mutations in the pH-Sensing G-protein-Coupled Receptor GPR68 Cause Amelogenesis Imperfecta

Amelogenesis is the process of dental enamel formation, leading to the deposition of the hardest tissue in the human body. This process requires the intricate regulation of ion transport and controlled changes to the developing enamel matrix pH. The means by which the enamel organ regulates pH during amelogenesis is largely unknown. We identified rare homozygous variants in GPR68 in three families with Amelogenesis Imperfecta, a genetically and phenotypically heterogeneous group of inherited conditions associated with abnormal enamel formation. Each of these homozygous variants (a large in-frame deletion, a frameshift deletion and a missense) were predicted to result in loss of function. GPR68 encodes a proton sensing G-protein-coupled receptor with sensitivity in the pH range that occurs in the developing enamel matrix during amelogenesis. Immunohistochemistry of rat mandibles confirmed localisation of GPR68 in the enamel organ at all stages of amelogenesis. Our data identify a role for GPR68 as a proton sensor that is required for proper enamel formation

MiR-195 and Its Target SEMA6D Regulate Chemoresponse in Breast Cancer

From MDPI via Jisc Publications RouterHistory: accepted 2021-11-26, pub-electronic 2021-11-28Publication status: PublishedBackground: poor prognosis primary breast cancers are typically treated with cytotoxic chemotherapy. However, recurrences remain relatively common even after this aggressive therapy. Comparison of matched tumours pre- and post-chemotherapy can allow identification of molecular characteristics of therapy resistance and thereby potentially aid discovery of novel predictive markers or targets for chemosensitisation. Through this comparison, we aimed to identify microRNAs associated with chemoresistance, define microRNA target genes, and assess targets as predictors of chemotherapy response. Methods: cancer cells were laser microdissected from matched breast cancer tissues pre- and post-chemotherapy from estrogen receptor positive/HER2 negative breast cancers showing partial responses to epirubicin/cyclophosphamide chemotherapy (n = 5). MicroRNA expression was profiled using qPCR arrays. MicroRNA/mRNA expression was manipulated in estrogen receptor positive/HER2 negative breast cancer cell lines (MCF7 and MDA-MB-175 cells) with mimics, inhibitors or siRNAs, and chemoresponse was assessed using MTT and colony forming survival assays. MicroRNA targets were identified by RNA-sequencing of microRNA mimic pull-downs, and comparison of these with mRNAs containing predicted microRNA binding sites. Survival correlations were tested using the METABRIC expression dataset (n = 1979). Results: miR-195 and miR-26b were consistently up-regulated after therapy, and changes in their expression in cell lines caused significant differences in chemotherapy sensitivity, in accordance with up-regulation driving resistance. SEMA6D was defined and confirmed as a target of the microRNAs. Reduced SEMA6D expression was significantly associated with chemoresistance, in accordance with SEMA6D being a down-stream effector of the microRNAs. Finally, low SEMA6D expression in breast cancers was significantly associated with poor survival after chemotherapy, but not after other therapies. Conclusions: microRNAs and their targets influence chemoresponse, allowing the identification of SEMA6D as a predictive marker for chemotherapy response that could be used to direct therapy or as a target in chemosensitisation strategies

Haemoglobin, anaemia, dementia and cognitive decline in the elderly, a systematic review

<p>Abstract</p> <p>Background</p> <p>Anaemia may increase risk of dementia or cognitive decline. There is also evidence that high haemoglobin levels increase risk of stroke, and consequently possible cognitive impairment. The elderly are more at risk of developing dementia and are also more likely to suffer from anaemia, although there is relatively little longitudinal literature addressing this association.</p> <p>Methods</p> <p>To evaluate the evidence for any relationship between incident cognitive decline or dementia in the elderly and anaemia or haemoglobin level, we conducted a systematic review and meta-analyses of peer reviewed publications. Medline, Embase and PsychInfo were searched for English language publications between 1996 and 2006. Criteria for inclusion were longitudinal studies of subjects aged ≥65, with primary outcomes of incident dementia or cognitive decline. Other designs were excluded.</p> <p>Results</p> <p>Three papers were identified and only two were able to be combined into a meta-analysis. The pooled hazard ratio for these two studies was 1.94 (95 percent confidence intervals of 1.32–2.87) showing a significantly increased risk of incident dementia with anaemia. It was not possible to investigate the effect of higher levels of haemoglobin.</p> <p>Conclusion</p> <p>Anaemia is one factor to bear in mind when evaluating risk of incident dementia. However, there are few data available and the studies were methodologically varied so a cautionary note needs to be sounded and our primary recommendation is that further robust research be carried out.</p

Personalized Antihypertensive Treatment Optimization With Smartphone-Enabled Remote Precision Dosing of Amlodipine During the COVID-19 Pandemic (PERSONAL-CovidBP Trial).

BACKGROUND: The objective of the PERSONAL-CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID-19 Pandemic) trial was to assess the efficacy and safety of smartphone-enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID-19 pandemic. METHODS AND RESULTS: This was an open-label, remote, dose titration trial using daily home self-monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5-7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10-12)/7 (95% CI, 6-7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events. CONCLUSIONS: Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App-assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long-term care. REGISTRATION: URL: clinicaltrials.gov. Identifier: NCT04559074

Amelogenesis Imperfecta caused by N-Terminal Enamelin Point Mutations in Mice and Men is driven by Endoplasmic Reticulum Stress

‘Amelogenesis imperfecta’ (AI) describes a group of inherited diseases of dental enamel that have major clinical impact. Here, we identify the aetiology driving AI in mice carrying a p.S55I mutation in enamelin; one of the most commonly mutated proteins underlying AI in humans. Our data indicate that the mutation inhibits the ameloblast secretory pathway leading to ER stress and an activated unfolded protein response (UPR). Initially, with the support of the UPR acting in pro-survival mode, Enam(p.S55I) heterozygous mice secreted structurally normal enamel. However, enamel secreted thereafter was structurally abnormal; presumably due to the UPR modulating ameloblast behaviour and function in an attempt to relieve ER stress. Homozygous mutant mice failed to produce enamel. We also identified a novel heterozygous ENAM(p.L31R) mutation causing AI in humans. We hypothesize that ER stress is the aetiological factor in this case of human AI as it shared the characteristic phenotype described above for the Enam(p.S55I) mouse. We previously demonstrated that AI in mice carrying the Amelx(p.Y64H) mutation is a proteinopathy. The current data indicate that AI in Enam(p.S55I) mice is also a proteinopathy, and based on comparative phenotypic analysis, we suggest that human AI resulting from the ENAM(p.L31R) mutation is another proteinopathic disease. Identifying a common aetiology for AI resulting from mutations in two different genes opens the way for developing pharmaceutical interventions designed to relieve ER stress or modulate the UPR during enamel development to ameliorate the clinical phenotype

Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta

We identified two homozygous missense variants (c.428C>T, p.(T143M) and c.746C>T, p.(P249L)) in ACPT, the gene encoding Acid Phosphatase, Testicular, which segregate with hypoplastic Amelogenesis imperfecta (AI) in two unrelated families. ACPT is reported to play a role in odontoblast differentiation and mineralisation by supplying phosphate during dentine formation. Analysis by computerised tomography and scanning electron microscopy of a primary molar tooth from an individual homozygous for the c.746C>T variant, revealed an enamel layer that was hypoplastic but mineralised with prismatic architecture. These findings implicate variants in ACPT as a cause of early failure of amelogenesis during the secretory phase