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Objectives: To evaluate urinary activated leucocyte cell adhesion molecule (ALCAM) and CD6 as predictors of lupus nephritis (LN) progression or disease resolution across a 1-year study., Methods: Serum and urine samples from biopsy proven LN subjects (n = 122) were prospectively collected over the course of a year at 3- or 6-month intervals (weeks 0, 12, 26, and 52) across multiple study sites and assessed for soluble ALCAM and CD6 levels. Urine creatinine from the same urine sample was used to normalize the levels of urinary ALCAM and urinary CD6. Measured levels of serum and urine ALCAM and CD6 were then analyzed against disease metrics cross-sectionally and longitudinally., Results: Cross-sectional analysis at baseline revealed that urinary ALCAM significantly correlated with urine protein creatinine ratio (UPCR), renal SLEDAI, and the Physician Global Assessment (PGA), and negatively correlated with serum C3 and C4. Receiver operating characteristic (ROC) curve analysis demonstrated that urinary ALCAM is a predictor of LN with an area under the curve (AUC) of 0.97, compared with urinary CD6 with an AUC of 0.71. Importantly, the change in urinary ALCAM over a 3-month period distinguished between non-responders and responders at week 52., Conclusion: Urinary ALCAM is reflective of changes in LN and may be predictive of response status., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer's disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer's disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Fulminant myocarditis secondary to leptospirosis is rare and associated with poor outcomes., Case Summary: We describe a 60-year-old gentleman with fulminant leptospiral myocarditis and profound cardiogenic shock requiring veno-arterial extracorporeal membrane oxygenator (VA-ECMO) support. He was given high-dose pulse steroids early on post-VA-ECMO implantation and achieved full recovery. To our knowledge, this is the first reported case of leptospiral myocarditis with multiorgan dysfunction successfully managed by VA-ECMO and high-dose pulse steroids., Discussion: This case report highlights the potential benefits of steroids in the management of leptospiral myocarditis which requires further validation. Early aggressive supportive management with ECMO should be considered in patients with fulminant leptospiral myocarditis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cells are powered by a large set of macromolecular complexes, which work together in a crowded environment. The in situ mechanisms of these complexes are unclear because their 3D distribution, organization, and interactions are largely unknown. Electron cryotomography (cryo-ET) can address these knowledge gaps because it produces cryotomograms-3D images that reveal biological structure at ∼4-nm resolution. Cryo-ET uses no fixation, dehydration, staining, or plastic embedment, so cellular features are visualized in a life-like, frozen-hydrated state. To study chromatin and mitotic machinery in situ, we subjected yeast cells to genetic and chemical perturbations, cryosectioned them, and then imaged the cells by cryo-ET., Findings: Here we share >1,000 cryo-ET raw datasets of cryosectioned budding yeast Saccharomyces cerevisiaecollected as part of previously published studies. These data will be valuable to cell biologists who are interested in the nanoscale organization of yeasts and of eukaryotic cells in general. All the unpublished tilt series and a subset of corresponding cryotomograms have been deposited in the EMPIAR resource for the community to use freely. To improve tilt series discoverability, we have uploaded metadata and preliminary notes to publicly accessible Google Sheets, EMPIAR, and GigaDB., Conclusions: Cellular cryo-ET data can be mined to obtain new cell-biological, structural, and 3D statistical insights in situ. These data contain structures not visible in traditional electron-microscopy data. Template matching and subtomogram averaging of known macromolecular complexes can reveal their 3D distributions and low-resolution structures. Furthermore, these data can serve as testbeds for high-throughput image-analysis pipelines, as training sets for feature-recognition software, for feasibility analysis when planning new structural-cell-biology projects, and as practice data for students., (© The Author(s) 2019. Published by Oxford University Press.)

Introduction: osteoarthritis (OA) of knee has been reported as a risk factor for falls and reduced balance in the elderly. This systematic review evaluated the effectiveness of physical therapies in improving balance and reducing falls risk among patients with knee OA., Methods: a computerised search was performed to identify relevant studies up to November 2013. Two investigators identified eligible studies and extracted data independently. The quality of the included studies was assessed by the PeDro score., Results: a total of 15 randomised controlled trials involving 1482 patients were identified. The mean PeDro score was 7. The pooled standardised mean difference in balance outcome for strength training = 0.3346 (95% CI: 0.3207-0.60, P = 0.01 < 0.00001, P for heterogeneity = 0.85, I(2) = 0%). Tai Chi = 0.7597 (95% CI: 0.5130-1.2043, P<=0.0014, P for heterogeneity = 0.26, I(2) = 0%) and aerobic exercises = 0.6880 (95% CI: 0.5704-1.302, P < 0.00001, P for heterogeneity = 0.71, I(2) = 0%). While pooled results for falls risk outcomes in, strength training, Tai chi and aerobics also showed a significant reduction in reduced risk of falls significantly with pooled result 0.55 (95% CI: 0.41-0.68, P < 0.00001, P for heterogeneity = 0.39, I(2) = 6%)., Conclusion: strength training, Tai Chi and aerobics exercises improved balance and falls risk in older individuals with knee OA, while water-based exercises and light treatment did not significantly improve balance outcomes. Strength training, Tai Chi and aerobics exercises can therefore be recommended as falls prevention strategies for individuals with OA. However, a large randomised controlled study using actual falls outcomes is recommended to determine the appropriate dosage and to measure the potential benefits in falls reduction., (© The Author 2014. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Osteoarthritis and falls are common conditions affecting older individuals which are associated with disability and escalating health expenditure. It has been widely assumed that osteoarthritis is an established risk factor for falls in older people. The relationship between osteoarthritis and falls has, quite surprisingly, not been adequately elucidated, and published reports have been conflicting. Our review of the existing literature has found limited evidence supporting the current assumption that the presence of osteoarthritis is associated with increased risk of falls with suggestions that osteoarthritis may actually be protective against falls related fractures. In addition, joint arthroplasty appears to increase the risk of falls in individuals with osteoarthritis.

Objective: Glycosylation is the most common post-translational modification and is altered in disease. The typical glycosylation change in patients with inflammatory arthritis (IA) is a decrease in galactosylation levels on IgG. The aim of this study is to evaluate the effect of anti-TNF therapy on whole serum glycosylation from IA patients and determine whether these alterations in the glycome change upon treatment of the disease., Methods: Serum samples were collected from 54 IA patients before treatment and at 1 and 12 months after commencing anti-TNF therapy. N-linked glycans from whole serum samples were analysed using a high-throughput hydrophilic interaction liquid chromatography-based method., Results: Glycosylation on the serum proteins of IA patients changed significantly with anti-TNF treatment. We observed an increase in galactosylated glycans from IgG, also an increase in core-fucosylated biantennary galactosylated glycans and a decrease in sialylated triantennary glycans with and without outer arm fucose. This increase in galactosylated IgG glycans suggests a reversing of the N-glycome towards normal healthy profiles. These changes are strongly correlated with decreasing CRP, suggesting a link between glycosylation changes and decreases in inflammatory processes., Conclusion: Glycosylation changes in the serum of IA patients on anti-TNF therapy are strongly associated with a decrease in inflammatory processes and reflect the effect of anti-TNF on the immune system.

Aims: Resting 12-lead electrocardiograms (ECGs) have been employed in the pre-participation evaluation of young asymptomatic subjects to detect pre-existing heart diseases. Although the incorporation of routine ECG in pre-participation screening remains controversial, there is increasing evidence that cardiomyopathies and ion channelopathies have ECG changes as the initial manifestation. The causes of sudden cardiac death in young people show significant geographical variation. We aim to determine the prevalence and spectrum of ECG abnormalities in a young male South-East Asian population., Methods and Results: The Singapore Armed Forces Electrocardiogram and Echocardiogram (SAFE) protocol is an ECG-based pre-participation cardiac screening programme modelled after the Italian system. From October 2008 to May 2009, a total of 18 476 young male conscripts (mean age 19.5 years old, range 16-27) underwent mandatory pre-enlistment medical screening at a single medical facility. Subjects with abnormal ECG findings were classified into two groups: Group A had ECG changes that fulfilled a pre-specified checklist to screen for hypertrophic cardiomyopathy and were referred for transthoracic echocardiogram; Group B had other ECG abnormalities [such as Brugada pattern, Wolff-Parkinson-White (WPW) pattern, long QTc] and were referred for secondary screening at a tertiary institution. Of the 18 476 subjects screened, 7.0% (n= 1285) had ECG abnormalities. Of note, 19 (0.10%) had Brugada pattern, 25 (0.14%) had WPW pattern, and 31 (0.17%) had prolonged QT interval on ECG. The prevalence of ECG abnormalities was significantly higher in Chinese than in South Asians (7.2 vs. 5.7%, P= 0.003)., Conclusion: The prevalence of ECG abnormalities in a young, South-East Asian male population was 7.0%. There were significant ethnic differences, with ECG abnormalities more prevalent in Chinese than in South Asians (7.2 vs. 5.7%, P= 0.003). The inclusion of universal ECG, in addition to history and physical examination, may increase the sensitivity of a cardiovascular screening programme. Knowledge of the spectrum and prevalence of ECG abnormalities and disease conditions would be pivotal in designing customized screening programmes.

Aims: Hypertrophic cardiomyopathy is a leading cause of sudden cardiac death (SCD) in young people in the USA. Pre-participation screening for athletes might reduce the incidence of SCD. In Singapore, military service is compulsory for all young able-bodied male citizens. The Singapore Armed Forces Electrocardiogram and Echocardiogram (SAFE) pre-participation screening protocol based on the Italian programme was introduced. This study evaluates the prevalence of hypertrophic cardiomyopathy (HCM) in a young male South-East Asian population., Methods and Results: From October 2008 to May 2009, all male military conscripts underwent pre-participation screening. For all conscripts whose electrocardiogram (ECG) findings fulfilled any of these pre-specified criteria (Group A), direct referral for a transthoracic echocardiogram was mandatory. Conscripts with ECG findings other than pre-specified criteria (e.g. T-wave inversions, repolarization abnormalities) were referred for secondary screening by cardiologists (Group B), which could include echocardiography. Out of 18 476 subjects screened during the study period, 988 (5.3%) subjects were fast tracked for echocardiogram (Group A). Of them, there were three (0.3%) cases with severe abnormalities; there was one case each of HCM, bicuspid aortic valve with significant aortic valve regurgitation, and atrial septal defect with right ventricular systolic dysfunction. The patient with HCM had left axis deviation on ECG. None of the 215 patients who underwent echocardiography following cardiology consult (Group B) had HCM., Conclusion: The prevalence of HCM in our young male population (mean age 19.5, range 16-27) using an ECG-based screening protocol was 0.005%; this appeared lower than published data from other geographical cohorts. Possible explanations include a later age of phenotypic manifestation in our population, limitations of the ECG criteria for screening, or a truly lower prevalence of HCM. More population-based longitudinal studies would be needed to ascertain the true prevalence of HCM in our South-East Asian population.

The anabolic and androgenic activities of the formate to undecanoate esters of nandrolone and formate to valerate esters of androstanolone, after intramuscular injection, have been determined in rat. The response to a given dose was measured as cumulative weight (the area under the plot of weight of indicator organ against time). Levator anus muscle was used to assess anabolic activity, and the sum of the cumulative weight for prostate and seminal vesicles for androgenic activity. Log dose-log cumulative weights plots were parallel, and biological activities were expressed as the cumulative weight corresponding to a 2 muM dose, calculated from the regression lines. Anabolic-androgenic ratios for both series were calculated and were found to be minimum in the region of the propionate and butyrate. The anabolic-androgenic ratios of the nandrolone esters continued to increase after the minimum, as the series ascended. This method is believed to give a reliable assessment of anabolic and androgenic activities of steroid esters.