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Physiological changes during pregnancy support foetal growth, including adaptations in pancreatic islets to maintain glucose homeostasis. We investigate these adaptations using rare, high-quality pancreatic tissue from pregnant human donors and matched controls. We profile islets from pregnant donors using proteomics and assess α- and β-cell characteristics, as well as prolactin receptor and serotonin 2B receptor expression. Proteomic profiling of microdissected human islets identifies 7546 proteins but shows minimal differences in protein expression. In pregnancy, we show that islet area increases 1.9-fold, α- and β-cell areas increase 4.3- and 1.9-fold, driven by an increase in cell number rather than hypertrophy. Prolactin receptor expression is higher in α but not β cells, and serotonin 2B receptor is undetectable in β cells. Glucagon-like peptide-1 abundance increases 2.9-fold in α cells. These findings indicate that the molecular mechanisms driving pregnancy-induced islet adaptations in humans differ from those in mice, highlighting the need for human-based studies. Here the authors show that human pancreatic islets adapt during pregnancy with increased α-cell area and GLP-1 abundance, while key differences from islet adaptations in mouse pregnancy include unchanged β-cell PRLR abundance and absent β-cell 5-HT 2B receptor expression.

Antibodies are essential research tools whose performance directly impacts research conclusions and reproducibility. Owing to its central role in Alzheimer’s disease and other dementias, hundreds of distinct antibody clones have been developed against the microtubule-associated protein Tau and its multiple proteoforms. Despite this breadth of offer, limited understanding of their performance and poor antibody selectivity have hindered research progress. Here, we validate a large panel of Tau antibodies by Western blot (79 reagents) and immunohistochemistry (35 reagents). We address the reagents’ ability to detect the target proteoform, selectivity, the impact of protein phosphorylation on antibody binding and performance in human brain samples. While most antibodies detected Tau at high levels, many failed to detect it at lower, endogenous levels. By WB, non-selective binding to other proteins affected over half of the antibodies tested, with several cross-reacting with the related MAP2 protein, whereas the “oligomeric Tau” T22 antibody reacted with monomeric Tau by WB, thus calling into question its specificity to Tau oligomers. Despite the presumption that “total” Tau antibodies are agnostic to post-translational modifications, we found that phosphorylation partially inhibits binding for many such antibodies, including the popular Tau-5 clone. We further combine high-sensitivity reagents, mass-spectrometry proteomics and cDNA sequencing to demonstrate that presumptive Tau “knockout” human cells continue to express residual protein arising through exon skipping, providing evidence of previously unappreciated gene plasticity. Finally, probing of human brain samples with a large panel of antibodies revealed the presence of C-term-truncated versions of all main Tau brain isoforms in both control and tauopathy donors. Ultimately, we identify a validated panel of Tau antibodies that can be employed in Western blotting and/or immunohistochemistry to reliably detect even low levels of Tau expression with high selectivity. This work represents an extensive resource that will enable the re-interpretation of published data, improve reproducibility in Tau research, and overall accelerate scientific progress.

Introduction Double malnutrition (co-existing overnutrition and undernutrition) is increasingly prevalent in sub-Saharan Africa due to rapid epidemiological and nutritional transitions. In this region, studies of double malnutrition have largely been conducted at country and household level, with individual-level studies primarily limited to children and women of reproductive age. We investigated the prevalence and determinants of individual-level double malnutrition in middle-aged and older adults who constitute an increasing proportion of the sub-Saharan African population. Methods 250 individuals aged 40–70 years (50% women) and resident in the Agincourt Health and socio-Demographic Surveillance System in rural Mpumalanga province, South Africa, were randomly selected. Double malnutrition was defined as overweight/obesity and anaemia only, overweight/obesity and iodine insufficiency, or overweight/obesity and any micronutrient deficiency (anaemia and/or iodine insufficiency). The Chi-squared goodness of fit test was used to compare the expected and observed numbers of individuals with the type of double malnutrition. Logistic regression was used to investigate determinants of each type of double malnutrition. Results Double malnutrition was present in 22–36% of participants, depending on the definition used. All types of double malnutrition were more common in women than in men (overweight/obesity and anaemia: 34% vs. 10.2%, p  < 0.01; overweight/obesity and iodine insufficiency: 32% vs. 12.2%, p  < 0.01 and overweight/obesity and any micronutrient deficiency: 50.5% vs. 20.4%, p  < 0.01). There were no differences between the overall expected and observed numbers of individuals with combinations of overweight and micronutrient deficiencies [overweight/obesity and anaemia ( p  = 0.28), overweight/obesity and iodine insufficiency ( p  = 0.27) or overweight/obesity and any micronutrient deficiency ( p  = 0.99)]. In models adjusted for socio-demographic factors, HIV and antiretroviral drug status, and food security or dietary diversity, men were 84–85% less likely than women to have overweight/obesity and anaemia, 65% less likely to have overweight/obesity and iodine insufficiency and 74% less likely to have overweight/obesity and any micronutrient deficiency. Conclusions Individual-level double malnutrition is prevalent in middle-aged and older adults in a rural sub-Saharan African community. Interventions to improve nutrition in similar settings should target individuals throughout the life course and a focus on women may be warranted.

Cushing’s syndrome (CS) may present with different neurological and/or psychiatric symptoms including anxiety, depression, cognitive impairment and psychosis. Psychosis is a rare clinical manifestation, with literature limited to case reports. We report a case of a 52-year-old woman with psychosis secondary to CS who was mis-diagnosed as schizophrenia-like psychosis. This case highlights the importance of considering CS as a differential when ruling out medical causes in patients with either new or persistent mental health disturbances.

Most cases of hypertension are because of essential hypertension, however 5% – 15% of cases can be a result of a secondary cause. In this article, we focus on the endocrine causes of secondary hypertension with a particular focus on pheochromocytomas (PCCs) and paragangliomas (PGLs). Around 15 endocrine disorders can initially present with hypertension. Amongst those PCCs and PGLs are rare but potentially life-threatening causes. An early diagnosis and timely referral can be life-saving. Herein, we present an approach for screening and diagnosis of these patients and focus on the importance of genetic testing.

A 24-year-old man presented to the Chris Hani Baragwanath Academic Hospital emergency department with recurrent seizures having previously been diagnosed with epilepsy from age 14. The biochemical investigations and brain imaging were suggestive of seizures secondary to hypocalcemia, and a diagnosis of idiopathic hypoparathyroidism was confirmed. After calcium and vitamin D replacement, the patient recovered well and is seizure free, and off antiepileptic therapy. This case highlights the occurrence of brain calcinosis in idiopathic hypoparathyroidism; the occurrence of acute symptomatic seizures due to provoking factors other than epilepsy; and the importance, in the correct clinical setting, of considering alternative, and sometimes treatable, causes of seizures other than epilepsy.

During pregnancy adaptive changes support fetal growth and prepare the mother for childbirth. This includes the pancreatic islets, in which insulin secretion from β cells doubles by the third trimester. When these adaptations fail, gestational diabetes mellitus can occur, negatively impacting outcomes. These islet adaptations are closely linked to placental growth, with insulin secretion increasing as the placenta develops and returning to normal post-delivery. In mouse models, placental signals, such as hormones and extracellular vesicles (EVs), enhance islet function and β-cell mass. However, it remains unclear if these mechanisms apply to humans. This thesis investigates islet changes during human pregnancy ex vivo, using rare pancreatic tissue from pregnant women, and explores the role of placental small EVs (psEVs) in β-cell biology using a human-based model system. In the first part of the study, human islets were isolated using laser capture microdissection and analysed via liquid chromatography-mass spectrometry (LC-MS/MS), generating the largest dataset of proteins from islets isolated from pregnant women to date with over 7,000 proteins detected. Comparative analysis between pregnant and non-pregnant samples identified differences in only four proteins. Immunohistochemistry, coupled with unbiased computational analysis, revealed that whole islet, α-, and β-cell areas increased during pregnancy due to an increase in cell number, similar to findings in mice. However, unlike in mice, serotonin 2B receptor was absent in human β cells, and prolactin receptor expression remained unchanged. A notable increase in glucagon-like peptide-1 (GLP-1) within α cells was observed, which may enhance β-cell function through paracrine signalling. In the second part of the study, psEVs were isolated from human placentae and their effects tested in vitro on a human β-cell line, EndoC-βH3. psEVs increased β-cell insulin gene expression and insulin content but did not enhance glucose-stimulated insulin secretion. Proteomic analysis via LC-MS/MS identified an increase in Annexin A1 (ANXA1) in psEV-treated Endoc-βH3 cells, suggesting a potential mechanistic role in psEV-mediated effects. In conclusion, islet adaptations in human pregnancy differ to those in mice and psEVs increase insulin content potentially through ANXA1.

Throughout pregnancy, some degree of insulin resistance is necessary to divert glucose towards the developing foetus. In gestational diabetes mellitus (GDM), insulin resistance is exacerbated in combination with insulin deficiency, causing new-onset maternal hyperglycaemia. The rapid reversal of insulin resistance following delivery strongly implicates the placenta in GDM pathogenesis. In this case–control study, we investigated the proteomic cargo of human syncytiotrophoblast-derived extracellular vesicles (STBEVs), which facilitate maternal–fetal signalling during pregnancy, in a UK-based cohort comprising patients with a gestational age of 38–40 weeks. Medium/large (m/l) and small (s) STBEVs were isolated from GDM (n = 4) and normal (n = 5) placentae using ex vivo dual-lobe perfusion and subjected to mass spectrometry. Bioinformatics were used to identify differentially carried proteins and mechanistic pathways. In m/lSTBEVs, 56 proteins were differently expressed while in sSTBEVs, no proteins reached statistical difference. Differences were also observed in the proteomic cargo between m/lSTBEVs and sSTBEVs, indicating that the two subtypes of STBEVs may have divergent modes of action and downstream effects. In silico functional enrichment analysis of differentially expressed proteins in m/lSTBEVs from GDM and normal pregnancy found positive regulation of cytoskeleton organisation as the most significantly enriched biological process. This work presents the first comparison of two populations of STBEVs’ protein cargos (m/l and sSTBEVs) from GDM and normal pregnancy isolated using placenta perfusion. Further investigation of differentially expressed proteins may contribute to an understanding of GDM pathogenesis and the development of novel diagnostic and therapeutic tools.

We report on a 42 - year old woman was referred following an incidental finding of bilateral macronodular (nodules > 1cm) adrenal glands after a computed tomography scan for investigation of an unrelated urological problem. Clear features of Cushing’s syndrome were elicited on initial clincal evaluation and screening tests confirmed the diagnosis biochemically: midnight salivary cortisol 15.4nmol/L (0.2 - 3nmol/L), 24 hour urine free cortisol > 662.4nmol/L (8.3 - 118.7nmol/L per 24 hours) and an 8am serum cortisol measured 951nmol/L following 1mg dexamethasone suppression test (< 50nm/L). A serum adrenocorticotropic hormone (ACTH) measured 0.3pmol/L (1.6 - 13.9pmol/L) suggesting, in light of the CT findings, an adrenal source of the elevated cortisol. Screening for aberrant adrenal receptors to catecholamines, Gastric inhibitory peptide, ACTH, vasopressin and Gonadotropin releasing hormone was performed. A positive biochemical response to ACTH and vasopressin was noted as measured serum cortisol increased to 1600pmol/L (upper limit of the assay). Following a unilateral adrenalectomy, were pathological examination of the respected adrenal gland confirmed adrenal hyperplasia, the patient had both clinical and biochemical resolution of hypercortisolemia. 2 weeks following surgery her midnight salivary cortisol measured 2.1nmol/L (0.2 - 3nmol/L) and 24 hour urine free cortisol 218nmol/L (8.3 - 118.7nmol/L per 24 hours). Her 8am ACTH also increased to 2.9pmol/L (1.6 - 13.9pmol/L). Biochemical screening of her sister showed no evidence of Cushing’s syndrome. Bilateral macronodualr hyperplasia (BMAH) represents a rare cause of Cushing’s syndrome may be diagnosed incidentally and is often associated with an insidious onset. We use this case to highlight the complexities of provocative testing for aberrant adrenal receptors which occur with BMAH and the utilization of unilateral adrenalectomy to achieve clinical and biochemical remission of Cushing’s syndrome thus, removing the need for post - operative steroid replacement following bilateral adrenalectomy.