Disrupted prenatal RNA processing and myogenesis in congenital myotonic dystrophy.

Myotonic dystrophy type 1 (DM1) is a CTG microsatellite expansion (CTGexp) disorder caused by expression of CUGexp RNAs. These mutant RNAs alter the activities of RNA processing factors, including MBNL proteins, leading to re-expression of fetal isoforms in adult tissues and DM1 pathology. While this pathogenesis model accounts for adult-onset disease, the molecular basis of congenital DM (CDM) is unknown. Here, we test the hypothesis that disruption of developmentally regulated RNA alternative processing pathways contributes to CDM disease. We identify prominent alternative splicing and polyadenylation abnormalities in infant CDM muscle, and, although most are also misregulated in adult-onset DM1, dysregulation is significantly more severe in CDM. Furthermore, analysis of alternative splicing during human myogenesis reveals that CDM-relevant exons undergo prenatal RNA isoform transitions and are predicted to be disrupted by CUGexp-associated mechanisms in utero. To test this possibility and the contribution of MBNLs to CDM pathogenesis, we generated mouse Mbnl double (Mbnl1; Mbnl2) and triple (Mbnl1; Mbnl2; Mbnl3) muscle-specific knockout models that recapitulate the congenital myopathy, gene expression, and spliceopathy defects characteristic of CDM. This study demonstrates that RNA misprocessing is a major pathogenic factor in CDM and provides novel mouse models to further examine roles for cotranscriptional/post-transcriptional gene regulation during development.

Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice.

Repeat associated non-AUG (RAN) translation is found in a growing number of microsatellite expansion diseases, but the mechanisms remain unclear. We show that RAN translation is highly regulated by the double-stranded RNA-dependent protein kinase (PKR). In cells, structured CAG, CCUG, CAGG, and G4C2 expansion RNAs activate PKR, which leads to increased levels of multiple RAN proteins. Blocking PKR using PKR-K296R, the TAR RNA binding protein or PKR-KO cells, reduces RAN protein levels. p-PKR is elevated in C9orf72 ALS/FTD human and mouse brains, and inhibiting PKR in C9orf72 BAC transgenic mice using AAV-PKR-K296R or the Food and Drug Administration (FDA)-approved drug metformin, decreases RAN proteins, and improves behavior and pathology. In summary, targeting PKR, including by use of metformin, is a promising therapeutic approach for C9orf72 ALS/FTD and other expansion diseases.

The Future of Medical Abortion Care: an Internal Medicine Obligation.

Abortion care is an essential part of women's reproductive health. Due to increasing state restrictions on abortion care and the United States Supreme Court decision to overturn the landmark case of Roe v. Wade, it is becoming ever more important to increase medical abortion access for all women. Internal Medicine (IM) physicians are able to provide reproductive healthcare including medical abortions. As women in over 20 states are at risk of not having any access to abortion, it is our obligation as IM physicians to provide this care and help curb the effects of these restrictive laws and therefore train the next generation of internists to continue doing so.

Oestrogens, adipose tissues and environmental exposures influence obesity and diabetes across the lifecycle.

Endogenous oestrogens regulate essential functions to include menstrual cycles, energy balance, adipose tissue distribution, pancreatic ß-cell function, insulin sensitivity and lipid homeostasis. Oestrogens are a family of hormones which include oestradiol (E2), oestrone (E1) and oestriol (E3). Oestrogens function by binding and activating oestrogen receptors (ERs). Phytoestrogens are plant-derived compounds which exhibit oestrogenic-like activity and can bind to ERs. Phytoestrogens exert potential oestrogenic-like benefits; however, their effects are context-dependent and require cautious consideration regarding generalised health benefits. Xenoestrogens are synthetic compounds which have been determined to disrupt endocrine function through binding to ERs. Xenoestrogens enter the body through various routes and given their chemical structure they can accumulate, posing long-term health risks. Xenoestrogens interfere with endogenous oestrogens and their functions contributing to conditions like cancer, infertility, and metabolic disorders. Understanding the interplay between endogenous and exogenous oestrogens is critical in order to determine their potential health consequences and requires further investigation. This manuscript provides a summary of the role endogenous oestrogens have in regulating metabolic functions. Additionally, we discuss the impact phytoestrogens and synthetic xenoestrogens have on biological systems across various life stages. We highlight their mechanisms of action, potential benefits, risks and discuss the need for further research to bridge gaps in understanding and mitigate exposure-related health risks.

The evolutionary impact and influence of oestrogens on adipose tissue structure and function.

Oestrogens are sex steroid hormones that have gained prominence over the years owing to their crucial roles in human health and reproduction functions which have been preserved throughout evolution. One of oestrogens actions, and the focus of this review, is their ability to determine adipose tissue distribution, function and adipose tissue 'health'. Body fat distribution is sexually dimorphic, affecting males and females differently. These differences are also apparent in the development of the metabolic syndrome and other chronic conditions where oestrogens are critical. In this review, we summarize the different molecular mechanisms, pathways and resulting pathophysiology which are a result of oestrogens actions in and on adipose tissues. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part I)'.

The Role of Dietary Potassium in the Cardiovascular Protective Effects of Plant-Based Diets.

Dietary intervention is an essential factor in managing a multitude of chronic health conditions such as cardiovascular and chronic kidney disease. In recent decades, there has been a host of research suggesting the potential benefit of plant-based diets in mitigating the health outcomes of these conditions. Plant-based diets are rich in vegetables and fruits, while limiting processed food and animal protein sources. The underlying physiological mechanism involves the interaction of several macronutrients and micronutrients such as plant protein, carbohydrates, and dietary potassium. Specifically, plant-based foods rich in potassium provide cardiorenal protective effects to include urinary alkalization and increased sodium excretion. These diets induce adaptive physiologic responses that improve kidney and cardiovascular hemodynamics and improve overall metabolic health. A shift toward consuming plant-based diets even in subjects with cardiorenal decrements may reduce their morbidity and mortality. Nonetheless, randomized controlled trials are needed to confirm the clinical benefits of plant-based diets.

Special Considerations for Management of Diabetes in Adult Patients with Intellectual and Developmental Disabilities.

Diabetes mellitus (DM) is a chronic health condition that is very prevalent worldwide. It has been demonstrated that individuals with intellectual and developmental disabilities (IDDs) are at a disproportionately high risk for developing diabetes. Persons with IDDs are estimated to be 2-3 times more likely to develop DM compared to the general population. The elevated risk of developing diabetes within the population of adults with IDDs is multifactorial and includes contributions from genetics, lifestyle, medication use and misuse, boundaries to appropriate medical care, a higher incidence of comorbid mental health disorders, and others. Further, inadequate screening for and management of diabetes for these patients results in heightened risk for adverse cardiovascular events and inferior health care outcomes. To improve patient outcomes for this unique patient population, health care providers need to be well trained in the optimal modalities of screening, diagnosis, and management of diabetes in adults with IDDs. This requires the development of effective diabetes intervention and health promotion programs aimed at patients with IDDs, utilizing a patient-centered approach to screening and management, and conducting further research to assess the impact of these interventions.

The AANS Harvey Cushing Medal: a demographic and academic analysis of its recipients.

Background: The Harvey Cushing Medal, awarded by the American Association of Neurological Surgeons, is the premier accolade in neurosurgery. The study's purpose was to examine the qualities and accomplishments of previous winners, emphasizing potential selection biases, with the aim to promote social justice and guide young neurosurgeons in their career paths. Results: Predominantly, recipients graduated from top-ranked United States News and World Report institutions and specialized in cerebrovascular and neuro-oncologic/skull base neurosurgery. A significant proportion held roles as department or division chairs and led neurosurgical organizations. All awardees were male, and there was a notable trend of increasing publication counts among more recent recipients. Conclusions: Commonalities among Harvey Cushing Medal winners include graduating from top institutions, holding significant leadership roles, and having an extensive publication history. However, the absence of female and underrepresented minority awardees underscores an urgent need for greater diversity in the selection process.

Focused selection of open cerebrovascular cases for residents interested in cerebrovascular neurosurgery.

INTRODUCTION: National and international trends continue to show greater emphasis on endovascular techniques for the treatment of cerebrovascular disease. The cerebrovascular neurosurgeon however must be adequately equipped to treat these patients via both open and endovascular techniques. METHODS: The decline in open cerebrovascular cases for aneurysm clipping has forced many trainees to pursue open cerebrovascular fellowships to increase case volume. An alternative strategy has been employed at our institution, which is early identification of subspecialty focus with resident driven self-selection of open cerebrovascular cases. RESULTS: This has allowed recent graduates to obtain enfolded endovascular training and a significant number of open cerebrovascular cases in order to obtain competence and exposure. DISCUSSION: We advocate for further self-selection paradigms supplemented with simulation training in order to obviate the need for extended post-residency fellowships.

Euglycaemic diabetic ketoacidosis in a patient with pancreatitis and type 2 diabetes on empagliflozin.

Sodium glucose cotransporter-2 (SGLT2) inhibitors are glucose-lowering drugs with proven efficacy in treating type 2 diabetes mellitus, and more recently, have been shown to improve heart failure outcomes in patients without diabetes. A rare complication of SGLT2 inhibitor use is the development of euglycaemic diabetic ketoacidosis (EDKA), characterised by euglycaemia (blood glucose level <250 mg/dL), metabolic acidosis (arterial pH <7.3 and serum bicarbonate <18 mEq/L), and ketonaemia. Given patients with EDKA do not present with the typical manifestations of diabetic ketoacidosis, including marked hyperglycaemia and dehydration, the diagnosis of EDKA may be missed and initiation of treatment delayed. We present the case of a man with recent SGLT2 inhibitor use and multiple other risk factors who developed EDKA.

Early chemoprophylaxis for deep venous thrombosis does not increase the risk of hematoma expansion in patients presenting with spontaneous intracerebral hemorrhage.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) is a significant cause of morbidity and mortality worldwide. The development of venous thromboembolism (VTE), including deep venous thrombosis or pulmonary embolism, is correlated with negative outcomes following ICH. Due to the risk of hematoma expansion associated with the use of VTE chemoprophylaxis, there remains significant debate about the optimal timing for its initiation following ICH. We analyzed the risk of early chemoprophylaxis on hematoma expansion following ICH. METHODS: We performed a retrospective analysis of patients presenting with spontaneous ICH at single institution between 2011 and 2018. The rate of hematoma expansion was compared between patients that received early chemoprophylaxis (on admission) and those that received conventional chemoprophylaxis (>24 h). RESULTS: Data for 235 patients were available for analysis. Eleven patients (7.5%) in the early prophylaxis cohort and seven patients (8.0%) in the conventional prophylaxis cohort developed VTE (P = 0.9). Hematoma expansion also did not differ significantly (early 19%, conventional 23%, P = 0.5). CONCLUSION: The use of early chemoprophylaxis against venous thromboembolic events following ICH appears safe in our patient population without increasing the risk of hematoma expansion. Given the increased risk of poor outcome in the setting of VTE, early VTE chemoprophylaxis should be considered in patients who present with ICH. Larger, prospective, and randomized studies are necessary to better elucidate the risk of early chemoprophylaxis and potential reduction in venous thromboembolic events.

Pediatric pathology all grown up - An interesting case of adult tethered spinal cord.

BACKGROUND: Cervical myelopathy in an adult is typically the result of degenerative disease or trauma. Dysraphism is rarely the cause. CASE DESCRIPTION: The authors report the case of a 35-year-old male drywall installer who presented with 2 years of progressive left upper extremity weakness, numbness, and hand clumsiness. Only upon detailed questioning did he mention that he had neck surgery just after birth, but he did not know what was done. He then also reported that he routinely shaved a patch of lower back hair, but denied bowel, bladder, or lower extremity dysfunction. Magnetic resonance imaging of the cervical spine demonstrated T2 hyperintensity at C4-C5 with dorsal projection of the neural elements into the subcutaneous tissues concerning for a retethered cervical myelomeningocele. Lumbar imaging revealed a diastematomyelia at L4. He underwent surgical intervention for detethering and repaired of the cervical myelomeningocele. Four months postoperatively, he had almost complete resolution of symptoms, and imaging showed a satisfactory detethering. The diastematomyelia remained asymptomatic and is being observed. CONCLUSION: Tethered cervical cord is a rare cause for myelopathy in the adult patient. In the symptomatic patient, surgical repair with detethering is indicated to prevent disease progression and often results in clinical improvement.

Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model.

The intronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD, produces sense- and antisense-expansion RNAs and six dipeptide repeat-associated, non-ATG (RAN) proteins, but their roles in disease are unclear. We generated high-affinity human antibodies targeting GA or GP RAN proteins. These antibodies cross the blood-brain barrier and co-localize with intracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA1 interacts with TRIM21, and α-GA1 treatment reduced GA levels, increased GA turnover, and decreased RAN toxicity and co-aggregation of proteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA1 reduced GA as well as GP and GR proteins, improved behavioral deficits, decreased neuroinflammation and neurodegeneration, and increased survival. Glycosylation of the Fc region of α-GA1 is important for cell entry and efficacy. These data demonstrate that RAN proteins drive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeutic approach for C9orf72 ALS/FTD and other RAN-protein diseases.

C9orf72 BAC Mouse Model with Motor Deficits and Neurodegenerative Features of ALS/FTD.

To define how the C9orf72 GGGGCC expansion mutation causes ALS/FTD and to facilitate therapy development, a mouse model that recapitulates the molecular and phenotypic features of the disease is urgently needed. Two groups recently reported BAC mouse models that produce RNA foci and RAN proteins but, surprisingly, do not develop the neurodegenerative or behavioral features of ALS/FTD. We now report a BAC mouse model of C9orf72 ALS/FTD that shows decreased survival, paralysis, muscle denervation, motor neuron loss, anxiety-like behavior, and cortical and hippocampal neurodegeneration. These mice express C9orf72 sense transcripts and upregulated antisense transcripts. In contrast to sense RNA foci, antisense foci preferentially accumulate in ALS/FTD-vulnerable cell populations. RAN protein accumulation increases with age and disease, and TDP-43 inclusions are found in degenerating brain regions in end-stage animals. The ALS/FTD phenotypes in our mice provide a unique tool that will facilitate developing therapies targeting pathways that prevent neurodegeneration and increase survival.