Electrolyte, acid-base, and mineral metabolism disorders are among the most common and clinically significant problems experienced in internal medicine patients. Their development reflects disturbances in regulated homeostatic mechanisms involving the kidneys, bones, endocrine systems, and cellular ion transport. Disorders such as hyponatremia, hypernatremia, hypokalemia, hyperkalemia, metabolic acidosis, metabolic alkalosis, and abnormalities of calcium and phosphorus metabolism are associated with substantial morbidity and mortality when not promptly recognized and appropriately treated. Accurate diagnosis requires a deep understanding of the underlying pathophysiology, assessment of volume status, interpretation of laboratory findings, and identification of contributing kidney, endocrine, medications, and systemic factors. This review describes the physiological mechanisms governing electrolyte and acid-base homeostasis and discusses the clinical presentation, diagnostic evaluation, and evidence-based management of common electrolyte disorders encountered by Internists. We place emphasis on distinguishing etiologies and applying practical diagnostic algorithms to guide treatment decisions. In addition, the review highlights the interconnected regulation of calcium and phosphorus by parathyroid hormone, vitamin D, and fibroblast growth factor 23 and its relevance in kidney disease and other disorders. By integrating foundational physiology with current clinical practice guidelines, this review provides internists with a practical framework to solve electrolyte issues they face with confidence.
Progressive multiple sclerosis (PMS) represents a severe and disabling form of MS characterized by a gradual accumulation of neurological impairment and limited responsiveness to conventional disease-modifying therapies. Unlike the relapsing forms of the disease, progressive MS is driven not only by peripheral immune dysregulation but also by persistent neuroinflammation, microglial activation, mitochondrial dysfunction, and progressive neurodegeneration within the central nervous system. These complex and overlapping pathogenic mechanisms contribute to irreversible axonal loss and pose significant challenges for therapeutic intervention. Although recent advances in immunomodulatory treatments have improved outcomes for some patients, currently available therapies provide only limited benefits in slowing disease progression. Consequently, the identification of novel molecular pathways and therapeutic targets has become a major focus in the development of more effective strategies for progressive MS. Rapid progress in understanding the cellular and molecular basis of disease progression has facilitated the exploration of innovative therapeutic approaches, including targeted immunotherapies, neuroprotective agents, remyelination-promoting strategies, and emerging cell-based interventions. Here, in this review, we summarize current advances in the therapeutic landscape of progressive MS, highlighting recently approved treatments as well as promising agents under clinical investigation. Particular emphasis is placed on the underlying mechanisms of action of these therapies and their potential to modify disease progression, restore neural function, and support the development of personalized treatment strategies for patients with PMS.
BACKGROUND:Pregnancy loss affects up to 15% of clinically recognized pregnancies, posing a major clinical and emotional burden. While chromosomal abnormalities account for most early miscarriages, many previously unexplained cases involve monogenic, mitochondrial, epigenetic, immunogenetic, and paternal factors. Advances in genomic technologies have improved detection of pathogenic variants in both sporadic and recurrent pregnancy loss. OBJECTIVE:To synthesize current evidence on genetic determinants of pregnancy loss across chromosomal, monogenic, mitochondrial, epigenetic, immunologic, and thrombophilia-related pathways, and evaluate how genomic diagnostics inform management and reproductive counseling. METHODS:This narrative review integrates data from studies on chromosomal abnormalities, copy-number variants, maternal-effect genes, paternal genetic contributions, mitochondrial dysfunction, epigenetic dysregulation, immune-mediated mechanisms, and inherited thrombophilias. Evidence from next-generation sequencing, chromosomal microarray, whole-exome sequencing, and preimplantation genetic testing highlights diagnostic yield and clinical relevance. RESULTS:Chromosomal abnormalities, including aneuploidy and pathogenic copy-number variants, remain the predominant cause of early pregnancy loss. Mutations in maternal-effect genes, ciliogenesis and morphogenesis defects, mitochondrial variants, imprinting disturbances, and paternal factors, such as sperm DNA fragmentation, also contribute to implantation failure, embryonic arrest, and recurrent loss. Immunogenetic and thrombophilia-associated variants affect placental development and late outcomes. Genomic platforms (CMA, WES, NGS, PGT) increase diagnostic detection and improve counseling, especially for recurrent loss. CONCLUSION:Pregnancy loss arises from a spectrum of genetic mechanisms beyond chromosomal abnormalities. Integrating genomic, immunologic, and environmental assessment improves diagnostic precision, supports risk stratification, and informs targeted management. Modern genetic testing should be part of comprehensive evaluation for pregnancy loss. SHORT SUMMARY:Genetic contributors to pregnancy loss span chromosomal abnormalities, single-gene disorders, mitochondrial variants, epigenetic disturbances, immune dysregulation, and thrombophilia. Advances in genomic testing improve diagnostic precision and support individualized reproductive counseling for affected patients.
Hypothermia is classically defined as a reduction in the body's core temperature below 95.0°F (35.0 °C). Most reported cases of hypothermia are due to environmental exposure to low ambient temperatures (accidental hypothermia). Other causes of hypothermia include sepsis, severe hypothyroidism (myxedema coma), acute spinal cord injury, diabetic ketoacidosis, multisystem trauma, and prolonged cardiac arrest. Frostbite, chillblain and trench foot all have specific therapies to prevent limb loss. There have been significant advances in these therapeutic options over the past decade which are detailed in this issue.
BACKGROUND:Glucagon-like peptide-1 receptor agonists have been shown to have neuroprotective effects in metabolic diseases, but their application in neurodegenerative diseases (stroke and Parkinson's disease) has not been adequately studied. OBJECTIVES:To assess the neuroprotective effects of GLP-1 receptor agonists in experimental stroke and Parkinson's disease models, in terms of mechanisms, properties of intervention, and major neurological outcomes. METHODS:A systematic review was performed according to PRISMA. Four databases Cochrane CENTRAL, PubMed, Web of Science and Scopus were searched and 1643 records identified and 13 experimental animal studies were included. The SYRCLE tool was used to extract data and assess the risk of bias. RESULTS:13 experimental studies published in 2013-2026 were included, which involved models of stroke and Parkinson disease. The MCAO models were the main models used in stroke studies, with a significant decrease in infarct volume, such as 15.4 % ± 1.3 % (liraglutide) and 40 % reduction with linagliptin. The score in neurological deficit was also found to improve (1.1 ± 0.14; P < 0.05) and the size of the infarct in treated groups had also reduced (36.5 % to 8.2 %; P = 0.001). The research on Parkinson disease showed that there was a notable improvement in motor functions (P < 0.001), preservation of dopaminergic neurons, and a decrease in the aggregation of α-synuclein. GLP-1 agonists decreased neuroinflammatory (TNF-α, IL-1b, IL-6), oxidative (ROS, 4-HNE), and apoptotic (increased Bcl-2, decreased Bax) markers. The treatment was between 24 h and 20 weeks, and the doses also differed among the agents. The overall quality of risk of bias assessment was moderate, with four studies having a high risk because of small sample size and inadequate reporting on the randomization and blinding. CONCLUSION:GLP-1 receptor agonists have powerful neuroprotective activity in preclinical models of stroke and Parkinson disease, which is multi-targeted. To ensure translational potential and to maximize therapeutic strategies, standardized studies and clinical trials are needed.
BACKGROUND:Thromboembolic risk is increased in obesity and cardiometabolic disorders. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) also facilitate weight loss and cardiovascular benefits, yet their effects on thromboembolic events risk reduction in high-risk populations are not completely understood. METHODS:The PRISMA 2020 guidelines were followed to search Scopus, PubMed, Cochrane Library and Web of Science (WoS). We identified 110 records, 8 of which were included in this review. Data extraction, risk of bias assessment and narrative synthesis were independently conducted. RESULTS:GLP-1RAs consistently demonstrated greater weight reduction compared with controls. Semaglutide trials reported up to 15.2 % weight loss versus 2.6 % in controls (p < 0.0001), while liraglutide showed approximately 5 % reduction versus no change. Cardiovascular outcome trials showed significant risk reduction, with hazard ratios of 0.80 (0.72-0.90) and 0.74 (0.58-0.95), indicating decreased major cardiovascular events. However, direct venous thromboembolism reporting was limited; one study showed fewer events (1 vs 3) without statistical significance. Safety profiles were acceptable, with slightly increased gallbladder events (2.8 % vs 2.3 %), rare pancreatitis, and no consistent cancer risk. Serious adverse events were similar or lower in intervention groups (33.4 % vs 36.4 %). CONCLUSION:GLP-1RAs yield substantial weight loss and cardiovascular risk reduction in a high-risk group. There is limited direct evidence about thromboembolism, but there is evidence that it may be beneficial. Their role in reducing thromboembolic risk needs to be confirmed in further large-scale studies.
The respiratory tract (i.e., airways and alveoli) is in close contact with the milieu that is outside the human body and thus, in addition to its role in exchange of gases, it is needed to protect the human being from outside threats such as microbes and pollution. Respiratory tract diseases can have major detrimental effects on human health with increased risks for morbidity and mortality. An example of this dilemma is the orphan disease, primary ciliary dyskinesia (PCD), a complex genetic disorder linked with myriad genetic mutations involving over 50 genes and over 2000 pathogenic variants that lead to dysfunction of vital human components including the respiratory tract, auditory system, mechanisms of fertility and others. The core defect involves abnormal function and motion of microscopic organelles called cilia found throughout the human body with abnormal mucociliary clearance (i.e., aberrant mucociliary escalator). The regulation of motile cilia that are involved in various aspects of physiology such as respiration and reproduction is via thousands of genes. PCD pathophysiology, genetic underpinnings, diagnosis and principles of treatment are considered in this review of primary ciliary dyskinesia in pediatric persons (i.e., newborns, children and adolescents). Primary ciliary dyskinesia (PCD) is one of many ciliopathies that is identified as a condition with remarkable phenotypic and genetic variability. In this fluid fluctuation phenomenon, some PCD patients exhibit classic features such as chronic respiratory disease, situs abnormalities, and infertility, while others may present with milder or atypical disease. In certain cases, ultrastructural analysis of cilia may appear normal despite underlying dysfunction. Disease severity can range from early-onset bronchiectasis to relatively preserved pulmonary function into adulthood, reflecting perplexing genotype-phenotype diversity. Testing for PCD requires an experienced team with expertise in sophisticated technology that includes nasal nitric oxide (nNO) analysis, transmission electron microscopy (TEM), immunofluorescence analysis (IFA), high-speed video-microscopy analysis (HSVMA), three-dimensional explant spheroid formation (3D-E; ex vivo technique), genetic studies and others. Genetic testing is recommended for those suspected of having PCD, as for example in certain neonates (i.e., persistent respiratory distress, unexplained rhinorrhea with chronic cough, situs inversus), at-risk children (i.e., having persistent wet cough, chronic sinusitis, unexplained bronchiectasis, recurrent otitis media with airway symptomatology) and adults with early childhood respiratory symptoms often associated with infertility. The medical evaluation is complicated by various factors including the absence of a gold standard for a precise diagnosis. Also, as the clinician or clinical team considers a patient with possible PCD, the testing that is done should keep in mind the differential diagnoses of PCD; these conditions include cystic fibrosis (CF), various immune disorders, numerous infections (i.e., tuberculosis, aspergillosis, others), alpha-1-antitrypsin deficiency (AATD) and others as noted in this article. As emerging cutting-edge 21st century research seeks treatment of PCD via gene therapy, current management involves intense therapy of upper and lower respiratory tract infections (i.e., rhinosinusitis, otitis media, pneumonia) as well as bronchiectasis with focused efforts at dealing with impaired mucus clearance. Primary ciliary dyskinesia is a classic example of how microscopic (electron microscopic) maladies can lead to major macroscopic maladies in newborns, children, adolescents and adults.
