The immunomodulatory effect of oral NaHCO3 is mediated by the splenic nerve: multivariate impact revealed by artificial neural networks.

Stimulation of the inflammatory reflex (IR) is a promising strategy for treating systemic inflammatory disorders. Recent studies suggest oral sodium bicarbonate (NaHCO3) as a potential activator of the IR, offering a safe and cost-effective treatment approach. However, the mechanisms underlying NaHCO3-induced anti-inflammatory effects remain unclear. We investigated whether oral NaHCO3's immunomodulatory effects are mediated by the splenic nerve. Female rats received NaHCO3 or water (H2O) for four days, and splenic immune markers were assessed using flow cytometry. NaHCO3 led to a significant increase (p < 0.05, and/or partial eta squared > 0.06) in anti-inflammatory markers, including CD11bc + CD206 + (M2-like) macrophages, CD3 + CD4 + FoxP3 + cells (Tregs), and Tregs/M1-like ratio. Conversely, proinflammatory markers, such as CD11bc + CD38 + TNFα + (M1-like) macrophages, M1-like/M2-like ratio, and SSChigh/SSClow ratio of FSChighCD11bc + cells, decreased in the spleen following NaHCO3 administration. These effects were abolished in spleen-denervated rats, suggesting the necessity of the splenic nerve in mediating NaHCO3-induced immunomodulation. Artificial neural networks accurately classified NaHCO3 and H2O treatment in sham rats but failed in spleen-denervated rats, highlighting the splenic nerve's critical role. Additionally, spleen denervation independently influenced Tregs, M2-like macrophages, Tregs/M1-like ratio, and CD11bc + CD38 + cells, indicating distinct effects from both surgery and treatment. Principal component analysis (PCA) further supported the separate effects. Our findings suggest that the splenic nerve transmits oral NaHCO3-induced immunomodulatory changes to the spleen, emphasizing NaHCO3's potential as an IR activator with therapeutic implications for a wide spectrum of systemic inflammatory conditions.

The Role of Triglycerides in Atherosclerosis: Recent Pathophysiologic Insights and Therapeutic Implications.

Triglycerides have long been recognized as a cardiovascular disease risk factor. However, their precise role in atherosclerosis and potential utility as a therapeutic target remains debated topics. This review aims to shed light on these aspects by exploring the complex relationship between triglycerides and atherosclerosis from pathophysiological and pharmacological perspectives. Triglycerides, primarily carried by chylomicrons and very low-density lipoproteins, play an essential role in energy storage and utilization. Dysregulation of triglyceride homeostasis and triglyceride- rich lipoproteins metabolism often leads to hypertriglyceridemia and subsequently increases atherosclerosis risk. Triglyceride-rich lipoproteins remnants interact with arterial wall endothelial cells, get retained in the subendothelial space, and elicit inflammatory responses, thereby accelerating atherogenesis. Despite the clear association between high triglyceride levels and increased cardiovascular disease risk, intervention trials targeting triglyceride reduction have produced mixed results. We discuss a range of triglyceride-lowering agents, from fibrates to omega-3 fatty acids, with a focus on their mechanism of action, efficacy, and major clinical trial outcomes. Notably, the role of newer agents, such as angiopoietin-like protein 3 and apolipoprotein C3 inhibitors, is also explored. We highlight the challenges and controversies, including the ongoing debate on the causal role of triglyceride in atherosclerosis and the discordant outcomes of recent clinical trials. The potential confounding effects of associated risk factors, such as elevated apolipoprotein B, insulin resistance, and metabolic syndrome, are considered. In conclusion, this review underscores the importance of a nuanced approach to understanding the role of triglycerides in atherosclerosis and their potential as a therapeutic target. Further research is needed to unravel the complex interplay between triglycerides, triglyceride-rich lipoproteins, and associated factors in atherosclerosis pathogenesis and refine triglyceride-targeted therapeutic strategies.

Hyperhomocysteinemia and Accelerated Aging: The Pathogenic Role of Increased Homocysteine in Atherosclerosis, Osteoporosis, and Neurodegeneration.

Cardiovascular diseases and osteoporosis, seemingly unrelated disorders that occur with advanced age, share major pathogenetic mechanisms contributing to accelerated atherosclerosis and bone loss. Hyperhomocysteinemia (hHcy) is among these mechanisms that can cause both vascular and bone disease. In its more severe form, hHcy can present early in life as homocystinuria, an inborn error of metabolic pathways of the sulfur-containing amino acid methionine. In its milder forms, hHcy may go undiagnosed and untreated into adulthood. As such, hHcy may serve as a potential therapeutic target for cardiovascular disease, osteoporosis, thrombophilia, and neurodegeneration, collectively representing accelerated aging. Multiple trials to lower cardiovascular risk and improve bone density with homocysteine-lowering agents, yet none has proven to be clinically meaningful. To understand this unmet clinical need, this review will provide mechanistic insight into the pathogenesis of vascular and bone disease in hHcy, using homocystinuria as a model for accelerated atherosclerosis and bone density loss, a model for accelerated aging.

A Novel Finding of Increased ß-Aminoisobutyric Acid Levels in Classic Homocystinuria With Homocysteine-Lowering Treatment.

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Although commonly seen as a milder elevation of homocysteine levels in adult patients, on rare occasions, the internist may face extremely elevated homocysteine levels (>100 µmol/L). In such rare cases, the search for a monogenic disease is warranted. In this report, we present a patient with classical homocystinuria, where the diagnosis was delayed due to various factors. The patient experienced a constellation of symptoms over an extended period, including visual problems, recurrent thrombosis, and neurodevelopmental delay. Delayed diagnosis of genetic diseases is problematic, as patients may grow from pediatric care to adult internal medicine, where knowledge and exposure to such a rare genetic disorder are limited. A diagnosis was finally confirmed with amino acid profiling, revealing extremely elevated homocysteine levels, which were reduced with sequential treatment modalities, including folate, vitamin B12, vitamin B6, methionine restriction, and betaine. We also present derangements in other amino acids, namely, methionine, taurine, serine, and urea cycle products. With treatment, a progressive increase in body weight is noticed. Furthermore, we present a novel finding of increased levels of ß-aminoisobutyric acid with homocysteine-lowering treatment. ß-aminisobutyric acid is a myokine that potentiates some of the metabolic benefits of exercising muscle such as improved insulin resistance and browning of white adipose tissue.

Low Bone Mass and Recurrent Fractures in Neurofibromatosis With Concomitant Hemoglobin SC Disease.

Bone disease and bone loss are common features in certain monogenic diseases such as RASopathies, including neurofibromatosis (NF). Similarly, bone complications are frequent in hemoglobinopathies, another group of Mendelian diseases. This paper reports a young patient with both NF and hemoglobin SC (HbSC) diseases who had multiple vertebral fractures with osteopenia. We also discuss the cellular and pathophysiological mechanisms underlying both diseases and the factors responsible for bone pain and low bone mass in NF and hemoglobinopathies such as HbSC. This case emphasizes the importance of careful evaluation and management of osteoporosis in patients with HbSC and NF1, as both are relatively common monogenic diseases in certain communities.

Moyamoya Syndrome (MMS) in a Patient With Sickle Cell Disease (SCD) and Protein S Deficiency.

The association between Moyamoya syndrome (MMS) and sickle cell disease (SCD) has been well-established in pediatric populations; however, limited literature exists documenting the characteristics and management of MMS in adult SCD patients. Studies have indicated the role of endovascular management in secondary stroke prevention for pediatric populations, with no current guidelines available for adult populations. Here, we describe a unique case of MMS in a 30-year-old patient with SCD and incidental protein S deficiency. Our unique case highlights a patient at high risk for neurosurgical intervention due to her hypercoagulable state who has benefitted from medical management. We also discuss current literature for the prevention of secondary cerebral vascular events and the role of further studies involving adult populations with MMS and SCD.

Autoimmune Encephalitis With Autoimmune Diabetes: A Case of Horror Autotoxicus.

Diagnosing autoimmune encephalitis relies on clinical, radiological, and serological studies. Several autoantibodies have been implicated and recognized, with dozens of potential targets identified in the past 20 years. Despite that progress, some patients with encephalitis present a diagnostic dilemma with a seronegative status. The presence of other autoimmune diseases in a patient with encephalitis should provide a clue to the autoimmune nature of a developing neurological syndrome (cognitive, psychiatric, behavioral, and catatonia). In this report, we describe the case of a young man with type 1 diabetes mellitus who was diagnosed with seronegative autoimmune encephalitis after presenting with catatonia. We describe the lengthy clinical course, the various therapeutic trials, and his clinical outcome and response to B-cell depleting agent. This study also discusses the potential pathophysiologic pathways, providing a rationale for the diagnostic workup and therapeutic options for autoimmune encephalopathy in this case presentation.

Artificial Hallucinations in ChatGPT: Implications in Scientific Writing.

While still in its infancy, ChatGPT (Generative Pretrained Transformer), introduced in November 2022, is bound to hugely impact many industries, including healthcare, medical education, biomedical research, and scientific writing. Implications of ChatGPT, that new chatbot introduced by OpenAI on academic writing, is largely unknown. In response to the Journal of Medical Science (Cureus) Turing Test - call for case reports written with the assistance of ChatGPT, we present two cases one of homocystinuria-associated osteoporosis, and the other is on late-onset Pompe disease (LOPD), a rare metabolic disorder. We tested ChatGPT to write about the pathogenesis of these conditions. We documented the positive, negative, and rather troubling aspects of our newly introduced chatbot's performance.

A Case Report of Autoimmune Phenomena With Underlying Breast Cancer: Occam's Razor Versus Hickam's Dictum.

The association between malignancies and autoimmunity had been well-established. The proposed pathophysiology and causality can be bidirectional. For example, a paraneoplastic syndrome can be triggered by an underlying malignancy or vice versa, where chronic inflammation of organs affected by autoimmunity can induce malignant transformation such as the case with inflammatory bowel disease and colorectal cancer or primary sclerosing cholangitis and hepatobiliary cancer. This report presents a case of autoimmune phenomena, namely, autoimmune hemolytic anemia, pernicious anemia, and Graves disease associated with newly diagnosed breast cancer. We also highlight the postulated pathophysiologic mechanisms in an attempt to answer the question of whether the occurrence of these autoimmune phenomena in our patient is a result of the law of parsimony (Occam's razor), where clinical variables are pathogenically related, or the counterargument, where random events and diseases can take place simultaneously (Hickam's dictum).

Duplication of AKT2 Gene in Ovarian Cancer: A Potentially Novel Mechanism for Tumor-Induced Hypoglycemia.

Severe hypoglycemia occurs with different types of tumors, including islet cell and non-islet cell tumors. Non-islet cell tumor hypoglycemia (NICTH) is a rare and potentially life-threatening complication of malignancy. The primary underlying mechanism of NICTH proposed in the literature includes paraneoplastic overproduction of insulin-like growth factor-2 (IGF-2), the production of autoantibodies against insulin or its receptors, or the presence of extensive metastatic burden replacing hepatic tissue or adrenal glands. In this report, we propose a potentially novel mechanism underlying NICTH involving stimulation of the insulin signaling pathway in a 58-year-old woman with a rare ovarian tumor of Müllerian origin that carries a duplication of the AKT2 gene. AKT2 is a molecular mediator of insulin signaling. To our knowledge, this is the first reported case of tumor-induced hypoglycemia associated with AKT2 gene duplication. In this report also, we discuss the currently available diagnostic modalities and highlight the therapeutic rationale in patients with NICTH, a highly vulnerable population.

Primary Hypoparathyroidism Presenting as Idiopathic Intracranial Hypertension in a Patient With Barakat Syndrome.

Unlike hyperparathyroidism, hypoparathyroidism is rarely encountered in clinical practice. Usually, it results from surgical resection, an autoimmune phenomenon, or an infiltrative process. Under certain circumstances, one may encounter a genetic etiology of hypoparathyroidism, often combined with myriad other syndromic manifestations. We report a case of a young female with congenital deafness and subacute visual loss. Hypocalcemia and primary hypoparathyroidism were subsequently discovered, and the cause of the vision loss was diagnosed as idiopathic intracranial hypertension, likely secondary to severe primary hypoparathyroidism. The patient was also found to have small bilateral kidneys, with tubular loss of magnesium and calcium, yet with a normal glomerular filtration rate. The constellation of congenital deafness, hypoparathyroidism, and renal dysfunction suggests Barakat syndrome, one of the less common causes of syndromic primary hypoparathyroidism.

Hypercalcemia in a 67-Year-Old Female Following the Use of Calcium Sulfate Beads: A Case Report and Review of Literature.

While the milk-alkali syndrome is traditionally viewed as the sole cause of exogenous hypercalcemia, the wide use of calcium sulfate (CS) in orthopedic procedures introduced another important item to be considered in the differential diagnosis. Calcium sulfate beads are increasingly used as void fillers and prophylactic measures to prevent postoperative hardware infections. However, hypercalcemia secondary to rapid calcium absorption from calcium sulfate beads is generally an underrecognized adverse effect and likely underreported. Furthermore, with calcium sulfate beads, hypercalcemia can dramatically present with alteration in mental status. In this report, we present a case of a 67-year-old female who underwent two orthopedic procedures, where calcium sulfate beads were used in both. The patient, on both occasions, developed significant hypercalcemia, manifested as agitation and suicidal thoughts, with each episode resolving after proper hydration and lowering of serum calcium. Also, in this report, we examined the literature and highlighted the female predominance in the reported cases, often manifesting in postoperative day (POD) 4. Given the acuity and severity of hypercalcemia, it is paramount to anticipate hypercalcemia, monitor serum calcium postoperatively to allow timely interventions, and avoid potentially serious complications.

Acute Colonic Pseudo-Obstruction Following the Use of Dexmedetomidine.

Dexmedetomidine is a preferred agent for light sedation with minimal adverse effects. We report a case of acute colonic pseudo-obstruction following dexmedetomidine use in a patient with alcohol withdrawal. He was treated with benzodiazepines first to control the withdrawal symptoms, then escalated to dexmedetomidine once delirium tremens ensued. Later on, the patient developed abdominal distension and vomiting. Imaging showed dilated bowel loops and absence of peristalsis on ultrasound. Decompression with the nasogastric (NG) tube was done, with high output from the NG tube. Dexmedetomidine infusion was used twice, and once it was stopped, the NG tube output was reduced, with the resumption of gastrointestinal motility and improvement of the abdominal distension. Recent similar reports of functional intestinal obstruction following alpha-2 (α2) agonist use necessitate further studies of intestinal motility following dexmedetomidine use and awareness of the possible side effect of dexmedetomidine on intestinal motility.

Diabetes Mellitus Manifests As Focal Dystonia.

Diabetes is one of the most common chronic diseases affecting over 400 million patients worldwide, many of which are affected with devastating macrovascular and microvascular complications. Diabetes affects both the peripheral and the central nervous systems. One of the unusual effects of hyperglycemia is involuntary movement, termed hyperglycemia-induced involuntary movement (HIIM). Here, we present a case of a middle-aged woman with neck dystonia as the initial manifestation of type 2 diabetes. Achieving euglycemia with insulin alone resulted in complete resolution of the neck dystonia.