Identification of retinoblastoma binding protein 7 (Rbbp7) as a mediator against tau acetylation and subsequent neuronal loss in Alzheimer's disease and related tauopathies.

Evidence indicates that tau hyper-phosphorylation and subsequent neurofibrillary tangle formation contribute to the extensive neuronal death in Alzheimer's disease (AD) and related tauopathies. Recent work has identified that increased tau acetylation can promote tau phosphorylation. Tau acetylation occurs at lysine 280 resulting from increased expression of the lysine acetyltransferase p300. The exact upstream mechanisms mediating p300 expression remain elusive. Additional work highlights the role of the epigenome in tau pathogenesis, suggesting that dysregulation of epigenetic proteins may contribute to acetylation and hyper-phosphorylation of tau. Here, we identify and focus on the histone-binding subunit of the Nucleosome Remodeling and Deacetylase (NuRD) complex: Retinoblastoma-Binding Protein 7 (Rbbp7). Rbbp7 chaperones chromatin remodeling proteins to their nuclear histone substrates, including histone acetylases and deacetylases. Notably, Rbbp7 binds to p300, suggesting that it may play a role in modulating tau acetylation. We interrogated Rbbp7 in post-mortem brain tissue, cell lines and mouse models of AD. We found reduced Rbbp7 mRNA expression in AD cases, a significant negative correlation with CERAD (neuritic plaque density) and Braak Staging (pathogenic tau inclusions) and a significant positive correlation with post-mortem brain weight. We also found a neuron-specific downregulation of Rbbp7 mRNA in AD patients. Rbbp7 protein levels were significantly decreased in 3xTg-AD and PS19 mice compared to NonTg, but no decreases were found in APP/PS1 mice that lack tau pathology. In vitro, Rbbp7 overexpression rescued TauP301L-induced cytotoxicity in immortalized hippocampal cells and primary cortical neurons. In vivo, hippocampal Rbbp7 overexpression rescued neuronal death in the CA1 of PS19 mice. Mechanistically, we found that increased Rbbp7 reduced p300 levels, tau acetylation at lysine 280 and tau phosphorylation at AT8 and AT100 sites. Collectively, these data identify a novel role of Rbbp7, protecting against tau-related pathologies, and highlight its potential as a therapeutic target in AD and related tauopathies.

Maternal choline supplementation ameliorates Alzheimer's disease pathology by reducing brain homocysteine levels across multiple generations.

The lack of effective treatments for Alzheimer's disease (AD) is alarming, considering the number of people currently affected by this disorder and the projected increase over the next few decades. Elevated homocysteine (Hcy) levels double the risk of developing AD. Choline, a primary dietary source of methyl groups, converts Hcy to methionine and reduces age-dependent cognitive decline. Here, we tested the transgenerational benefits of maternal choline supplementation (ChS; 5.0 g/kg choline chloride) in two generations (Gen) of APP/PS1 mice. We first exposed 2.5-month-old mice to the ChS diet and allowed them to breed with each other to generate Gen-1 mice. Gen-1 mice were exposed to the ChS diet only during gestation and lactation; once weaned at postnatal day 21, Gen-1 mice were then kept on the control diet for the remainder of their life. We also bred a subset of Gen-1 mice to each other and obtained Gen-2 mice; these mice were never exposed to ChS. We found that ChS reduced Aß load and microglia activation, and improved cognitive deficits in old Gen-1 and Gen-2 APP/PS1 mice. Mechanistically, these changes were linked to a reduction in brain Hcy levels in both generations. Further, RNA-Seq data from APP/PS1 hippocampal tissue revealed that ChS significantly changed the expression of 27 genes. These genes were enriched for inflammation, histone modifications, and neuronal death functional classes. Our results are the first to demonstrate a transgenerational benefit of ChS and suggest that modifying the maternal diet with additional choline reduces AD pathology across multiple generations.

Hyperkalemic paralysis in primary adrenal insufficiency.

Hyperkalemic paralysis due to Addison's disease is rare, and potentially life-threatening entity presenting with flaccid motor weakness. This case under discussion highlights Hyperkalemic paralysis as initial symptomatic manifestation of primary adrenal insufficiency.

Neem oil poisoning: Case report of an adult with toxic encephalopathy.

Neem oil has widespread use in Indian subcontinent due to its many bioactive properties. Azadirachtin, an active ingredient, is implicated in causing the effects seen in neem oil poisoning. Neem oil poisoning is rare in adults. This report highlights the toxicity associated with neem oil poisoning in an elderly male. The patient presented with vomiting, seizures, metabolic acidosis, and toxic encephalopathy. The patient recovered completely with symptomatic treatment.

Multi-organ Dysfunction Syndrome with Dual Organophosphate Pesticides Poisoning.

Organophosphate (OP) pesticide self-poisoning is common in developing countries. Poisoning with dual OP compounds is rare. Multi-organ dysfunction after OP poisoning has a high mortality rate. We report the case of a 27-year-old man who developed multi-organ dysfunction syndrome with fatal outcome after intentional ingestion of 50:50 mixture of two OP compounds, dichlorvos and profenofos.

Dietary choline intake is necessary to prevent systems-wide organ pathology and reduce Alzheimer's disease hallmarks.

There is an urgent need to identify modifiable environmental risk factors that reduce the incidence of Alzheimer's disease (AD). The B-like vitamin choline plays key roles in body- and brain-related functions. Choline produced endogenously by the phosphatidylethanolamine N-methyltransferase protein in the liver is not sufficient for adequate physiological functions, necessitating daily dietary intake. ~90% of Americans do not reach the recommended daily intake of dietary choline. Thus, it's imperative to determine whether dietary choline deficiency increases disease outcomes. Here, we placed 3xTg-AD, a model of AD, and non-transgenic (NonTg) control mice on either a standard laboratory diet with sufficient choline (ChN; 2.0 g/kg choline bitartrate) or a choline-deficient diet (Ch-; 0.0 g/kg choline bitartrate) from 3 to 12 (early to late adulthood) months of age. A Ch- diet reduced blood plasma choline levels, increased weight, and impaired both motor function and glucose metabolism in NonTg mice, with 3xTg-AD mice showing greater deficits. Tissue analyses showed cardiac and liver pathology, elevated soluble and insoluble Amyloid-ß and Thioflavin S structures, and tau hyperphosphorylation at various pathological epitopes in the hippocampus and cortex of 3xTg-AD Ch- mice. To gain mechanistic insight, we performed unbiased proteomics of hippocampal and blood plasma samples. Dietary choline deficiency altered hippocampal networks associated with microtubule function and postsynaptic membrane regulation. In plasma, dietary choline deficiency altered protein networks associated with insulin metabolism, mitochondrial function, inflammation, and fructose metabolic processing. Our data highlight that dietary choline intake is necessary to prevent systems-wide organ pathology and reduce hallmark AD pathologies.

Technical Feasibility of Whole-eye Vascular Composite Allotransplantation: A Systematic Review.

There are over 43 million individuals in the world who are blind. As retinal ganglion cells are incapable of regeneration, treatment modalities for this condition are limited. Since first incepted in 1885, whole-eye transplantation (WET) has been proposed as the ultimate cure for blindness. As the field evolves, different aspects of the surgery have been individually explored, including allograft viability, retinal survival, and optic nerve regeneration. Due to the paucity in the WET literature, we aimed to systematically review proposed WET surgical techniques to assess surgical feasibility. Additionally, we hope to identify barriers to future clinical application and potential ethical concerns that could be raised with surgery. Methods: We conducted a systematic review of PubMed, Embase, Cochrane Library, and Scopus from inception to June 10, 2022, to identify articles pertaining to WET. Data collection included model organisms studied, surgical techniques utilized, and postoperative functional outcomes. Results: Our results yielded 33 articles, including 14 mammalian and 19 cold-blooded models. In studies performing microvascular anastomosis in mammals, 96% of allografts survived after surgery. With nervous coaptation, 82.9% of retinas had positive electroretinogram signals after surgery, indicating functional retinal cells after transplantation. Results on optic nerve function were inconclusive. Ocular-motor functionality was rarely addressed. Conclusions: Regarding allograft survival, WET appears feasible with no complications to the recipient recorded in previous literature. Functional restoration is potentially achievable with a demonstrated positive retinal survival in live models. Nevertheless, the potential of optic nerve regeneration remains undetermined.

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. While the causes of AD are not known, several risk factors have been identified. Among these, type two diabetes (T2D), a chronic metabolic disease, is one of the most prevalent risk factors for AD. Insulin resistance, which is associated with T2D, is defined as diminished or absent insulin signaling and is reflected by peripheral blood hyperglycemia and impaired glucose clearance. In this study, we used complementary approaches to probe for peripheral insulin resistance, central nervous system (CNS) insulin sensitivity and energy homeostasis in Tg2576 and 3xTg-AD mice, two widely used animal models of AD. We report that CNS insulin signaling abnormalities are evident months before peripheral insulin resistance. In addition, we find that brain energy metabolism is differentially altered in both mouse models, with 3xTg-AD mice showing more extensive changes. Collectively, our data suggest that early AD may reflect engagement of different signaling networks that influence CNS metabolism, which in turn may alter peripheral insulin signaling.

Meningitis with polymerase chain reaction for varicella zoster positivity in cerebrospinal flid of a young immunocompetent adult.

Meningitis caused by varicella zoster virus (VZV) is quite rare among young immunocompetent adults though immunocompromised patients are often seen to be affected by reactivation of VZV presenting with primary clinical features of dermatomal rashes and neurological sequelae. Here, we report the clinical scenario of a young, healthy male who had presented with fever, headache, and onset of dermatomal rashes later than the fever and was eventually diagnosed to be a case of VZV meningitis. We would like to highlight the fact that even young immunocompetent patients though rarely, might contract VZV meningitis and clinicians should have a high index of suspicion and keen eyes to catch the more obvious features of VZV infection on complete physical examination and must not harbor any reservations in ordering polymerase chain reaction for VZV DNA or initiating aggressive antiviral therapy.

Fulminant guillain-barré syndrome with myocarditis.

Guillain-Barré syndrome (GBS) represents a diverse spectrum of diseases, with variable pathophysiological mechanisms, clinical manifestation, presentation pattern, and degree of severity. We report a rare case of fatal fulminant GBS complicated with myocarditis during the course of illness.

A rare debilitating neurological adverse effect of ranolazine due to drug interaction with clarithromycin.

Medication errors may occur at any point during patient care in the health care system. Drug interaction in known with macrolide antibiotics and ranolazine and is primarily related to effects on the cytochrome P4503A (CYP3A) metabolic pathway. This case highlights medication errors that resulted in rare debilitating neurological adverse effects of ranolazine in an elderly due to drug interaction with clarithromycin.

Acute renal failure due to rhabdomyolysis following a seizure.

Acute renal failure, oliguric or nonoliguric, is the most common complication of rhabdomyolysis. Rhabdomyolysis should be suspected in patients presenting with states of increased muscular activity, such as seizures, agitation, strenuous muscle exercise, or dystonia. We report an adult who developed acute renal failure associated with rhabdomyolysis following a seizure. The patient made complete recovery with hemodialysis. This report illustrates importance of early recognition of rhabdomyolysis following a seizure episode to prevent the risk of acute renal failure.

Fatal anaphylactic reaction to iron sucrose in pregnancy.

Iron-deficiency anemia in pregnancy can have serious deleterious effects for both mother and fetus. Parenteral iron therapy in iron-deficiency anemia is recommended in patients where oral iron therapy is ineffective due to malabsorption states and non-compliance. Compared to oral iron therapy, intravenous iron results in much more rapid resolution of iron-deficiency anemia with minimal adverse reactions. Iron sucrose has a favorable safety profile and is an alternative to other forms of parenteral iron therapy in correction of iron stores depletion. Immune mechanisms and iron agent releasing bioactive, partially unbound iron into the circulation, resulting in oxidative stress appears to cause severe adverse reactions. Although iron sucrose has a favorable safety profile in comparison to other parenteral iron preparations, this report highlights a fatal anaphylactic shock to iron sucrose in a pregnant woman with severe iron deficiency non-compliant to oral iron therapy.

Norfloxacin-induced hypoglycemia and urticaria.

Fluoroquinolone-induced hypoglycemia is not a common adverse drug reaction. However, it has been reported with most of the available agents and appears to be more common in elderly patients with a history of type 2 diabetes who are receiving oral sulfonylureas. The exact mechanism of this effect is unknown but is postulated to be a result of blockage of Adenosine 5'-Triphosphate (ATP)-sensitive potassium channels in pancreatic ß-cell membranes. This report highlights hypoglycemia with urticaria as an adverse drug reaction of norfloxacin in a middle aged non-diabetic patient. Clinicians should be alert about the possibility of its potential adverse effect in patients who are receiving norfloxacin therapy.