Fifteen-minute update: International normalised ratio as the treatment end point in children with acute paracetamol poisoning

Paracetamol is one of the most frequent reasons for poisonings across the UK with an estimated 90,000 patients and 150 deaths annually. International normalised ratio (INR) may be elevated due to hepatocellular damage and is frequently used to monitor progress on N-acetyl cysteine. N-acetyl cysteine is associated with reduced activity of vitamin K dependent clotting factors leading to a benign elevation of INR. In asymptomatic children with normal aspartate transaminase/alanine transaminase, isolated borderline elevation of INR following paracetamol overdose should be reviewed for possible N-acetyl cysteine induced elevation of INR. Due to these factors, in those with borderline persistent elevation of INR, N-acetyl cysteine can be safety stopped if INR is falling on two or more consecutive tests and is <3.0.

Case Report: The Association of Wilson Disease in a Patient With Ataxia and GLUT-1 Deficiency

Background: Wilson disease (WD) and glucose transporter type 1 (GLUT1) deficiency syndrome are two syndromes with different modes of inheritance but share certain similarities on neurological presentation. To date we have not found previous reports of an association between these two disorders.Case Presentation: Here we describe a 9-year-old male with global developmental delay that presented with intermittent and sudden onset weakness that first occurred at age 3. He was diagnosed with a mutation in the SLC2A1 (Solute Carrier Family 2 Member 1) gene, which results in GLUT1 deficiency. A ketogenic diet could not be started because of unexplained elevated liver enzymes. Due to his liver enzymes' persistent elevation, further investigations demonstrated mildly decreased ceruloplasmin levels, high basal 24-h urinary copper excretion, and an elevated hepatic parenchymal copper concentration on liver biopsy, consistent with WD. Genetic testing revealed two separate mutations in the ATP7B (ATPase Copper Transporting Beta) gene, consistent with WD. The patient was treated with a low copper diet, zinc acetate, and trientine hydrochloride. When liver enzymes normalized, he was subsequently started on a ketogenic diet with improvement in neurological symptoms. His neurological symptoms were most likely secondary to GLUT1 deficiency syndrome, as WD's neurological symptoms are primarily observed in the second decade of life.Conclusion: Recent studies have demonstrated the importance of genetic testing upon unexplained persistent elevation of liver enzymes. This case highlights the importance of carefully evaluating a patient with an unexplained liver disorder, even in the presence of primary neurological disease, as it can have significant therapeutic implications.

Glutamate Dehydrogenase as a Promising Target for Hyperinsulinism Hyperammonemia Syndrome Therapy.

: Hyperinsulinism-hyperammonemia syndrome (HHS) is a rare disease characterized by recurrent hypoglycemia and persistent elevation of plasma ammonia, and it can lead to severe epilepsy and permanent brain damage. It has been demonstrated that functional mutations of glutamate dehydrogenase (GDH), an enzyme in the mitochondrial matrix, are responsible for the HHS. Thus, GDH has become a promising target for the small molecule therapeutic intervention of HHS. Several medicinal chemistry studies are currently aimed at GDH, however, to date, none of the compounds reported has been entered clinical trials. This perspective summarizes the progress in the discovery and development of GDH inhibitors, including the pathogenesis of HHS, potential binding sites, screening methods, and research models. Future therapeutic perspectives are offered to provide a reference for discovering potent GDH modulators and encourage additional research that will provide more comprehensive guidance for drug development.

The viscosity and thrombocytic-aggregation disorders in patients, suffering myocardial infarction with the ST segment elevation

Objective. Analysis of changes in viscosity and disorders of the thrombocytes-aggregation process under impact of various tactical, diagnostic and intervention approaches in patients, suffering myocardial infarction with persistent elevation of ST segment in presence of multivascular affection of coronary arteries. Materials and methods. In the investigation four tactical and treatment-diagnostic approaches were used through year of observation. Results. In patients, suffering myocardial infarction and persistent elevation of ST segment the hyperviscosity and hypercoagulation syndromes were revealed, which have manifested in first weeks by compensatory growth of thrombocytes quantity, the blood viscosity, level of fibrinogen and aggregation properties of thrombocytes. Conduction of additional more profound examination of coronary blood circulation and further application of postponed stenting of the infarction-dependent arteries have promoted lesser amplitude of fluctuations of all laboratory indices, than in other tactical and treatment approaches. Conclusion. Standard tactical and treatment-diagnostic principles in management of such category of patients do not permit to improve the state of the viscosity and coagulation-aggregation parameters principally, even while application of double antiaggregation therapy.

Effects of Experimental Sleep Restriction on Ambulatory and Sleep Blood Pressure in Healthy Young Adults: A Randomized Crossover Study

Although insufficient sleep is associated with increased cardiovascular risk, evidence of a causal relationship is lacking. We investigated the effects of prolonged sleep restriction on 24-hour ambulatory blood pressure (BP) and other cardiovascular measures in 20 healthy young participants (aged 23.4±4.8 years, 9 females), who underwent a randomized, controlled, crossover, 16-day inpatient study consisting of 4 days of acclimation, 9 days of sleep restriction (4 hours of sleep/night) or control sleep (9 hours), and 3 days of recovery. Subjects consumed a weight maintenance diet with controlled nutrient composition throughout. A 24-hour BP (primary outcome) and cardiovascular biomarkers were measured repeatedly. Polysomnographic monitoring was continuous. Comparing sleep restriction versus control sleep, 24-hour mean BP was higher (adjusted mean difference, day 12: 2.1 mm Hg [95% CI, 0.6–3.6], corrected P =0.016), endothelial function was attenuated ( P <0.001), and plasma norepinephrine increased ( P =0.011). Despite increased deep sleep, BP was elevated while asleep during sleep restriction and recovery. Post hoc analysis revealed that 24-hour BP, wakefulness, and sleep BP increased during experimental and recovery phases of sleep restriction only in women, in whom 24-hour and sleep systolic BP increased by 8.0 (5.1–10.8) and 11.3 (5.9–16.7) mm Hg, respectively (both P <0.001). Shortened sleep causes persistent elevation in 24-hour and sleep-time BP. Pressor effects are evident despite closely controlled food intake and weight, suggesting that they are primarily driven by the shortened sleep duration. BP increases are especially striking and sustained in women, possibly suggesting lack of adaptation to sleep loss and thus greater vulnerability to its adverse cardiovascular effects.

Persistent elevation of plasma vitamin B12 is strongly associated with solid cancer

Elevated plasma vitamin B12 has been associated with solid cancers, based on a single B12 measurement. We evaluated the incidence of solid cancers following B12 measurement in patients with persistent elevated B12, compared to patients without elevated B12 and to patients with non-persistent elevated B12. The study population included patients with at least two plasma B12 measurements without already known elevated-B12-related causes. Patients with elevated plasma B12 (≥ 1000 ng/L) at first measurement (n = 344) were matched for age and sex with patients having 2 normal B12 measurements (< 1000 ng/L) (NN group, n = 344). The patients with elevated plasma B12 at first measurement were split into 2 groups, according to the presence (EE group, n = 144) or the absence (EN group, n = 200) of persistent elevated plasma B12 at second measurement. We compared the cancer-free survival during 60 months between the groups after adjustment for the other elevated-B12-related causes in a survival competing risk model. Compared to the NN group, a persistent elevated plasma B12 ≥ 1000 ng/mL was strongly associated with the occurrence of solid cancer (HR 5.90 [95% CI 2.79–12.45], p < 0.001), contrary to non-persistent plasma B12 elevation (p = 0.29). These results could help to select patients in whom the screening for solid cancers would be of interest.

Alpelisib Induced Hyperglycemic Ketoacidosis; Broadening the Adverse Effect Profile of an Emerging Cancer Therapy

Introduction: Alpelisib (PIQRAY) is a Phosphatidylinositol 3-Kinase Inhibitor (PIP-3K) recently approved by the united states food and drug administration (FDA) for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-mutated, advanced, or metastatic breast cancer in post-menopausal women or men with an adjuvant to Fulvestrant. Hyperglycemia is a well-known side effect of Alpelisib. However, hyperglycemic ketoacidosis is a rare and life-threatening side effect. Case Presentation: A 63-year-old Caucasian woman with ER/PR+, HER2- metastatic breast cancer presented to the emergency room (ER) with polydipsia, polyuria, dryness of the mouth and skin, along with a 12-pound weight loss over a period of three weeks. Alpelisib was initiated three months prior to her presentation with Hba1c: 6.4% and random BG: 89 mg/dl at the time. Her initial lab work in the ER revealed blood glucose of 474 mg/dl, sodium 129 mmol/L, potassium 5.1 mmol/L, and an anion gap of 15 with a Co2 of 19 mmol/L, HCO3 of 20 mmol/L, and a blood ketones level of 2.6. Her urinalysis revealed glucosuria and ketonuria. She was admitted to the general medical floor and Alpelisib was held. In light of her insulin naivety and no history of diabetes mellitus, it was decided to treat her with subcutaneous insulin with hourly titration based on monitoring of serum glucose and electrolytes with IV hydration. She required a total of 31 units of regular insulin along with 15 units of long-acting insulin. Her ketosis resolved within 12 hours of admission. Endocrinology was consulted and she was discharged on long-acting insulin 15. On follow-up, Alpelisib was resumed, metformin added along with long-acting insulin. Despite anti-diabetic therapy, due to persistent hyperglycemia (fasting blood glucose &gt;300 mg/dl), Alpelisib was discontinued 3 weeks after presentation. Conclusion: Alpelisib-induced hyperglycemic ketoacidosis is an uncommonly reported adverse event with only 3 reported cases to the best of our knowledge. While there are guidelines available to manage Alpelisib induced hyperglycemia, there are no specific recommendations for patients presenting with hyperglycemia and ketoacidosis in terms of admission to intensive care unit (ICU) or general medical floor (GMF), use of the type, route, and dosage of insulin and continuation of insulin for the persistent elevation of FBG despite interruption of Alpelisib. Alternative approaches for the treatment of breast cancer should be considered with continual hyperglycemia despite appropriate management. Multidisciplinary discussion involving the oncologist as well as an endocrinologist can be useful for the management of persistent elevation of FPG even after substantial Alpelisib free days.

Hepatitis E Virus Seroprevalence Among Liver Transplant Recipients with Persistent Elevation of Liver Enzymes: A Single Center Report

Background: Chronic hepatitis E infection has been reported in solid organ transplant recipients following acute hepatitis due to the compromised immune status. Almost all reports are from areas where hepatitis E virus (HEV) genotypes 3 and 4 are the dominant genotypes. This study was conducted to investigate the role of hepatitis E infection as an etiology for liver enzymes elevation in liver transplant recipients from the largest liver transplant program in Iran. Methods: In a prospective study from June to December 2015, in a single liver transplantation center in Iran, all adult liver recipients who were investigated for the etiology of persistent elevation of liver enzymes were tested for HEV serology status. Results: Of 122 patients included in the study, 19 (15.6%) were positive for HEV serology. Seropositive patients were significantly older than seronegative ones (mean age 43.79 vs. 31.58, P < 0.001); however, they were not different in other characteristics including sex distribution and mean of liver enzymes in each occasion. Liver biopsies were done in 16 HEV seropositive patients and none of the biopsies showed evidence for acute or chronic viral hepatitis. Conclusion: In this study, with 15.6% rate of HEV seropositivity in liver recipients with persistent elevation of liver enzymes, we were not able to confirm any clinical evidence for active acute or chronic hepatitis E infection. This could theoretically be attributed to the fact that the dominant prevalent HEV genotype in our endemic area is not associated with a chronic form of infection.

Comparing Theories for the Maintenance of Late LTP and Long-Term Memory: Computational Analysis of the Roles of Kinase Feedback Pathways and Synaptic Reactivation

A fundamental neuroscience question is how memories are maintained from days to a lifetime, given turnover of proteins that underlie expression of long-term synaptic potentiation (LTP) or “tag” synapses as eligible for LTP. A likely solution relies on synaptic positive feedback loops, prominently including persistent activation of Ca2+/calmodulin kinase II (CaMKII) and self-activated synthesis of protein kinase M ζ (PKMζ). Data also suggest positive feedback based on recurrent synaptic reactivation within neuron assemblies, or engrams, is necessary to maintain memories. The relative importance of these mechanisms is controversial. To explore the likelihood that each mechanism is necessary or sufficient to maintain memory, we simulated maintenance of LTP with a simplified model incorporating persistent kinase activation, synaptic tagging, and preferential reactivation of strong synapses, and analyzed implications of recent data. We simulated three model variants, each maintaining LTP with one feedback loop: autonomous, self-activated PKMζ synthesis (model variant I); self-activated CamKII (model variant II); and recurrent reactivation of strengthened synapses (model variant III). Variant I predicts that, for successful maintenance of LTP, either 1) PKMζ contributes to synaptic tagging, or 2) a low constitutive tag level persists during maintenance independent of PKMζ, or 3) maintenance of LTP is independent of tagging. Variant II maintains LTP and suggests persistent CaMKII activation could maintain PKMζ activity, a feedforward interaction not previously considered. However, we note data challenging the CaMKII feedback loop. In Variant III synaptic reactivation drives, and thus predicts, recurrent or persistent activation of CamKII and other necessary kinases, plausibly contributing to persistent elevation of PKMζ levels. Reactivation is thus predicted to sustain recurrent rounds of synaptic tagging and incorporation of plasticity-related proteins. We also suggest (model variant IV) that synaptic reactivation and autonomous kinase activation could synergistically maintain LTP. We propose experiments that could discriminate these maintenance mechanisms.