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Hyperkinetic Movement Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Morales-Briceno Hugo, Victor S.C. Fung, Annu Aggarwal, Philip Thompson
Metabolic: Thiamine responsive basal ganglia disease.Mitochondrial thiamine transporter deficiency.Lesch–Nyhan syndrome (LNS).Glucose transporter type 1 deficiency (GLUT1).
Alcohol-Related Dementia and Brain Damage
Published in Jenny Svanberg, Adrienne Withall, Brian Draper, Stephen Bowden, Alcohol and the Adult Brain, 2014
Nutritional status is a clear factor in risk for ARBD. The prevalence of thiamine deficiency in a population influences the prevalence of WE; however, the susceptibility to develop WKS in the presence of thiamine deficiency is influenced by less well-known genetic and environmental factors (Dumitrescu et al., 2011). A correlation between per capita consumption of alcohol and prevalence of WE has not been found (Harper et al., 1995). This may be due to the influence of national thiamine supplementation programs in some countries and not others; changes in patterns of drinking including rates of binge drinking and improved early treatment options (Thomson and Marshall, 2006). Genetic defects may also impact the ability of an individual to cope with borderline thiamine deficient states and resistance to adequate treatment (Dumitrescu et al., 2011). These defects may include mutation of the X-linked thiamine transketolase-like 1 gene or the gene that encodes for human thiamine transporter 1 – SLCA19. Genetic variants of the enzymes involved in ethanol metabolism may also predispose to WE (Sechi and Serra, 2007). Furthermore, APOE ε4 carrier status, a known genetic risk factor for development of Alzheimer's disease, may modify the effect of alcohol on risk of dementia. The protective effects of light to moderate alcohol consumption against dementia and cognitive decline are more likely in the absence of an APOE ε4 allele. The response to thiamine deficiency may also be population specific: Asians are more likely to develop a cardiovascular (wet) Beriberi, while Europeans tend to develop features of polyneuropathy and WE (Sechi and Serra, 2007).
Novel treatments to tackle myelofibrosis
Published in Expert Review of Hematology, 2018
Eran Zimran, Alla Keyzner, Camelia Iancu-Rubin, Ronald Hoffman, Marina Kremyanskaya
WE is a neurological disorder linked to thiamine deficiency. In a cohort of 92 MPN patients from the UK, there was no evidence of thiamine deficiency as determined by peripheral blood levels, regardless of disease entity, treatment or spleen size, supporting the concept that development of WE in patients treated with fedratinib is drug-related [49]. In a study conducted by Incyte Corporation, fedratinib was shown to inhibit the human thiamine transporter (hTHTR2) in human cell-lines (while other JAK inhibitors did not), providing a molecular basis for the development of WE upon fedratinib treatment, due to its structural similarity to thiamine [50]. Conversely, in a non-industry funded study, fedratinib did not lead to experimental WE or to thiamine deficiency in an in vivo model, and did not inhibit thiamine uptake by human astrocytes in vitro. Rats treated with fedratinib exhibited mild weight loss and occasional cases of diarrhea that were attributed to GI irritation. The authors suggested that gastrointestinal adverse effects of fedratinib including nausea and diarrhea may have indirectly contributed to WE in several patients [51]. Additional analyses are needed to elucidate the risk of WE with fedratinib treatment, with the hope that close surveillance of gastrointestinal toxicities and dietary intake may overcome the above concerns and enable further development of this drug with apparent potential clinical benefit.
Pathophysiology of essential hypertension: an update
Published in Expert Review of Cardiovascular Therapy, 2018
Tarun Saxena, Azeema Ozefa Ali, Manjari Saxena
Genetic factors influence BP regulation as shown by comparisons of monozygotic and dizygotic twins, and genetically related versus adopted children. Other gene-associated studies include: Minor alleles by two mis-sense mutation in corin gene. Corin enzymatically converts pro-ANP and pro-BNP into biologically active natriuretic peptides. Natriuretic peptides normally defend against hypertension and genetic impairment in the defence mechanism may lead to hypertension.In a recent study, it is discovered that genetic variants in thiamine transporter leads to increased cardiac output and decreased peripheral resistance.One of the group of common variants involves the UMOD gene, that encodes uromodulin. Uromodulin overexpression causes activation of the furosemide sensitive renal sodium cotransporter NKCC2. Pharmacological inhibition of NKCC2 by furosemide was more effective in lowering BP in hypertensive patients.GWAS studies have identified that any genetic defect in eNOS activity would predispose to high BP.Moreover, several single gene disorders cause relatively rare forms of hypertension by altering net sodium reabsorption. In some studies, sequence variation in both angiotensinogen and the angiotensin receptors has been associated with hypertension.
MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale
Published in Expert Review of Anti-infective Therapy, 2021
Paul E. Marik, Pierre Kory, Joseph Varon, Jose Iglesias, G Umberto Meduri
Thiamine is a water-soluble vitamin absorbed through thiamine transporter proteins in the proximal gastrointestinal tract. It exists in multiple forms through the addition of one or more phosphate groups [40]. The human adult can store around 30 mg of thiamine; these stores become rapidly depleted with decreased intake and metabolic stress; consequently, thiamine deficiency is common in critically ill patients [41–44]. Thiamine deficiency is particularly common in hospitalized elderly patients, those patients at greatest risk of developing COVID-19 [44–46]. In addition, functional thiamine deficiency is very common in patients with chronic renal failure [47]. Thiamine is the precursor of thiamine pyrophosphate (TPP), the essential coenzyme of several decarboxylases required for glucose metabolism, the Krebs cycle, the generation of ATP, the pentose-phosphate pathway, and the production of NADPH [40]. Thiamine being a co-factor of pentose-phosphate pathways, produce NADP during glutathione cycling, which, decreases reactive oxygen species, decreases microvascular dysfunction, decreases cellular apoptosis and improves endothelial dysfunction [48,49]. In addition, thiamine has anti-inflammatory effects and anti-oxidative effects, suppressing the oxidative stress-induced activation of NF-kB [48,50]. It is important to note that magnesium in an essential co-factor for TPP activity [51,52]. We suggest that the addition of thiamine to methylprednisolone, ascorbic acid and heparin will act synergistically to restore microvascular function in patients with COVID-19. In addition, thiamine is essential for cellular energy production and together with ascorbic acid and glucocorticoids may limit delirium in critically ill COVID-19 patients [53]. While the optimal dosing strategy of thiamine is unclear, based on the work of Donnino et al we suggest a dose of 200 mg IV 12 hourly for 7 day [43], followed by oral thiamine supplementation. There are no known contraindications to the use of intravenous thiamine. However, anaphylaxis is an extremely rare complication following intravenous thiamine administration [54,55].