Showing papers on "Thiamine published in 2015"

Thiamine deficiency: an update of pathophysiologic mechanisms and future therapeutic considerations.

Abstract: Thiamine is an essential vitamin that is necessary to maintain the functional integrity of cells in the brain Its deficiency is the underlying cause of Wernicke's encephalopathy (WE), a disorder primarily associated with, but not limited to, chronic alcoholism Thiamine deficiency leads to the development of impaired energy metabolism due to mitochondrial dysfunction in focal regions of the brain resulting in cerebral vulnerability The consequences of this include oxidative stress, excitotoxicity, inflammatory responses, decreased neurogenesis, blood-brain barrier disruption, lactic acidosis and a reduction in astrocyte functional integrity involving a loss of glutamate transporters and other astrocyte-specific proteins which together contribute in a major way to the resulting neurodegeneration Exactly how these factors acting in concert lead to the demise of neurons is unclear In this review we reassess their relative importance in the light of more recent findings and discuss therapeutic possibilities that may provide hope for the future for individuals with WE

Molecular mechanisms of the non-coenzyme action of thiamin in brain: biochemical, structural and pathway analysis

Abstract: Thiamin (vitamin B1) is a pharmacological agent boosting central metabolism through the action of the coenzyme thiamin diphosphate (ThDP). However, positive effects, including improved cognition, of high thiamin doses in neurodegeneration may be observed without increased ThDP or ThDP-dependent enzymes in brain. Here, we determine protein partners and metabolic pathways where thiamin acts beyond its coenzyme role. Malate dehydrogenase, glutamate dehydrogenase and pyridoxal kinase were identified as abundant proteins binding to thiamin- or thiazolium-modified sorbents. Kinetic studies, supported by structural analysis, revealed allosteric regulation of these proteins by thiamin and/or its derivatives. Thiamin triphosphate and adenylated thiamin triphosphate activate glutamate dehydrogenase. Thiamin and ThDP regulate malate dehydrogenase isoforms and pyridoxal kinase. Thiamin regulation of enzymes related to malate-aspartate shuttle may impact on malate/citrate exchange, responsible for exporting acetyl residues from mitochondria. Indeed, bioinformatic analyses found an association between thiamin- and thiazolium-binding proteins and the term acetylation. Our interdisciplinary study shows that thiamin is not only a coenzyme for acetyl-CoA production, but also an allosteric regulator of acetyl-CoA metabolism including regulatory acetylation of proteins and acetylcholine biosynthesis. Moreover, thiamin action in neurodegeneration may also involve neurodegeneration-related 14-3-3, DJ-1 and β-amyloid precursor proteins identified among the thiamin- and/or thiazolium-binding proteins.

Beriberi (Thiamine Deficiency) and High Infant Mortality in Northern Laos

Abstract: Background Infantile beriberi (thiamine deficiency) occurs mainly in infants breastfed by mothers with inadequate intake of thiamine, typically among vulnerable populations. We describe possible and probable cases of infantile thiamine deficiency in northern Laos. Methodology/Principal Findings Three surveys were conducted in Luang Namtha Province. First, we performed a retrospective survey of all infants with a diagnosis of thiamine deficiency admitted to the 5 hospitals in the province (2007–2009). Second, we prospectively recorded all infants with cardiac failure at Luang Namtha Hospital. Third, we further investigated all mothers with infants (1–6 months) living in 22 villages of the thiamine deficiency patients’ origin. We performed a cross-sectional survey of all mothers and infants using a pre-tested questionnaire, physical examination and squat test. Infant mortality was estimated by verbal autopsy. From March to June 2010, four suspected infants with thiamine deficiency were admitted to Luang Namtha Provincial hospital. All recovered after parenteral thiamine injection. Between 2007 and 2009, 54 infants with possible/probable thiamine deficiency were diagnosed with acute severe cardiac failure, 49 (90.2%) were cured after parenteral thiamine; three died (5.6%). In the 22 villages, of 468 live born infants, 50 (10.6%, 95% CI: 8.0–13.8) died during the first year. A peak of mortality (36 deaths) was reported between 1 and 3 months. Verbal autopsy suggested that 17 deaths (3.6%) were due to suspected infantile thiamine deficiency. Of 127 mothers, 60 (47.2%) reported edema and paresthesia as well as a positive squat test during pregnancy; 125 (98.4%) respected post-partum food avoidance and all ate polished rice. Of 127 infants, 2 (1.6%) had probable thiamine deficiency, and 8 (6.8%) possible thiamine deficiency. Conclusion Thiamine deficiency may be a major cause of infant mortality among ethnic groups in northern Laos. Mothers’ and children’s symptoms are compatible with thiamine deficiency. The severity of this nutritional situation requires urgent attention in Laos.

Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

Abstract: The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.

Overexpression of Plastid Transketolase in Tobacco Results in a Thiamine Auxotrophic Phenotype

Abstract: To investigate the effect of increased plastid transketolase on photosynthetic capacity and growth, tobacco (Nicotiana tabacum) plants with increased levels of transketolase protein were produced. This was achieved using a cassette composed of a full-length Arabidopsis thaliana transketolase cDNA under the control of the cauliflower mosaic virus 35S promoter. The results revealed a major and unexpected effect of plastid transketolase overexpression as the transgenic tobacco plants exhibited a slow-growth phenotype and chlorotic phenotype. These phenotypes were complemented by germinating the seeds of transketolase-overexpressing lines in media containing either thiamine pyrophosphate or thiamine. Thiamine levels in the seeds and cotyledons were lower in transketolase-overexpressing lines than in wild-type plants. When transketolase-overexpressing plants were supplemented with thiamine or thiamine pyrophosphate throughout the life cycle, they grew normally and the seed produced from these plants generated plants that did not have a growth or chlorotic phenotype. Our results reveal the crucial importance of the level of transketolase activity to provide the precursor for synthesis of intermediates and to enable plants to produce thiamine and thiamine pyrophosphate for growth and development. The mechanism determining transketolase protein levels remains to be elucidated, but the data presented provide evidence that this may contribute to the complex regulatory mechanisms maintaining thiamine homeostasis in plants.

Clinicopathologic features of folate-deficiency neuropathy

Abstract: Objective: The clinical significance and characteristics of neuropathy caused by folate deficiency remain to be established. Methods: We examined the clinicopathologic features of 18 consecutive patients with neuropathy caused by folate deficiency who presented with low serum folate levels but normal blood thiamine and serum cobalamin levels in the absence of chronic alcoholism. Results: Symptoms were relatively uniform, characterized by slowly progressive polyneuropathy with predominant involvement of the lower extremities, with a tendency to manifest as sensory rather than motor neuropathy and predominant deep rather than superficial sensory loss. The electrophysiologic features were consistent with axonal neuropathy. The histopathologic features of sural nerve biopsy specimens indicated large fiber–predominant axonal loss without segmental demyelination. Although macrocytosis was found in 7 patients, only 3 patients exhibited hemoglobin levels less than 10 g/dL. During the same study period, we found 12 patients who had low blood thiamine levels but normal serum folate and cobalamin levels without chronic alcoholism. Compared with patients who had thiamine-deficiency neuropathy, patients with a folate deficiency showed significantly slower progression ( p p p p Conclusions: Folate-deficiency neuropathy was characterized by a slowly progressive and sensory-dominant pattern, which was different from thiamine-deficiency neuropathy (i.e., beriberi neuropathy). This study demonstrates the importance of folate deficiency in the differential diagnosis of neuropathy, particularly in countries where folic acid fortification has not yet been practiced.

Effects of different dietary concentrate to forage ratio and thiamine supplementation on the rumen fermentation and ruminal bacterial community in dairy cows

Abstract: A subacute ruminal acidosis (SARA) model was induced gradually by increasing the proportion of dietary concentrate to evaluate the effect of thiamine supplementation on the structure of bacterial community in dairy cows. Three Holstein dairy cows with rumen cannula were randomly assigned to a replicated 3 × 3 Latin square design trial and received three diets during three successive 21-day periods in each square. The three dietary treatments were as follows: a low-concentrate diet (control), a high-concentrate SARA-induced diet (SARA) and a high-concentrate SARA-induced diet with 180 mg thiamine/kg DM (SARA+thiamine). Real-time–polymerase chain reaction assay was used to quantify the population variation of SARA-related ruminal bacteria in these cows. The results showed that SARA was induced gradually when cows were fed with the high-concentrate diets. The mean ruminal pH value was higher in the control cows than in those of SARA and SARA+thiamine groups, the mean was decreased in cows fed on SARA diet, and the depression was alleviated by supplemented thiamine and the difference was significant (P 0.05). It was concluded that thiamine supplementation to high-concentrate diets at concentrations of 180 mg/kg DM could help alleviate SARA by increasing rumen pH and balancing the population of lactic acid-producing and -consuming bacteria.

PKR downregulation prevents neurodegeneration and β -amyloid production in a thiamine-deficient model

Abstract: Brain thiamine homeostasis has an important role in energy metabolism and displays reduced activity in Alzheimer's disease (AD). Thiamine deficiency (TD) induces regionally specific neuronal death in the animal and human brains associated with a mild chronic impairment of oxidative metabolism. These features make the TD model amenable to investigate the cellular mechanisms of neurodegeneration. Once activated by various cellular stresses, including oxidative stress, PKR acts as a pro-apoptotic kinase and negatively controls the protein translation leading to an increase of BACE1 translation. In this study, we used a mouse TD model to assess the involvement of PKR in neuronal death and the molecular mechanisms of AD. Our results showed that the TD model activates the PKR-eIF2α pathway, increases the BACE1 expression levels of Aβ in specific thalamus nuclei and induces motor deficits and neurodegeneration. These effects are reversed by PKR downregulation (using a specific inhibitor or in PKR knockout mice).

Study of Protein Biomarkers of Diabetes Mellitus Type 2 and Therapy with Vitamin B1.

Abstract: In the present research work, the levels of protein biomarkers specific to diabetes mellitus type 2 in the Pakistani population using proteomic technology have been identified and characterized and effect of high dose thiamine has been seen on the levels of these marker proteins. Diabetic patients and normal healthy controls were recruited from the Sheikh Zayed Hospital, Lahore, Pakistan. Total biochemical assays and proteins were estimated by modern proteomic techniques. Some proteins were up- and downregulated in diabetic samples as compared to control and decreased after thiamine therapy, while other protein markers did not show a significant change after the thiamine therapy. The effect of high dose thiamine on the levels of these identified protein biomarkers in the human urine has also been observed. Assessment of the levels of these biomarkers will be helpful in not only early diagnosis but also prognosis of diabetes mellitus type 2.

Rapid Reversal of Severe Lactic Acidosis After Thiamine Administration in Critically Ill Adults A Report of 3 Cases

Abstract: Background: Thiamine plays a critical role in energy metabolism. Critically ill patients may have thiamine deficiency and increased mortality due to potentially irreversible consequences. The aim of this study was to show the impact of thiamine deficiency in a series of patients and the rapid response to thiamine replacement, showing the changes in clinical and metabolic conditions over time. Methods: We described 3 cases of hospitalized patients who had received parenteral nutrition (PN) without vitamin supplementation. All the patients were admitted to the ICU between 2010 and 2011 with a severe form of lactic acidosis, an unstable circulatory state, and a different neurological disorder (a lethargic state, a severe form of impaired near-coma consciousness, and Wernicke encephalopathy). Results: Intravenous (IV) administration of thiamine was associated with a rapid and marked restoration of acid-base balance, hemodynamic stability and the disappearance of neurological disturbances, and normalization of...

You Are What You Eat

Abstract: Wernicke encephalopathy consists of a triad of ophthalmoplegia, ataxia, and altered mental status. It is caused by thiamine deficiency and although it is commonly seen in alcoholics, patients undergoing gastric bypass surgery for morbid obesity could be a new group of patients to watch for. Florid papilloedema and optic neuropathy are not commonly seen but are still consistent with the diagnosis of Wernicke encephalopathy. The most striking feature remains the dramatic recovery after replacement of thiamine.

Identification of vitamin B1 metabolism as a tumor-specific radiosensitizing pathway using a high-throughput colony formation screen

Abstract: // Gaganpreet S. Tiwana 1,* , Remko Prevo 1,* , Francesca M. Buffa 1 , Sheng Yu 1 , Daniel V. Ebner 2 , Alison Howarth 2 , Lisa K. Folkes 1 , Balam Budwal 1 , Kwun-Ye Chu 1 , Lisa Durrant 1 , Ruth J. Muschel 1 , W. Gillies McKenna 1 and Geoff S. Higgins 1 1 Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Department of Oncology, University of Oxford, Oxford, UK 2 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK * These authors contributed equally to this work Correspondence to: W. Gillies McKenna, email: // Geoff S. Higgins, email: // Keywords : Tumor radiosensitivity, High-throughput screening, Thiamine, TPK1 Received : November 24, 2014 Accepted : January 22, 2015 Published : February 28, 2015 Abstract Colony formation is the gold standard assay for determining reproductive cell death after radiation treatment, since effects on proliferation often do not reflect survival. We have developed a high-throughput radiosensitivity screening method based on clonogenicity and screened a siRNA library against kinases. Thiamine pyrophosphokinase-1 (TPK1), a key component of Vitamin B1/thiamine metabolism, was identified as a target for radiosensitization. TPK1 knockdown caused significant radiosensitization in cancer but not normal tissue cell lines. Other means of blocking this pathway, knockdown of thiamine transporter-1 (THTR1) or treatment with the thiamine analogue pyrithiamine hydrobromide (PyrH) caused significant tumor specific radiosensitization. There was persistent DNA damage in cells irradiated after TPK1 and THTR1 knockdown or PyrH treatment. Thus this screen allowed the identification of thiamine metabolism as a novel radiosensitization target that affects DNA repair. Short-term modulation of thiamine metabolism could be a clinically exploitable strategy to achieve tumor specific radiosensitization.

Shoshin Beriberi in Critically-Ill patients: case series

Abstract: Thiamine plays a fundamental role in cellular metabolism. The classical syndrome caused by thiamine deficiency is beriberi, and its fulminant variant, once considered an uncommon finding, is now encountered among the critically ill. We present a case series of four critically ill non-septic non-alcoholic patients with severe lactic acidosis and refractory cardio-circulatory collapse caused by acute fulminant beriberi, which drastically responded to thiamine administration. In critical care settings, increased awareness of this life-threatening but reversible condition is a requirement, especially among patients receiving parenteral nutrition and those with unexplained recalcitrant lactic acidosis.

Palliative treatment of thiamine-related encephalopathy (Wernicke's encephalopathy) in cancer: A case series and review of the literature.

Abstract: Objective: Thiamine-related encephalopathy (Wernicke's encephalopathy) is a neuropsychiatric syndrome caused by a vitamin B1 (thiamine) deficiency often associated with alcoholism. Cancer predisposes patients to thiamine deficiency unrelated to alcoholism, though many cases are missed clinically. The present report adds to the literature on thiamine as a palliative tool for thiamine-related encephalopathy (TRE) in cancer. Method: From a larger series of TRE in cancer, we report on three cases with terminal illness. Results: Case 1. A 61-year old woman with Hodgkin's lymphoma developed TRE over 13 days. Precipitants included a hypermetabolic state in the background of subacute thiamine deficiency. Diagnosis was supported by abnormal serum thiamine and positive MRI findings. Mental status improved within 36 hours of initiating thiamine 500 mg IV t.i.d. Case 2. A 68-year-old man with colon cancer metastatic to liver and bone developed TRE precipitated by C. difficile–related diarrhea superimposed on 3 months of low appetite and weight loss. Diagnosis was supported by abnormal serum thiamine, and thiamine 500 mg IV t.i.d. was initiated. Improvements in mental status began within 36 hours. Case 3. An 80-year-old man with squamous cell carcinoma developed TRE precipitated by systemic infection in the context of three weeks of dysphagia. Antibiotic treatment did not reverse his cognitive symptoms, and a diagnosis of TRE was made based on operationalized criteria. Thiamine 100 mg IV daily did not reverse his symptoms. On his 30th day of admission, thiamine was increased to 500 mg IV t.i.d., resulting in a rapid reversal of altered mental status. Significance of Results: This report adds to the list of cancer types in which TRE/Wernicke's encephalopathy has been reported. It supports the use of higher doses of thiamine than are typically recommended in North America. Improvement following treatment allowed patients to engage with family and treatment teams prior to death.

Thiamine responsive megaloblastic anemia syndrome: a novel homozygous SLC19A2 gene mutation identified.

Abstract: Thiamine responsive megaloblastic anemia syndrome (TRMAS) is a rare autosomal recessive disorder especially in countries where consanguinity is uncommon. Three main features are characteristic of the disease – megaloblastic anemia, early onset deafness, and non-type I diabetes. TRMAS is a Mendelian disorder; a gene SLC19A2 coding high affinity thiamine transporter mediating vitamin B1 uptake through cell membrane has been identified. We present the first patient with TRMAS in Lithuania – a 3-year-old boy born to a non-consanguineous family with a novel homozygous SLC19A2 gene mutation. The patient had insulin dependent diabetes (onset 11 months), respiratory illness (onset 11 months), bilateral profound hearing loss (onset at 7 months, verified at 20 months), refractory anemia (onset 2 years), and decreased vision acuity and photophobia (onset 2.5 years). The psychomotor abilities developed according to age. Phenotypic evaluation did not reveal any dysmorphic features. The clinical diagnosis of TRMAS was suspected and daily supplementation with thiamine 100 mg was started. The condition of the patient markedly improved several days after the initiation of treatment. The results of SLC19A2 gene molecular testing confirmed the clinical diagnosis – novel homozygous c.[205G>T], p.[(Val69Phe)] mutation changing conserved amino acid residue or even interfering the mRNA splicing. Clinical heterogeneity, diverse dynamics, and wide spectrum of symptoms are aggravating factors in the diagnosis. The possibility of treatment demands early recognition of disorder to facilitate the improvement of the patient's condition. © 2015 Wiley Periodicals, Inc.

Long-Term Treatment with High-Dose Thiamine in Parkinson Disease: An Open-Label Pilot Study.

Abstract: Objectives: To investigate the potential clinical, restorative, and neuroprotective effects of long-term treatment with thiamine in Parkinson disease (PD). Design: Observational open-label pilot study. Setting: Outpatient neurologic rehabilitation clinic. Patients and Methods: Starting in June 2012, we have recruited 50 patients with PD (33 men and 17 women; mean age, 70.4 ± 12.9 years; mean disease duration, 7.3 ± 6.7 years). All the patients were assessed at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) and the Fatigue Severity Scale (FSS) and began treatment with 100 mg of thiamine administered intramuscularly twice a week, without any change to personal therapy. All the patients were re-evaluated after 1 month and then every 3 months during treatment. Results: Thiamine treatment led to significant improvement of motor and nonmotor symptoms: mean UPDRS scores (parts I–IV) improved from 38.55 ± 15.24 to 18.16 ± 15.08 (p = 2.4 × 10−14, t test for paired data) within 3 months...

The impact of thiamine supplementation on blood pressure, serum lipids and C-reactive protein in individuals with hyperglycemia: a randomised, double-blind cross-over trial

Abstract: Background The adverse effects of hyperglycemia may be potentiated when it is accompanied with hypertension and dyslipidemia. This study assessed the effects of high dose thiamine on blood pressure, serum lipids and C-reactive protein (hs-CRP) in individuals with impaired glucose metabolism. Methods This was a double-blind, randomised trial, where 12 hyperglycemic subjects (10 cases of impaired glucose tolerance and 2 new cases of type 2 diabetes mellitus) received both placebo and thiamine capsules (3 × 100 mg/day) for six weeks in a cross-over manner. Anthropometric measurements, systolic and diastolic blood pressure (SBP & DBP), serum cholesterol, triglyceride, HDL-cholesterol, LDL-cholesterol, hs-CRP and thiamine status were evaluated at the start, after three weeks and on the completion of each arm. Results DBP was significantly decreased in participants consuming thiamine supplements for six weeks (67.9 ± 5.8 mm Hg) relative to baseline (71.4 ± 7.4 mm Hg, p = 0.005) and week 3 (70.9. ± 5.8 mm Hg, p = 0.02). This was accompanied with a tendency toward a lower SBP at week six relative to baseline (116.5 ± 11.0 vs. 120.7 ± 15.3 mm Hg, p = 0.06). Also, mean arterial pressure (MAP) determined in the supplement arm after six weeks was significantly lower than baseline (84.1 ± 6.5 vs. 87.8 ± 9.0, p = 0.005). These variables did not change in the placebo arm. No significant change was detected in the supplement or placebo arms when lipid profile and hs-CRP were assessed. Conclusion/interpretation High dose thiamine supplementation may have beneficial effects on the blood pressure of individuals with hyperglycemia at early stages, and may have a role in the prevention of further vascular complications. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12611000051943

Role of Dietary Protein and Thiamine Intakes on Cognitive Function in Healthy Older People: A Systematic Review

Abstract: The effectiveness of nutritional interventions to prevent and maintain cognitive functioning in older adults has been gaining interest due to global population ageing. A systematic literature review was conducted to obtain and appraise relevant studies on the effects of dietary protein or thiamine on cognitive function in healthy older adults. Studies that reported on the use of nutritional supplementations and/or populations with significant cognitive impairment were excluded. Seventeen eligible studies were included. Evidence supporting an association between higher protein and/or thiamine intakes and better cognitive function is weak. There was no evidence to support the role of specific protein food sources, such as types of meat, on cognitive function. Some cross-sectional and case-control studies reported better cognition in those with higher dietary thiamine intakes, but the data remains inconclusive. Adequate protein and thiamine intake is more likely associated with achieving a good overall nutritional status which affects cognitive function rather than single nutrients. A lack of experimental studies in this area prevents the translation of these dietary messages for optimal cognitive functioning and delaying the decline in cognition with advancing age.

Low thiamine levels in children with type 1 diabetes and diabetic ketoacidosis: a pilot study.

Abstract: Objective Thiamine deficiency has been documented in adults with diabetes and in a single report of reversible encephalopathy in a child with diabetic ketoacidosis. In children who present with severe diabetic ketoacidosis, one of the most serious complications is cerebral edema of which the primary symptom may be encephalopathy. Thiamine deficiency in other disease states has been clearly linked with acute encephalopathy, but there are no data on thiamine status in children with diabetic ketoacidosis. This study describes the prevalence of thiamine deficiency in children with type 1 diabetes mellitus who present with diabetic ketoacidosis and are admitted to the ICU. Design A prospective observational pilot study. Setting PICU in a tertiary care children's hospital. Patients Children 2-18 years admitted to the ICU for treatment of diabetic ketoacidosis. Interventions Treatment of diabetic ketoacidosis. Measurements and main results Twenty-two patients were enrolled. The mean age was 13.7 ± 3.6 years. Five of 21 patients (23.8%) had thiamine deficiency prior to insulin administration. After 8 hours of insulin therapy, seven of 20 patients (35%) had thiamine deficiency, and four of these seven patients also had thiamine deficiency at presentation. Sixty-eight percent of patients had a decrease in thiamine levels after 8 hours of insulin therapy, with a mean fall of 20 ± 31.4 nmol/L. Conclusions Thiamine deficiency is common in children with diabetic ketoacidosis, and this deficiency may be worsened by treatment. When metabolic acidosis persists despite appropriate treatment of diabetic ketoacidosis, other factors such as thiamine deficiency should be considered.

Dry beriberi preceded Wernicke's encephalopathy: Thiamine deficiency after laparoscopic sleeve gastrectomy.

Abstract: In recent times, pediatric obesity has become widely prevalent. If first-line treatment with lifestyle modification fails, bariatric surgery may be indicated for severely obese patients. Many patients now travel abroad to get these surgeries done. Some of these patients receive inadequate postoperative care. We described a morbidly obese 17-year-old girl who had a laparoscopic sleeve gastrectomy procedure for weight loss. Due to severe nausea, she stopped her multivitamin supplementation. Within a few weeks, she developed symptoms of dry beriberi was soon followed by classic symptoms of Wernicke's encephalopathy. The prompt diagnosis was made with confirmation from serum thiamine level and brain magnetic resonance imaging. Thiamine supplementation reversed ophthalmological symptoms promptly. However, the patient needed inpatient rehabilitation for neuropathy. This case describes that thiamine deficiency can occur after restrictive bariatric surgery, despite lower risk of malnutrition in the absence of intestinal bypass procedure. This report highlights that in the presence of risk factors: dietary noncompliance, inadequate follow-up, and severe nausea with and without vomiting can precipitate the development of Wernicke's encephalopathy, even after restrictive surgery. Physicians may increasingly encounter thiamine and other nutrient deficiencies in increasing numbers due to increasing prevalence of obesity disorders and availability of bariatric surgeries. This report also emphasized the importance of identifying vague sensory symptoms in thiamine deficiency.

Synthesis of 11C-Labeled Thiamine and Fursultiamine for in Vivo Molecular Imaging of Vitamin B1 and Its Prodrug Using Positron Emission Tomography

Abstract: To enable in vivo analysis of the kinetics of vitamin B1 (thiamine) and its derivatives by positron emission tomography (PET), 11C-labeled thiamine ([11C]-1) has been synthesized. This was carried out via a rapid, multistep synthesis consisting of Pd0-mediated C-[11C]methylation of a thiazole ring for 3 min and benzylation with 5-(bromomethyl)pyrimidine for 7 min. The [11C]-1 was also converted to 11C-labeled fursultiamine ([11C]-2), a prodrug of vitamin B1, by disulfide formation with S-tetrahydrofurfurylthiosulfuric acid sodium salt. Characterization of [11C]-1 and [11C]-2 showed them to be suitable for use as PET probes for in vivo pharmacokinetic and medical studies. The total durations of the preparations of [11C]-1 and [11C]-2 were shorter than 60 and 70 min, respectively. The [11C]CH3I-based decay-corrected radiochemical yields of [11C]-1 and [11C]-2 were 9–16% and 4–10%, respectively. The radioactivities of the final injectable solutions of [11C]-1 and [11C]-2 were 400–700 and 100–250 MBq, respect...

Thiamine Deficiency‐Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3.1

Abstract: Alaskan Husky encephalopathy (AHE(1) ) is a fatal brain disease associated with a mutation in SLC19A3.1 (c.624insTTGC, c.625C>A). This gene encodes for a thiamine transporter 2 with a predominately (CNS) central nervous system distribution. Considering that brain is particularly vulnerable to thiamine deficiency because of its reliance on thiamine pyrophosphate (TPP)-dependent metabolic pathways involved in energy metabolism and neurotransmitter synthesis, we characterized the impact of this mutation on thiamine status, brain bioenergetics and the contribution of oxidative stress to this phenotype. In silico modeling of the mutated transporter indicated a significant loss of alpha-helices resulting in a more open protein structure suggesting an impaired thiamine transport ability. The cerebral cortex and thalamus of affected dogs were severely deficient in TPP-dependent enzymes accompanied by decreases in mitochondrial mass and oxidative phosphorylation (OXPHOS) capacity, and increases in oxidative stress. These results along with the behavioral and pathological findings indicate that the phenotype associated with AHE is consistent with a brain-specific thiamine deficiency, leading to brain mitochondrial dysfunction and increased oxidative stress. While some of the biochemical deficits, neurobehavior and affected brain areas in AHE were shared by Wernicke's and Korsakoff's syndromes, several differences were noted likely arising from a tissue-specific vs. that from a whole-body thiamine deficiency.

Micronutrients Involved in One-Carbon Metabolism and Risk of Breast Cancer Subtypes.

Abstract: Background Vitamins involved in one-carbon metabolism are hypothesized to influence breast cancer (BC) risk. However, epidemiologic studies that examined associations between B vitamin intake and BC risk have provided inconsistent results. We prospectively examined, in the Italian ORDET cohort, whether B vitamin consumption was associated with risk of BC and BC subtypes. Methods After a mean follow-up of 16.5 years, 391 BCs were diagnosed among 10,786 cohort women. B vitamin intakes were estimated from food frequency questionnaires. Cox proportional hazard models adjusted for energy intake and confounders, estimated hazard ratios (HR) with 95% confidence intervals (CIs) for BC according to intake. Results RRs were 0.61 (95% CI 0.38–0.97 highest vs. lowest quartile; P trend 0.025) for thiamine; 0.48 (95% CI 0.32–0.71; P trend <0.001) for riboflavin; 0.59 (95% CI 0.39–0.90; P trend 0.008) for vitamin B6, and 0.65 (95% CI 0.44–0.95; P trend 0.021) for folate. As regards risk of BC subtypes, high riboflavin and folate were significantly associated with lower risk of estrogen receptor positive (ER+) and progesterone receptor positive (PR+) cancers, and high thiamine was associated with lower risk of ER-PR- cancers. High riboflavin was associated with lower risk of both HER2+ and HER2- cancers, high folate with lower risk of HER2- disease, and high thiamine with HER2+ disease. Conclusions These findings support protective effects of thiamine and one-carbon metabolism vitamins (folate, riboflavin, and vitamin B6) against BC in general; while folate may also protect against ER+PR+ and HER2- disease; and thiamine against ER-PR-, and HER2+ disease.

Type B Lactic Acidosis Secondary to Thiamine Deficiency in a Child With Malignancy

Abstract: Type B lactic acidosis is an underrecognized clinical entity that must be distinguished from type A (hypoxic) lactic acidosis. We present the case of a 4-year-old boy with medulloblastoma who presented with lactic acidosis in the setting of septic shock. His hyperlactatemia persisted to high levels even after his hemodynamic status improved. After administration of intravenous thiamine, his lactate level rapidly normalized and remained stable. It was determined that his total parenteral nutrition was deficient in vitamins due to a national shortage. Because thiamine is an important cofactor for pyruvate dehydrogenase, he was unable to use glucose through aerobic metabolism pathways. We briefly review type A versus type B lactic acidosis in this case report.