Three Case Reports to Illustrate Clinical Applications in the Use of Erythrocyte Transketolase

Non-caloric nutrients (NCN) are extremely numerous and it is more than obvious that they work in a team relationship. These vitally important interactions are, for the most part, poorly understood. These brief case reports illustrate this in the therapeutic use of thiamin in a clinical setting. The initially abnormal erythrocyte transketolase activity (TKA) and/or the thiamin pyrophosphate effect (TPPE), indicating intracellular cofactor deficiency, usually improves with thiamin administration. Biochemical correction of the abnormality is, however, invariably dependent on the provision of other NCN, especially magnesium. In two patients reported here, this correction required several infusions containing magnesium and other NCN administered intravenously. In a third patient, hemoconcentration associated with an abnormal TPPE was normalized after administration of nutrients that included thiamin and magnesium

A Review of the Biochemistry, Metabolism and Clinical Benefits of Thiamin(e) and Its Derivatives

Thiamin(e), also known as vitamin B1, is now known to play a fundamental role in energy metabolism. Its discovery followed from the original early research on the ‘anti-beriberi factor’ found in rice polishings. After its synthesis in 1936, it led to many years of research to find its action in treating beriberi, a lethal scourge known for thousands of years, particularly in cultures dependent on rice as a staple. This paper refers to the previously described symptomatology of beriberi, emphasizing that it differs from that in pure, experimentally induced thiamine deficiency in human subjects. Emphasis is placed on some of the more unusual manifestations of thiamine deficiency and its potential role in modern nutrition. Its biochemistry and pathophysiology are discussed and some of the less common conditions associated with thiamine deficiency are reviewed. An understanding of the role of thiamine in modern nutrition is crucial in the rapidly advancing knowledge applicable to Complementary Alternative Medicine. References are given that provide insight into the use of this vitamin in clinical conditions that are not usually associated with nutritional deficiency. The role of allithiamine and its synthetic derivatives is discussed. Thiamine plays a vital role in metabolism of glucose. Thus, emphasis is placed on the fact that ingestion of excessive simple carbohydrates automatically increases the need for this vitamin. This is referred to as high calorie malnutrition

Dysautonomia, A Heuristic Approach to a Revised Model for Etiology of Disease

Dysautonomia refers to a disease where the autonomic nervous system is dysfunctional. This may be a central control mechanism, as in genetically determined familial dysautonomia (Riley-Day Syndrome), or peripherally in the distribution of the sympathetic and parasympathetic systems. There are multiple reports of a number of different diseases associated with dysautonomia. The etiology of this association has never been explained. There are also multiple publications on dysautonomia associated with specific non-caloric nutritional deficiencies. Beriberi is the prototype of autonomic dysfunction. It is the best known nutritional deficiency disease caused by an imbalance between ingested calories and the vitamins required for their oxidation, particularly thiamin. Long thought to be abolished in modern medical thinking, there are occasional isolated reports of the full-blown disease in developed Western cultures

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

Hiding in Plain Sight: Modern Thiamine Deficiency

Thiamine or vitamin B1 is an essential, water-soluble vitamin required for mitochondrial energetics—the production of adenosine triphosphate (ATP). It is a critical and rate-limiting cofactor to multiple enzymes involved in this process, including those at the entry points and at critical junctures for the glucose, fatty acid, and amino acid pathways. It has a very short half-life, limited storage capacity, and is susceptible to degradation and depletion by a number of products that epitomize modern life, including environmental and pharmaceutical chemicals. The RDA for thiamine is 1.1–1.2 mg for adult females and males, respectively. With an average diet, even a poor one, it is not difficult to meet that daily requirement, and yet, measurable thiamine deficiency has been observed across multiple patient populations with incidence rates ranging from 20% to over 90% depending upon the study. This suggests that the RDA requirement may be insufficient to meet the demands of modern living. Inasmuch as thiamine deficiency syndromes pose great risk of chronic morbidity, and if left untreated, mortality, a more comprehensive understanding thiamine chemistry, relative to energy production, modern living, and disease, may prove useful

Dysautonomia in Autism Spectrum Disorder: Case Reports of a Family with Review of the Literature

Case histories of a mother and her two children are reported. The mother was a recovered alcoholic. She and her two children, both of whom had symptoms that are typical of autistic spectrum disorder, had dysautonomia. All had intermittently abnormal erythrocyte transketolase studies indicating abnormal thiamine pyrophosphate homeostasis. Both children had unusual concentrations of urinary arsenic. All had symptomatic improvement with diet restriction and supplementary vitamin therapy but quickly relapsed after ingestion of sugar, milk, or wheat. The stress of a heavy metal burden, superimposed on existing genetic or epigenetic risk factors, may be important in the etiology of autism spectrum disorder when in combination. Dysautonomia has been associated with several diseases, including autism, without a common etiology. It is hypothesized that oxidative stress results in loss of cellular energy and causes retardation of hard wiring of the brain in infancy, affecting limbic system control of the autonomic nervous system