Evolutionary Perspective in Rickets and Vitamin D

Modern lifestyle limits our exposure to sunlight, which photosynthesizes vitamin D in the skin, and the incidence of nutritional rickets has been resurging. Vitamin D is one of the first hormones; it is photosynthesized in all organism from the phytoplankton to mammals. A selective sweep of the promoter of the vitamin D receptor (VDR) happened as soon as Homo sapiens migrated out of Africa; it co-adapted with skin color genes to provide adaptation to latitudes and the levels of exposure to ultraviolet (UV)B radiation along the route out of Africa. Exposure to UVB radiation balances the need for vitamin D photosynthesis and degradation of folic acid by UVB radiation. Skin color follows a latitude distribution: the darkest populations dwell in the tropical belt; and the fair-skinned populations inhabit the northern countries. Due to their greater need for calcium during their reproductive life, the skin color of women is lighter- than that of men. Vitamin D is essential for mineral homeostasis and has a wide variety of non-skeletal functions, of which the most important for natural selection is a regulatory function in the innate immune system. In the human fossil record, vitamin D deficiency coincided with bone tuberculosis. About 6,000 years ago, a diet which included cow's milk provided Neolithic humans with twice as much calcium and was more alkaline than that of its Paleolithic predecessors. Adiposity is negatively associated with the vitamin D status and obese individuals require 2–3 times more vitamin D than non-obese individuals to normalize circulating 25OHD levels. In an era of an obesity epidemic, we need more research to determine whether adiposity should be considered when determining the dietary requirements for vitamin D and calcium and the optimal serum 25OHD levels

Gene Expression Signature in Adipose Tissue of Acromegaly Patients.

To study the effect of chronic excess growth hormone on adipose tissue, we performed RNA sequencing in adipose tissue biopsies from patients with acromegaly (n = 7) or non-functioning pituitary adenomas (n = 11). The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex vivo for lipolysis and ceramide levels. Patients with acromegaly had higher glucose, higher insulin levels and higher HOMA-IR score. We observed several previously reported transcriptional changes (IGF1, IGFBP3, CISH, SOCS2) that are known to be induced by GH/IGF-1 in liver but are also induced in adipose tissue. We also identified several novel transcriptional changes, some of which may be important for GH/IGF responses (PTPN3 and PTPN4) and the effects of acromegaly on growth and proliferation. Several differentially expressed transcripts may be important in GH/IGF-1-induced metabolic changes. Specifically, induction of LPL, ABHD5, and NRIP1 can contribute to enhanced lipolysis and may explain the elevated adipose tissue lipolysis in acromegalic patients. Higher expression of TCF7L2 and the fatty acid desaturases FADS1, FADS2 and SCD could contribute to insulin resistance. Ceramides were not different between the two groups. In summary, we have identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly

Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations

Human mitochondrial RNase P (mt-RNase P) is responsible for 5' end processing of mitochondrial precursor tRNAs, a vital step in mitochondrial RNA maturation, and is comprised of three protein subunits: TRMT10C, SDR5C1 (HSD10), and PRORP. Pathogenic variants in TRMT10C and SDR5C1 are associated with distinct recessive or x-linked infantile onset disorders, resulting from defects in mitochondrial RNA processing. We report four unrelated families with multisystem disease associated with bi-allelic variants in PRORP, the metallonuclease subunit of mt-RNase P. Affected individuals presented with variable phenotypes comprising sensorineural hearing loss, primary ovarian insufficiency, developmental delay, and brain white matter changes. Fibroblasts from affected individuals in two families demonstrated decreased steady state levels of PRORP, an accumulation of unprocessed mitochondrial transcripts, and decreased steady state levels of mitochondrial-encoded proteins, which were rescued by introduction of the wild-type PRORP cDNA. In mt-tRNA processing assays performed with recombinant mt-RNase P proteins, the disease-associated variants resulted in diminished mitochondrial tRNA processing. Identification of disease-causing variants in PRORP indicates that pathogenic variants in all three subunits of mt-RNase P can cause mitochondrial dysfunction, each with distinct pleiotropic clinical presentations.Peer reviewe

Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes the strong heart study

AbstractObjectivesThe goal of this study was to determine if the haptoglobin phenotype was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM).BackgroundCardiovascular disease is the most frequent, severe, and costly complication of type 2 DM. There are clear geographic and ethnic differences in the risk of CVD among diabetic patients that cannot be fully explained by differences in conventional CVD risk factors. We have demonstrated that a functional allelic polymorphism in the haptoglobin gene acts as a major determinant of susceptibility for the development of diabetic microvascular complications.MethodsWe sought to determine if this paradigm concerning the haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a case-control sample from the Strong Heart study, a population-based longitudinal study of CVD in American Indians. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age 45 to 74 years. Median follow-up was six years.ResultsIn multivariate analyses controlling for conventional CVD risk factors, haptoglobin phenotype was a highly statistically significant, independent predictor of CVD in DM. The odds ratio of having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD was associated with the haptoglobin 2-1 phenotype.ConclusionsThis study suggests that determination of haptoglobin phenotype may contribute to the algorithm used in CVD risk stratification, and in evaluation of new therapies to prevent CVD in the diabetic patient

Towards a framework for comparing functionalities of multimorbidity clinical decision support: A literature-based feature set and benchmark cases.

Multimorbidity, the coexistence of two or more health conditions, has become more prevalent as mortality rates in many countries have declined and their populations have aged. Multimorbidity presents significant difficulties for Clinical Decision Support Systems (CDSS), particularly in cases where recommendations from relevant clinical guidelines offer conflicting advice. A number of research groups are developing computer-interpretable guideline (CIG) modeling formalisms that integrate recommendations from multiple Clinical Practice Guidelines (CPGs) for knowledge-based multimorbidity decision support. In this paper we describe work towards the development of a framework for comparing the different approaches to multimorbidity CIG-based clinical decision support (MGCDS). We present (1) a set of features for MGCDS, which were derived using a literature review and evaluated by physicians using a survey, and (2) a set of benchmarking case studies, which illustrate the clinical application of these features. This work represents the first necessary step in a broader research program aimed at the development of a benchmark framework that allows for standardized and comparable MGCDS evaluations, which will facilitate the assessment of functionalities of MGCDS, as well as highlight important gaps in the state-of-the-art. We also outline our future work on developing the framework, specifically, (3) a standard for reporting MGCDS solutions for the benchmark case studies, and (4) criteria for evaluating these MGCDS solutions. We plan to conduct a large-scale comparison study of existing MGCDS based on the comparative framework

Managing Diabetes in Patients Hospitalized in Internal Medicine Units

Diabetes and hyperglycemia are present in over one-third of inpatients in internal medicine units and are associated with worse prognosis in multiple morbidities. Treatment of inpatient hyperglycemia is usually with basal bolus insulin in a dose calculated by the patient’s weight, with lower doses recommended in patients who are at a higher risk for hypoglycemia. Other antihyperglycemic medications and insulin regimens can be used in selected patients. There are no adequately powered studies on the effect of improving glycemic control on hospitalization outcomes in non-critically ill patients in internal medicine units, and in most patients a modest glucose target of 140–180 mg/dL is recommended. A structured discharge plan should intensify antihyperglycemic treatment as needed and include an outpatient follow-up appointment shortly after discharge

A large-scale observational analysis of social media data reveals major public misperception of the attainability of drastic weight loss by dieting

Introduction: Diet forums in social media websites provide an opportunity to glimpse the experience of different weight loss diet strategies reported by tens of thousands of individuals. Methods: We analyzed all postings with weight information from the six major Reddit weight-loss diet forums (“subreddits”) as reported by forum participants. Results: Data were collected from January 2011 to April 2020 from all 55,900 users posting weight information. Average start BMI was in the overweight or obese range (26–34 kg/m2), and average goal BMI was in the normal range (21.5–24.5 kg/m2) for all subreddits. There is correlation between start BMI and goal BMI (R2=0.63, p<10-10) and between planned weight loss and reported weight loss (R2=0.56, p<10-10). Approximately 80% of forum participants reported a weight loss that was greater than 5% of their initial body weight. Actual reported weight loss was less than half of goal weight loss. Average reported weight loss and adherence were highest in the keto and loseit subreddits. More upvotes and fewer downvotes were associated with higher reported weight loss in five of the six subreddits. Conclusions: Despite the need for cautious interpretation of this data due to self-selection of users who updated weight loss and the possibility of unreliable weight reports, the study has several findings. Average goal BMI was in the normal weight range, demonstrating a highly unrealistic perception, in a very large lay-public cohort, of the plausibility of losing all excess weight. The success in weight loss and maintenance in self-selected individuals who continued reporting weight for many months may demonstrate the subjective value some individuals can obtain from forum participation