Insulin Receptor Genetic Variants Causal Association with Type 2 Diabetes: A Mendelian Randomization Study.

Background: Type 2 diabetes (T2D) is a prevalent chronic disease associated with several comorbidities. Objectives: This study investigated whether the risk of T2D varied with genetically predicted insulin (INS), insulin receptor (INS-R), or insulin-like growth factor 1 receptor (IGF-1R) using genetic variants in a Mendelian randomization (MR) study. Methods: A 2-sample MR study was conducted using summary statistics from 2 genome-wide association studies (GWASs). Genetic predictors of the exposures (INS, INS-R, and IGF-1R) were obtained from a publicly available proteomics GWAS of the INTERVAL randomized controlled trial of blood donation in the United Kingdom. For T2D, the study leveraged the DIAbetes Meta-ANalysis of Trans-Ethnic association studies (DIAMANTE) consortium. The estimated associations of INS, INS-R, and IGF-1R proteins with T2D were based on independent single nucleotide polymorphisms (SNPs) strongly (P < 5 × 10-6) predicting each exposure. These SNPs were applied to publicly available genetic associations with T2D from the DIAMANTE case (n = 74,124) and control (n = 824,006) study of people of European descent. SNP-specific Wald estimates were meta-analyzed using inverse variance weighting with multiplicative random effects. Sensitivity analysis was conducted using the weighted median (WM) and MR-Egger. Results: INS-R (based on 13 SNPs) was associated with a lower risk of T2D (OR: 0.95 per effect size; 95% CI: 0.92, 0.98; P = 0.001), with similar estimates from the WM and MR-Egger. Insulin (8 SNPs) and IGF-1R (10 SNPs) were not associated with T2D. However, 1 of the SNPs for INS-R was from the ABO blood group gene. Conclusions: This study is consistent with a causally protective association of the INS-R with T2D. INS-R in RBCs regulates glycolysis and thus may affect their functionality and integrity. However, a pleiotropic effect via the blood group ABO gene cannot be excluded. The INS-R may be a target for intervention by repurposing existing therapeutics or otherwise to reduce the risk of T2D.

A novel PIEZO1 mutation in a patient with dehydrated hereditary stomatocytosis: a case report and a brief review of literature.

BACKGROUND: Dehydrated hereditary stomatocytosis (DHS) or hereditary xerocytosis is a rare, autosomal dominant hemolytic anemia characterized by macrocytosis, presence of stomatocytes and dehydration of red blood cells (RBCs). The dehydration is caused by a defect in cellular cation content. The most frequent expression of the pathology is hemolytic well-compensated anemia with high reticulocyte count, a tendency to macrocytosis, increased mean corpuscular hemoglobin concentration (MCHC) and mild jaundice. We here describe a new mutation of PIEZO1 gene, the most frequent mutated gene in DHS, in a family affected by hereditary hemolytic anemia. CASE PRESENTATION: We describe the case of a 12-years-old girl with well-compensated chronic hemolysis, increased MCHC and a father who had the same hematological characteristics. After excluding secondary causes of chronic hemolysis and enzymatic defects of the RBCs, microscopic observation of the peripheral blood smear, tests of RBC lysis, ektacytometry, SDS-PAGE and in last instance genetic analysis has been performed. This complex diagnostic workup identified a new variant in the PIEZO1 gene, never described in literature, causative of DHS. This pathogenetic variant was also detected in the father. CONCLUSIONS: This case report highlights the importance of a correct and exhaustive diagnostic-workup in patients with clinical suspicious for hemolytic anemia in order to make a differential diagnosis. This is relevant for the management of these patients because splenectomy is contraindicated in DHS due to high thrombotic risk.

Genotoxicity and subchronic toxicological study of a novel ginsenoside derivative 25-OCH3-PPD in beagle dogs.

BACKGROUND: Ginsenosides have been widely used clinically for many years and were regarded as very safe. However, a few researches on the toxicities of these kinds of agents showed that some ginsenosides may have side-effect on the rats or dogs. So it is extremely necessary to further clarify the potential toxicity of ginsenosides. This study was carried out to investigate long-term toxicity and genotoxicity of 25-methoxydammarane-3, 12, 20-triol (25-OCH3-PPD), a new derivative of ginsenoside, in beagle dogs. METHODS: Twenty-four beagle dogs were divided randomly into four treatment groups and repeatedly orally administered with 25-OCH3-PPD capsule at 60, 120, and 240 mg/kg/day for 91 consecutive days. Ames, micronucleus, and chromosomal aberration tests were established to analyze the possible genotoxicity of 25-OCH3-PPD. RESULTS: There was no 25-OCH3-PPD-induced systemic toxicity in beagle dogs at any doses. The level of 25-OCH3-PPD at which no adverse effects were observed was found to be 240 mg/kg/day. The result of Ames test showed that there was no significant increase in the number of revertant colonies of 25-OCH3-PPD administrated groups compared to the vehicle control group. There were also no significant differences between 25-OCH3-PPD administrated groups at all dose levels and negative group in the micronucleus test and chromosomal aberration assay. CONCLUSION: The highest dose level of 25-OCH3-PPD at which no adverse effects were observed was found to be 240 mg/kg per day, and it is not a genotoxic agent either in somatic cells or germs cells. 25-OCH3-PPD is an extremely safe candidate compound for antitumor treatment.

Rouleaux formation of white blood cells and platelets in leukemia / Formação de rouleaux de glóbulos brancos e plaquetas em leucemia

The objective of this study was to measure the effects of glucose and salt level on white blood cells, red blood cells and platelets (PLTs) in the blood of a leukemic patient by using a white light microscope. Different concentrations of glucose and salt in the range of 0 mM to 500 mM were admixed in the blood sample to prepare blood smear. We revealed that shape of erythrocytes, leukocytes and platelets changes and form aggregates. Increasing concentrations of glucose cause to increases aggregation process of white blood cells, red blood cells and platelets. And the increasing concentration of sodium chloride causes to increase rouleaux formation and aggregation of platelets but dehydration due to increased sodium chloride concentration causes to break the aggregation of white blood cells. Comparison of CBC reports of these samples with and without analytes shows that total leukocyte count (TLC) decreases gradually towards normal ranges of leukocytes which is favorable in the treatment of leukemia but at the same time decreasing level of hemoglobin HGB, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and increasing level of red blood cell (RBCs) causes to reduce oxygen supply which is in favor of cancer growth and anemia. This work provides us the base for translation this in vitro study towards the in vivo case of blood microvasculature as a non-invasive methodology.

O objetivo deste estudo foi medir os efeitos da glicose e do nível de sal nos glóbulos brancos, glóbulos vermelhos e plaquetas (PLTs) no sangue de um paciente leucêmico usando um microscópio de luz branca. Foram misturadas diferentes concentrações de glicose e sal na gama de 0 mM a 500 mM na amostra de sangue para preparar esfregaço de sangue. Descrevemos que a forma dos eritrócitos, leucócitos e plaquetas muda e forma agregados. O aumento das concentrações de glicose aumenta o processo de agregação de glóbulos brancos, glóbulos vermelhos e plaquetas. E a crescente concentração de cloreto de sódio causa o aumento da formação de rouleaux e a agregação de plaquetas, mas a desidratação devido ao aumento da concentração de cloreto de sódio causa a quebra da agregação de glóbulos brancos. A comparação dos relatórios de CBC dessas amostras com e sem analitos mostra que a contagem total de leucócitos (TLC) diminui gradualmente para os intervalos normais de leucócitos, o que é favorável no tratamento da leucemia, mas ao mesmo tempo diminui o nível de hemoglobina HGB, hemoglobina corpuscular média (MCH ), a concentração média de hemoglobina corpuscular (MCHC) e o aumento do nível de glóbulos vermelhos (RBCs) reduz o suprimento de oxigênio, o que é a favor do crescimento do câncer e da anemia. Este trabalho fornece a base para a tradução deste estudo in vitro para o caso in vivo de microvasculatura de sangue como uma metodologia não-invasiva.

Lower mean corpuscular hemoglobin concentration is associated with poorer outcomes in intensive care unit admitted patients with acute myocardial infarction.

BACKGROUND: Accumulated studies have shown that hematological parameters [e.g., red blood cell distribution width (RDW), hemoglobin, platelet count] and serum potassium level can impact the prognosis of patients with acute myocardial infarction (AMI). However, no previous study has evaluated the prognostic values of these laboratory tests simultaneously. METHODS: This study is based on an intensive care unit (ICU) database named Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC II). Adult patients with AMI were included, and their hematological parameters and serum ion levels on admission were extracted. The relationships between these laboratory tests and hospital mortality were evaluated using a logistic regression model and receiver operating characteristic (ROC) curve analysis. The effects of these laboratory tests on 1-year mortality were evaluated using a Cox hazard regression model and Kaplan-Meier curve analysis. RESULTS: In univariable analysis, increased white blood cell (WBC), neutrophil percentage, mean corpuscular volume (MCV), RDW, potassium and decreased red blood cell (RBC), hemoglobin, mean corpuscular hemoglobin concentration (MCHC), hematocrit and percentage of lymphocyte, monocyte, basophil and eosinophil were significantly associated with hospital mortality. In multivariable analyses, basophil percentage, potassium, WBC and MCHC were independently associated with hospital morality, while WBC, RDW, MCHC, potassium and percentages of neutrophil and lymphocyte were associated with 1-year mortality. CONCLUSIONS: Hematological parameters and serum potassium can provide prognostic information in AMI patients. MCHC is an independent prognostic factor for both short and long term outcomes of AMI.