Increased Erythropoiesis in Mice Injected With Submicrogram Quantities of Pseudouridine-containing mRNA Encoding Erythropoietin

Advances in the optimization of in vitro-transcribed mRNA are bringing mRNA-mediated therapy closer to reality. In cultured cells, we recently achieved high levels of translation with high-performance liquid chromatography (HPLC)-purified, in vitro-transcribed mRNAs containing the modified nucleoside pseudouridine. Importantly, pseudouridine rendered the mRNA non-immunogenic. Here, using erythropoietin (EPO)-encoding mRNA complexed with TransIT-mRNA, we evaluated this new generation of mRNA in vivo. A single injection of 100 ng (0.005 mg/kg) mRNA elevated serum EPO levels in mice significantly by 6 hours and levels were maintained for 4 days. In comparison, mRNA containing uridine produced 10–100-fold lower levels of EPO lasting only 1 day. EPO translated from pseudouridine-mRNA was functional and caused a significant increase of both reticulocyte counts and hematocrits. As little as 10 ng mRNA doubled reticulocyte numbers. Weekly injection of 100 ng of EPO mRNA was sufficient to increase the hematocrit from 43 to 57%, which was maintained with continued treatment. Even when a large amount of pseudouridine-mRNA was injected, no inflammatory cytokines were detectable in plasma. Using macaques, we could also detect significantly-increased serum EPO levels following intraperitoneal injection of rhesus EPO mRNA. These results demonstrate that HPLC-purified, pseudouridine-containing mRNAs encoding therapeutic proteins have great potential for clinical applications

Prognostic value of coronary computed tomography angiography in diabetic patients without chest pain syndrome

AIMS: Diabetic patients with coronary artery disease (CAD) are often free of chest pain syndrome. A useful modality for non-invasive assessment of CAD is coronary computed tomography angiography (CTA). However, the prognostic value of CAD on coronary CTA in diabetic patients without chest pain syndrome is relatively unknown. Therefore, the aim was to investigate the long-term prognostic value of coronary CTA in a large population diabetic patients without chest pain syndrome. METHODS: Between 2005 and 2013, 525 diabetic patients without chest pain syndrome were prospectively included to undergo coronary artery calcium (CAC)-scoring followed by coronary CTA. During follow-up, the composite endpoint of all-cause mortality, non-fatal myocardial infarction (MI), and late revascularization (>90 days) was registered. RESULTS: In total, CAC-scoring was performed in 410 patients and coronary CTA in 444 patients (431 interpretable). After median follow-up of 5.0 (IQR 2.7-6.5) years, the composite endpoint occurred in 65 (14%) patients. Coronary CTA demonstrated a high prevalence of CAD (85%), mostly non-obstructive CAD (51%). Furthermore, patients with a normal CTA had an excellent prognosis (event-rate 3%). An incremental increase in event-rate was observed with increasing CAC-risk category or coronary stenosis severity. Finally, obstructive (50-70%) or severe CAD (>70%) was independently predictive of events (HR 11.10 [2.52;48.79] (P = .001), HR 15.16 [3.01;76.36] (P = .001)). Obstructive (50-70%) or severe CAD (>70%) provided increased value over baseline risk factors. CONCLUSION: Coronary CTA provided prognostic value in diabetic patients without chest pain syndrome. Most importantly, the prognosis of patients with a normal CTA was excellent

Changes in multidirectional LV strain in asymptomatic patients with type 2 diabetes mellitus: a 2-year follow-up study

Cardiolog

Comparison by Computed Tomographic Angiography-The Presence and Extent of Coronary Arterial Atherosclerosis in South Asians Versus Caucasians With Diabetes Mellitus

Cardiolog

The prevalence of disorders of the gut-brain axis in type 2 diabetes mellitus patients with metabolic dysfunction-associated fatty liver disease: an observational study

Background and study aim: Disorders of the gut-brain axis (DGBI) and metabolic dysfunction-associated liver disease (MAFLD) are frequently diagnosed and exhibit pathophysiological similarities. This study aimed to estimate the prevalence of DGBI in type 2 diabetes mellitus (T2DM) patients with MAFLD. Patients and methods: In this single center, observational study, in adults with T2DM demographics, diabetes-related parameters and liver tests were recorded. MAFLD was defined by the presence of hepatic steatosis on imaging. Functional dyspepsia (FD) and irritable bowel syndrome (IBS) were diagnosed based on Rome IV criteria. Quality of life (QOL), anxiety levels and depression levels were documented by validated questionnaires. Results: We included 77 patients, 44 with and 33 without steatosis. There were no significant differences in age, body mass index (BMI), waist circumference, HbA1c levels or metformin use between groups. IBS was significantly more prevalent in the liver steatosis group (9/44 vs. 2/33, p = .037), while a similar trend was observed for FD (9/35 vs. 2/31, p = .103). No differences were found in anxiety, depression and overall QOL. However, QOL subscales for health worry, food avoidance and social reaction were significantly higher in the liver steatosis group. Conclusions: In otherwise comparable T2DM patients, DGBI, and especially IBS, are more prevalent in the presence of MAFLD. This difference could not be attributed to increased levels of anxiety or depression. Future research should target the underlying pathophysiological mechanisms. (Acta gastroenterol. belg., 2021, 84, 541-547).</jats:p

Revisiting infant growth prior to childhood onset type 1 diabetes

P>Objective Accelerated early growth prior to childhood type 1 diabetes onset is associated with an increased risk for type 1 diabetes (T1D). We aimed to study early growth, correcting for the previously neglected confounder of familial effects. Design Infant growth was studied in a retrospective family case-control study of diabetic children in which siblings acted as matched familial controls allowing correction for confounders related to family particulars. Patients Weight and height data were collected from 213 juvenile onset type 1 diabetic children and their 255 healthy siblings. Growth in the first 4 years of life was studied using repeated measurement. The degree of early overgrowth was correlated with age of clinical onset. Results Birth weight and length did not differ between later diabetic children and their siblings. In the first year of life, weight standard deviation score (SDS) differed between patients and sibs (P = 0 center dot 0001). After the first year, both diabetic children and sibs showed parallel enhanced weight and height gain SDS until age 4 years. Earlier onset diabetes was associated with a higher weight SDS at 6 months of age. Conclusion In this family case-control study the association of increased growth with development of T1D is limited to the first year of life implying that increased growth beyond the first year can be attributed to familial growth patterns, rather than predisposition to T1D per se. Age at disease onset correlated with increased weight in the first 6 months of life, indicating importance of features very early in life on later development of T1D.Transplantation and autoimmunit