Genetic Risk Scores Identify People at High Risk of Developing Diabetic Kidney Disease: A Systematic Review.

CONTEXT: Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Measures to prevent and treat DKD require better identification of patients most at risk. In this systematic review, we summarize the existing evidence of genetic risk scores (GRSs) and their utility for predicting DKD in people with type 1 or type 2 diabetes. EVIDENCE ACQUISITION: We searched MEDLINE, Embase, Web of Science, and Cochrane Reviews in June 2022 to identify all existing and relevant literature. Main data items sought were study design, sample size, population, single nucleotide polymorphisms of interest, DKD-related outcomes, and relevant summary measures of result. The Critical Appraisal Skills Programme checklist was used to evaluate the methodological quality of studies. EVIDENCE SYNTHESIS: We identified 400 citations of which 15 are included in this review. Overall, 7 studies had positive results, 5 had mixed results, and 3 had negative results. Most studies with the strongest methodological quality (n = 9) reported statistically significant and favourable findings of a GRS's association with at least 1 measure of DKD. CONCLUSION: This systematic review presents evidence of the utility of GRSs to identify people with diabetes that are at high risk of developing DKD. In practice, a robust GRS could be used at the first clinical encounter with a person living with diabetes in order to stratify their risk of complications. Further prospective research is needed.

Insulin can be used to treat severe hypertriglyceridaemia in pregnant women without diabetes.

Severe hypertriglyceridaemia can lead to acute pancreatitis, which is associated with maternal and perinatal mortality when it occurs in pregnancy. Rapid reduction of triglyceride levels is a primary goal in the management of severe hypertriglyceridaemia, however, there are limited safe option for treatment in pregnancy. We present a case of a woman without diabetes presenting with severe hypertriglyceridaemia in late gestation who was safely and successfully treated with insulin and review the literature surrounding the management of this important condition.

Treatment implications of a delayed diagnosis of maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a rare form of monogeneic diabetes that classically presents as non-insulin requiring diabetes with evidence of autosomal dominant inheritance in individuals who are typically young and lean. However, these criteria do not capture all cases and can also overlap with other types of diabetes. The hepatocyte nuclear factor-1 alpha (HNF1A) mutation is a common cause of MODY and is highly sensitive to sulphonylureas, which should be first-line therapy. Our case represents the diagnostic challenges of HNF1A MODY and the implications of a delayed diagnosis, which can lead to reduced success of sulphonylurea treatment.

Laboratory and clinical management of leukocytospermia and hematospermia: a review.

Leukocytospermia and hematospermia are defined as the presence of abnormally high white blood cell and red blood cell concentration in the semen, respectively. Numerous etiologies and various implications on fertility have been identified. In a small proportion of men, the presence of white blood cells or red blood cells can adversely affect sperm quality by the production of reactive oxygen species. Several methods have been used to assess the presence of white blood cells and red blood cells in samples, such as identification of round cells, immunohistochemical staining using monoclonal antibodies, the Endtz test, the peroxidase test, and flow cytometry or microscopy. In addition, techniques have been identified to separate sperm samples from white blood cells and red blood cells for cryopreservation to improve outcomes in assisted reproductive technology. In this review, laboratory and clinical management of leukocytospermia and hematospermia are discussed. Currently available diagnostic methods and treatment options are outlined, and available optimal cryopreservation techniques for samples with white blood cells or red blood cells are summarized.

Genome-wide brain DNA methylation analysis suggests epigenetic reprogramming in Parkinson disease.

OBJECTIVE: Given the known strong relationship of DNA methylation with environmental exposure, we investigated whether brain regions affected in Parkinson disease (PD) were differentially methylated between PD cases and controls. METHODS: DNA chip arrays were used to perform a genome-wide screen of DNA methylation on the dorsal motor nucleus of the vagus (DMV), substantia nigra (SN), and cingulate gyrus (CG) of pathologically confirmed PD cases and controls selected using the criteria of Beecham et al. Analysis examined differentially methylated regions (DMRs) between cases and controls for each brain area. RNA sequencing and pathway analysis were also performed for each brain area. RESULTS: Thirty-eight PD cases and 41 controls were included in the analysis. Methylation studies revealed 234 significant DMR in the DMV, 44 in the SN, and 141 in the CG between cases and controls (Sidak p < 0.05). Pathway analysis of these genes showed significant enrichment for the Wnt signaling pathway (FDR < 0.01). CONCLUSIONS: Our data suggest that significant DNA methylation changes exist between cases and controls in PD, especially in the DMV, one of the areas affected earliest in PD. The etiology of these methylation changes is not yet known, but the predominance of methylation changes occurring in the DMV supports the hypothesis that vagus nerve function, perhaps involving the gastrointestinal system, is important in PD pathogenesis. These data also give independent support that genes involved in Wnt signaling are a likely factor in the neurodegenerative processes of PD.

Generation of disease-specific autopsy-confirmed iPSCs lines from postmortem isolated Peripheral Blood Mononuclear Cells.

Understanding the molecular mechanisms that underlie neurodegenerative disorders has been hampered by a lack of readily available model systems that replicate the complexity of the human disease. Recent advances in stem cell technology have facilitated the derivation of patient-specific stem cells from a variety of differentiated cell types. These induced pluripotent stem cells (iPSCs) are attractive disease models since they can be grown and differentiated to produce large numbers of disease-relevant cell types. However, most iPSC lines are derived in advance of, and without the benefit of, neuropathological confirmation of the donor - the gold standard for many disease classifications and measurement of disease severity. While others have reported the generation of autopsy-confirmed iPSC lines from patient explants, these methods require outgrowth of cadaver tissue, which require additional time and is often only successful ∼50% of the time. Here we report the rapid generation of autopsy-confirmed iPSC lines from peripheral blood mononuclear cells (PBMCs) drawn postmortem. Since this approach doesn't require the propagation of previously frozen cadaver tissue, iPSC can be rapidly and efficiently produced from patients with autopsy-confirmed pathology. These matched iPSC-derived patient-specific neurons and postmortem brain tissue will support studies of specific mechanisms that drive the pathogenesis of neurodegenerative diseases.

Overlap between Parkinson disease and Alzheimer disease in ABCA7 functional variants.

OBJECTIVE: Given their reported function in phagocytosis and clearance of protein aggregates in Alzheimer disease (AD), we hypothesized that variants in ATP-binding cassette transporter A7 (ABCA7) might be involved in Parkinson disease (PD). METHODS: ABCA7 variants were identified using whole-exome sequencing (WES) on 396 unrelated patients with PD and 222 healthy controls. In addition, we used the publicly available WES data from the Parkinson's Progression Markers Initiative (444 patients and 153 healthy controls) as a second, independent data set. RESULTS: We observed a higher frequency of loss-of-function (LOF) variants and rare putative highly functional variants (Combined Annotation Dependent Depletion [CADD] >20) in clinically diagnosed patients with PD than in healthy controls in both data sets. Overall, we identified LOF variants in 11 patients and 1 healthy control (odds ratio [OR] 4.94, Fisher exact p = 0.07). Four of these variants have been previously implicated in AD risk (p.E709AfsX86, p.W1214X, p.L1403RfsX7, and rs113809142). In addition, rare variants with CADD >20 were observed in 19 patients vs 3 healthy controls (OR 2.85, Fisher exact p = 0.06). CONCLUSION: The presence of ABCA7 LOF variants in clinically defined PD suggests that they might be risk factors for neurodegeneration in general, especially those variants hallmarked by protein aggregation. More studies will be needed to evaluate the overall impact of this transporter in neurodegenerative disease.