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In two brothers born to consanguineous parents, we identified an unusual neurological disease that manifested with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy. Via linkage analysis and exome sequencing, we identified homozygous c.2801C>T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C>T (p.(Arg171Trp)) in OSBPL11 (encoding oxysterol-binding protein-like protein 11). Although in silico analysis, histopathologic evidence and functional verification indicated that both variants were deleterious, segregation with the patient phenotype established that the POLR1A defect underlies the disease, as a clinically unaffected sister also was homozygous for the OSBPL11 variant. Decreased nucleolar RPA194 was observed in the skin fibroblasts of only the affected brothers, whereas intracellular cholesterol accumulation was observed in the skin biopsies of the patients and the sister homozygous for the OSBPL11 variant. Our findings provide the first report showing a complex leukodystrophy associated with POLR1A. Variants in three other RNA polymerase subunits, POLR1C, POLR3A and POLR3B, are known to cause recessive leukodystrophy similar to the disease afflicting the present family but with a later onset. Of those, POLR1C is also implicated in a mandibulofacial dysostosis syndrome without leukodystrophy as POLR1A is. This syndrome is absent in the family we present.

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Anabolic agents are doping substances which are commonly used in sports. Stanozolol, a 17α-alkylated derivative of testosterone, has a widespread use among athletes and bodybuilders. Several medical and behavioral adverse effects are associated with anabolic androgenic steroids (AAS) abuse, while the liver remains the most well recognized target organ. In the present study, the hepatic effects of stanozolol administration in rats at high doses resembling those used for doping purposes were investigated, in the presence or absence of exercise. Stanozolol and its metabolites, 16-β-hydroxystanozolol and 3′-hydroxystanozolol, were detected in rat livers using liquid chromatography-mass spectrometry (LC-MS). Telomerase activity, which is involved in cellular aging and tumorigenesis, was detected by examining telomerase reverse transcriptase (TERT) and phosphatase and tensin homolog (PTEN) expression levels in the livers of stanozolol-treated rats. Stanozolol induced telomerase activity at the molecular level in the liver tissue of rats and exercise reversed this induction, reflecting possible premature liver tissue aging. PTEN gene expression in the rat livers was practically unaffected either by exercise or by stanozolol administration.

Anabolic androgenic steroids (AAS) are performance-enhancing drugs commonly abused by atheletes. Stanozolol is a synthetic testosterone-derived anabolic steroid. Although it is well known that AAS have several side-effects, there are only few toxicological studies available on the toxic effects and mechanisms of action of stanozolol. The aim of this study was to investigate the genotoxic effects of stanozolol and to determine its effects on telomerase activity in Sprague-Dawley male rats. For this purpose, 34 male rats were divided into 5 groups as follows: i) the control group (n=5); ii) the propylene glycol (PG)-treated group (n=5); iii) the stanozolol-treated group (n=8); iv) the PG-treated group subjected to exercise (n=8); and v) the stanozolol-treated group subjected to exercise (n=8). PG is used as a solvent control in our study. Stanozolol (5 mg/kg) and PG (1 ml/kg) were injected subcutaneously 5 days/week for 28 days. After 28 days, the animals were sacrificed, and DNA damage evaluation (comet assay) and telomerase activity assays were then performed using peripheral blood mononuclear cells (PBMCs). Telomerase activity was measured by using the TeloTAGGG Telomerase PCR ELISA PLUS kit. The results of this study revealed that stanozolol treatment induced DNA damage, while exercise exerted a protective effect. Stanozolol treatment without exercise stimulation was associated with a significant increase in telomerase activity in the PBMCs.

IntroductionDiabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia, leading to damage in a number of tissues. Retinas, neurons, and kidneys are especially affected (1). Acute and chronic complications may occur. Chronic complications are divided into vascular and nonvascular complications. Vascular complications are subdivided into microvascular (retinopathy, neuropathy, nephropathy) and macrovascular complications (coronary artery disease, peripheral vascular disease, cerebrovascular disease). Oxidative stress, glycosylation, and protein kinase-C activation are shown in all tissues affected by microvascular complications (1-3). Glucose homeostasis in humans is important for the functioning of the nervous system. The brain is an insulin-sensitive organ with widespread and selective expression of the insulin receptor in the olfactory bulb, hypothalamus, hippocampus, amygdala, cerebral cortex, and cerebellum; hypoglycemia and hyperglycemia affect the central and peripheral nervous system, leading to severe dysfunction (1-3).Chronic hyperglycemia is associated with functional and structural blood-brain barrier (BBB) changes in cerebral microvessels (3). Diabetes is also associated with gradually developing end-organ damage in the central nervous system, known as diabetic encephalopathy, characterized by impairment of cognitive functions and electrophysiological changes. Chronically increased intracellular glucose concentration leads to functional, structural, and neurodegenerative changes (1).Studies performing biochemical and structural analysis of the brain relevant to the ultrastructural features of diabetes are limited, and the number of cerebellar studies are even more so. This study aimed to analyze the structural and ultrastructural cerebellar changes in streptozotocin (STZ)-induced diabetic rats (2,4-6). Materials and methodsTwenty male adult Sprague Dawley rats weighing 200-220 g were obtained from the Experimental Medicine Research Institute (DETAE). Fourteen of these animals were selected as the diabetic group, and after 12 h of Background/aim: Diabetic peripheral neuropathy has been extensively studied and reported, but the number of studies that have investigated diabetes-related changes in the central nervous system are limited, with even fewer studies on the cerebellum. The aim of this experimental study was to perform a histologic analysis of the diabetes-related changes in the cerebellums of diabetic rats.Materials and methods: Twenty Sprague Dawley rats weighing between 200 and 220 g were included in the study. Diabetes was induced in 14 of these rats by a single intraperitoneal injection of 65 mg/kg streptozotocin dissolved in saline, while 6 animals constituted the control group. The induction of diabetes was confirmed by measuring the blood glucose levels in the tail blood with a glucometer. Levels equal to or above 200 mg/dL were considered diabetic. Induction of diabetes failed in 3 animals, who were then excluded from the study.Results...