Simple risk score to screen for prediabetes: A cross-sectional study from the Qatar Biobank cohort

Aims/IntroductionThe progression from prediabetes to type 2 diabetes is preventable by lifestyle intervention and/or pharmacotherapy in a large fraction of individuals with prediabetes. Our objective was to develop a risk score to screen for prediabetes in the Middle East, where diabetes prevalence is one of the highest in the world.Materials and MethodsIn this cross‐sectional, case–control study, we used data of 4,895 controls and 2,373 prediabetic adults obtained from the Qatar Biobank cohort. Significant risk factors were identified by logistic regression and other machine learning methods. The receiver operating characteristic was used to calculate the area under curve, cut‐off point, sensitivity, specificity, positive and negative predictive values. The prediabetes risk score was developed from data of Qatari citizens, as well as long‐term (≥15 years) residents.ResultsThe significant risk factors for the Prediabetes Risk Score in Qatar were age, sex, body mass index, waist circumference and blood pressure. The risk score ranges from 0 to 45. The area under the curve of the score was 80% (95% confidence interval 78–83%), and the cut‐off point of 16 yielded sensitivity and specificity of 86.2% (95% confidence interval 82.7–89.2%) and 57.9% (95% confidence interval 65.5–71.4%), respectively. Prediabetes Risk Score in Qatar performed equally in Qatari nationals and long‐term residents.ConclusionsPrediabetes Risk Score in Qatar is the first prediabetes screening score developed in a Middle Eastern population. It only uses risk factors measured non‐invasively, is simple, cost‐effective, and can be easily understood by the general public and health providers. Prediabetes Risk Score in Qatar is an important tool for early detection of prediabetes, and can help tremendously in curbing the diabetes epidemic in the region.     

Preliminary validation of varicella zoster virus thymidine kinase as a novel reporter gene for PET

IntroductionImaging of gene expression with positron emission tomography (PET) has emerged as a powerful tool for biomedical research during the last decade. The prototypical herpes simplex virus type 1 thymidine kinase (HSV1-TK) PET reporter gene (PRG) is widely used and many other PRGs have also been validated. We investigated varicella zoster virus thymidine kinase (VZV-tk) as new PRG with radiolabeled bicyclic nucleoside analogues (BCNAs) as PET tracers.MethodsThe uptake and washout of four different radiolabeled BCNAs was evaluated in cells expressing VZV-tk after lentiviral vector (LV) transduction and in control cells. Metabolism of the tracers was assayed by high pressure liquid chromatography (HPLC). Mice bearing VZV-TK expressing xenografts were imaged with PET.ResultsHigh uptake in VZV-tk expressing cells was seen for 3 of the 4 tracers tested. The uptake of the tracers could be blocked by the presence of excess thymidine in the incubation solution. Cellular retention was variable, with one tracer showing an acceptable half-life of ~ 1 hour. The amount of intracellular tracer correlated with the titer of LV used to transduce the cells. VZV-TK dependent conversion into metabolites was shown by HPLC. No specific accumulation was observed in cells expressing a fusion protein containing an HSV1-TK moiety. VZV-tk expression in xenografts resulted in a 60% increase in uptake in vivo as measured with PET.ConclusionsWe have validated the combination of VZV-tk and radiolabeled BCNAs as new PRG/PRP system. Further optimization of the PRPs and the PRG are warranted to increase the signal.     

Diagnostic accuracy of history taking to assess lumbosacral nerve root compression

Background contextThe diagnosis of sciatica is primarily based on history and physical examination. Most physical tests used in isolation show poor diagnostic accuracy. Little is known about the diagnostic accuracy of history items.PurposeTo assess the diagnostic accuracy of history taking for the presence of lumbosacral nerve root compression or disc herniation on magnetic resonance imaging in patients with sciatica.Study designCross-sectional diagnostic study.Patient sampleA total of 395 adult patients with severe disabling radicular leg pain of 6 to 12 weeks duration were included.Outcome measuresLumbosacral nerve root compression and disc herniation on magnetic resonance imaging were independently assessed by two neuroradiologists and one neurosurgeon blinded to any clinical information.MethodsData were prospectively collected in nine hospitals. History was taken according to a standardized protocol. There were no study-specific conflicts of interest.ResultsExploring the diagnostic odds ratio of 20 history items revealed a significant contribution in diagnosing nerve root compression for “male sex,” “pain worse in leg than in back,” and “a non-sudden onset.” A significant contribution to the diagnosis of a herniated disc was found for “body mass index <30,” “a non-sudden onset,” and “sensory loss.” Multivariate logistic regression analysis of six history items pre-selected from the literature (age, gender, pain worse in leg than in back, sensory loss, muscle weakness, and more pain on coughing/sneezing/straining) revealed an area under the receiver operating characteristic curve of 0.65 (95% confidence interval, 0.58–0.71) for the model diagnosing nerve root compression and an area under the receiver operating characteristic curve of 0.66 (95% confidence interval, 0.58–0.74) for the model diagnosing disc herniation.ConclusionsA few history items used in isolation had significant diagnostic value and the diagnostic accuracy of a model with six pre-selected items was poor.     

Altered control of the hypothalamo-pituitary-adrenal axis in adult male rats exposed perinatally to food deprivation and/or dehydration

Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.     

The chronic oral administration of arginine aspartate decreases secretion of IGF-1 and IGFBP-3 in healthy volunteers

To investigate the effect of chronic oral arginine aspartate on the growth hormone (GH), GH-releasing hormone (GHRH), insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) secretions in healthy volunteers. Twenty-three healthy non-athlete volunteer males were administered arginine aspartate (30 g) orally once daily at 21:00 h for 21 consecutive days. Subjects were hospitalized on days 0, 1, 3, 5, 7, 14 and 21 of treatment. At each hospitalization, concentrations of GHRH, GH, IGF-1 and IGFBP-3 were measured over 4 h after arginine aspartate intake. GH, IGF-1 and IGFBP-3 concentrations were also determined over 12 h at days 0, 1 and 21. Compared with day 1, 4 h GH levels dropped at day 5 and subsequently rose to levels not significantly different from initial ones. The latter was substantiated by 12 h GH levels that did not significantly change from days 1 to 21. GHRH levels were not statistically different, although there was a trend in median values that seemed to inversely mirror those of GH. This dynamic over the course of the study for GH and GHRH was accompanied by a general decrease in IGF-1 and IGFBP-3. In healthy volunteers, a chronic oral treatment with 30 g/day arginine aspartate is followed by a decrease in IGF-1 and IGFBP-3 secretions.     

Survivin expression increases during aging and enhances the resistance of aged human fibroblasts to genotoxic stress

Survivin, an important anti-apoptotic protein, is highly expressed in most cancers, which generally arise in cells of older individuals. We have shown here accumulation of survivin and phospho-survivin in aged normal human skin fibroblasts and mice organs. This age-related accumulation of survivin was due to protein stabilization through association with the molecular chaperone Hsp90 protein, which was also up-regulated during aging. Interestingly, Hsp90 binds preferentially to phospho-survivin, which explains its higher stability. In addition, we provide clear evidence that aged cells exhibit apoptosis resistance when challenged with UV light, cisplatin, γ-rays or H₂O₂ as compared to their younger counterparts. In response to γ-rays and H₂O₂, the levels of Bcl-2 and both forms of survivin were up-regulated in old cells, but not in their corresponding young ones. This repression of survivin and phospho-survivin in young cells is p53 dependent. Importantly, survivin inhibition/down-regulation with flavopiridol or specific shRNAs increased the apoptotic response of old fibroblasts to various genotoxic agents, and restored the pro-apoptotic Bax/Bcl2 ratio and the increase in the levels of cleaved caspase-3 and PARP in old cells. These results show the role of survivin in the age-dependent resistance of human fibroblasts, and provide new insights into the molecular mechanisms that underlie the complex relationship between aging, apoptosis, and cancer.