Implicating the cholecystokinin B receptor in liver stem cell oncogenesis.

Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related deaths worldwide. Chronic inflammation and fibrosis are the greatest risk factors for the development of HCC. Although the cell of origin for HCC is uncertain, many theories believe this cancer may arise from liver progenitor cells or stem cells. Here, we describe the activation of hepatic stem cells that overexpress the cholecystokinin-B receptor (CCK-BR) after liver injury with either a DDC diet (0.1% 3, 5-diethoxy-carbonyl 1,4-dihydrocollidine) or a NASH-inducing CDE diet (choline-deficient ethionine) in murine models. Pharmacologic blockade of the CCK-BR with a receptor antagonist proglumide or knockout of the CCK-BR in genetically engineered mice during the injury diet reduces the expression of hepatic stem cells and prevents the formation of three-dimensional tumorspheres in culture. RNA sequencing of livers from DDC-fed mice treated with proglumide or DDC-fed CCK-BR knockout mice showed downregulation of differentially expressed genes involved in cell proliferation and oncogenesis and upregulation of tumor suppressor genes compared with controls. Inhibition of the CCK-BR decreases hepatic transaminases, fibrosis, cytokine expression, and alters the hepatic immune cell signature rendering the liver microenvironment less oncogenic. Furthermore, proglumide hastened recovery after liver injury by reversing fibrosis and improving markers of synthetic function. Proglumide is an older drug that is orally bioavailable and being repurposed for liver conditions. These findings support a promising therapeutic intervention applicable to patients to prevent the development of HCC and decrease hepatic fibrosis.NEW & NOTEWORTHY This investigation identified a novel pathway involving the activation of hepatic stem cells and liver oncogenesis. Receptor blockade or genetic disruption of the cholecystokinin-B receptor (CCK-BR) signaling pathway decreased the activation and proliferation of hepatic stem cells after liver injury without eliminating the regenerative capacity of healthy hepatocytes.

Household Water Is the Main Source of Iodine Consumption among Women in Hargeisa, Somaliland: A Cross-Sectional Study.

BACKGROUND: Iodine status surveys of women in Somaliland present widely conflicting results. Previous research indicates elevated concentrations of iodine (IQR 18-72 µg/L) in groundwater used for drinking and cooking, but the relation with iodine intake is not well characterized. OBJECTIVES: We aimed to investigate the contributions of household water iodine concentration (WIC), breastfeeding, total fluid intake, hydration levels, and urine volume on urinary iodine concentration (UIC) and excretion (UIE) over a 24-h period and to define iodine status from iodine intake estimates and median UIC, normalized to a mean urine volume of 1.38 L/d (hydration adjusted). METHODS: The study sample comprised 118 nonpregnant, healthy women aged 15-69 y. All participants resided in Hargeisa, and 27 were breastfeeding. Data collection consisted of a 24-h urine collection, a 24-h fluid intake diary, a beverage frequency questionnaire, and a structured recall interview. We measured UIC and WIC in all urine and in 49 household water samples using the Sandell-Kolthoff reaction. RESULTS: WIC ranged between 3 and 188 µg/L, with significant median differences across the water sources and city districts (P < 0.003). Nonbreastfeeding women were borderline iodine sufficient [hydration-adjusted median urinary iodine concentration (mUIC) 109 µg/L; 95% CI: 97, 121 µg/L], whereas breastfeeding women showed a mild iodine deficiency (73 µg/L; 95% CI: 54, 90 µg/L). There were strong correlations (ρ: 0.50-0.69, P = 0.001) between WIC and UIC, with iodine from household water contributing more than one-half of the total iodine intake. Multivariate regression showed hydration and breastfeeding status to be the main predictors of UIC. CONCLUSIONS: Iodine from household water is the main contributor to total iodine intake among women in Hargeisa, Somaliland. Variation in female hydration and spatial and temporal WIC may explain diverging mUIC between studies. Water sources at the extremes of low and high iodine concentrations increase the risk of subpopulations with insufficient or more than adequate iodine intake.

An Application for Measuring and Analyzing the Level of Performance Accuracy for Health Services Quality Indicators by Using Six-Sigma: A Study Case of Government Hospitals in Khartoum State.

The study aimed at acknowledging the Six Sigma methodology and the existence of the essential components for the application, as well as reducing the time for completing the operations, reducing the error rate to the lowest possible level, and improving the quality of operations. For this objective, the analytical descriptive methodology was used on a sample consisted of 300 administrative and medical staff from Khartoum State Hospitals (Khartoum, Omdurman, Bahri). To this end, a questionnaire was used for collecting data and for analyzing it and achieving the results of the study by using the statistical analysis package (SPSS). The study deduced a number of results, the most important of which are that the items of commitment and supreme command support for the senior leadership and the methods of abundant human resources on quality control, and the application of the Six Sigma methodology in government hospitals in Khartoum state achieved a satisfactory level, while continuous improvement paragraphs, processes, and systems on quality control and the application of Six Sigma methodology achieved high quality. There is a significant effect on the extent of commitment and support of the higher leadership on quality control and the application of the Six Sigma methodology. Similarly, there is a statistically significant effect on the application of continuous improvement methods on quality control and Six Sigma methodology. Also, there is a statistically significant effect on the application of the abundance of human resources methods variable on quality control and the application of Six Sigma methodology in governmental hospitals in Khartoum state. The study recommended to take interest in the Six Sigma methodology and assure the possibility of using it in Khartoum State's hospitals because of its scientific and practical importance in improving the quality of services and provided processes, and the need to provide qualified financial and human resources for using and developing Six Sigma methodology in hospitals, as well as great attention in training and providing departments heads with full knowledge of Six Sigma methodology and the fundamentals on which Six Sigma methodology, is based on its importance for hospitals. The study also recommended associating the promotions system in government hospitals in Khartoum state with the quality control program.

Estimates of fluid intake, urine output and hydration-levels in women from Somaliland: a cross-sectional study.

The study objective was to measure fluid intake and associations with background characteristics and hydration biomarkers in healthy, free-living, non-pregnant women aged 15-69 years from Hargeisa city. We also wanted to estimate the proportion of euhydrated participants and corresponding biomarker cut-off values. Data from 136 women, collected through diaries and questionnaires, 24h urine samples and anthropometric measurements, were obtained with a cross-sectional, purposeful sampling from fifty-two school and health clusters, representing approximately 2250 women. The mean (95 % CI) 24 h total fluid intake (TFI) for all women was 2⋅04 (1⋅88, 2⋅20) litres. In multivariate regression with weight, age, parity and a chronic health problem, only weight remained a predictor (P 0.034, B 0.0156 (l/kg)). Pure water, Somali tea and juice from powder and syrup represented 49⋅3, 24⋅6 and 11⋅7 % of TFI throughout the year, respectively. Mean (95 % CI) 24 h urine volume (Uvol) was 1⋅28 (1⋅17, 1⋅39) litres. TFI correlated strongly with 24 h urine units (r 0.67) and Uvol (r 0.59). Approximately 40 % of the women showed inadequate hydration, using a threshold of urine specific gravity (Usg) of 1⋅013 and urine colour (Ucol) of 4. Five percent had Usg > 1⋅020 and concomitant Ucol > 6, indicating dehydration. TFI lower cut-offs for euhydrated, non-breast-feeding women were 1⋅77 litres and for breast-feeding, 2⋅13 litres. Euhydration cut-off for Uvol was 0⋅95 litre, equalling 9⋅2 urine units. With the knowledge of adverse health effects of habitual hypohydration, Somaliland women should be encouraged to a higher fluid intake.

Arabic versions of the sleep timing questionnaire and the composite scale of morningness.

OBJECTIVES: To develop Arabic versions of English language questionnaires to estimate morningness/eveningness and sleep variables. METHODS: We translated the Composite scale of morningness (CSM) and the sleep timing questionnaire (STQ) [with added siesta questions] into Arabic; the Arabic versions were then back translated. The revised Arabic and the original English versions were next administered to bi-lingual Egyptians using a crossover design (n=25). The Arabic versions of both scales were subsequently administered to an independent Egyptian sample (n=79) and the siesta variables examined in relation to the CSM. RESULTS: Satisfactory correlations were present between the English and Arabic versions for total CSM scores (Spearman's ρ=0.90, p<0.001). All but one of the STQ variables were significantly correlated (Spearman's ρ=0.45-0.88, p≤0.05). In the Arabic version, the frequency of siesta naps per week was significantly correlated with the total CSM score, with evening types taking more naps (Spearman's ρ=-0.23, p≤0.05). CONCLUSIONS: Arabic versions of the STQ and CSM have been developed in Egypt, and are freely available. They can be used for behavioral research related to sleep and circadian function and can be adapted for use in other Arab speaking populations.

Reduced Fertility and Fecundity among Patients with Bipolar I Disorder and Schizophrenia in Egypt.

OBJECTIVE: To evaluate reproduction among patients with bipolar I disorder (BP1) or schizophrenia (SZ) in Egypt. METHODS: BP1 patients (n=113) were compared with community based, demographically balanced controls (n=124) and SZ patients (n=79, DSM-IV). All participants were evaluated using structured interviews and corroborative data were obtained from relatives. Standard indices of procreation were included in multivariate analyses that incorporated key demographic variables. RESULTS: Control individuals were significantly more likely to have children than BP1 or SZ patients (controls 46.8%, BP1 15.9%, SZ 17.7%), but the BP1-SZ differences were non-significant. The average number of children for BP1 patients (0.37±0.9) and SZ patients (0.38±0.9) was significantly lower than for controls (1.04±1.48) (BP1 vs controls, p<0.001; SZ vs controls, p<0.001). The frequency of marriages among BP1 patients was nominally higher than the SZ group, but was significantly lower than controls (BP1: 31.9% SZ: 27.8% control: 57.3%). Even among married individuals, BP1 (but not SZ) patients were childless more often than controls (p=0.001). The marital fertility, i.e., the average number of children among patients with conjugal relationships for controls (1.8±1.57) was significantly higher than BP1 patients (1.14±1.31, p=0.02), but not significantly different from SZ patients (1.36±1.32, p=0.2). CONCLUSION: Selected reproductive measures are significantly and substantially reduced among Egyptian BP1 patients. The reproductive indices are similar among BP1 and SZ patients, suggesting a role for general illness related variables. Regardless of the cause/s, the impairment constitutes important, under-investigated disability.

Does telomere length mediate associations between inbreeding and increased risk for bipolar I disorder and schizophrenia?

We have recently found that consanguinity is a risk factor for bipolar I disorder (BP1) and schizophrenia (SZ) in Egypt. Inbreeding has been associated with increased cellular stress and impaired physiological function in plants and animals. Previous studies have reported that telomere length (TL), an index of oxidative stress and cellular senescence is significantly reduced among patients with SZ or mood disorders compared with control individuals. Hence we evaluated TL as a possible mediator of the observed association between consanguinity and BP1/SZ risk. Patients with BP1 (n=108), or SZ (n=60) were compared with screened adult controls in separate experiments. TL was estimated using a quantitative PCR (qPCR) based assay. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ('DNA-based' rate); and from family history data ('self report'). Significant correlation between TL and DNA based inbreeding was not observed overall, though suggestive trends were present among the SZ cases. No significant case-control differences in TL were found after controlling for demographic variables. In conclusion, reduced TL may not explain a significant proportion of observed associations between consanguinity and risk for BP1/SZ.

Consanguinity and increased risk for schizophrenia in Egypt.

BACKGROUND: Consanguinity has been suggested as a risk factor for psychoses in some Middle Eastern countries, but adequate control data are unavailable. Our recent studies in Egypt have shown elevated parental consanguinity rates among patients with bipolar I disorder (BP1), compared with controls. We have now extended our analyses to schizophrenia (SZ) in the same population. METHODS: A case-control study was conducted at Mansoura University Hospital, Mansoura, Egypt (SZ, n=75; controls, n=126, and their available parents). The prevalence of consanguinity was estimated from family history data ('self report'), followed by DNA analysis using short tandem repeat polymorphisms (STRPs, n=63) ('DNA-based' rates). RESULTS: Self-reported consanguinity was significantly elevated among the patients (SZ: 46.6%, controls: 19.8%, OR 3.53, 95% CI 1.88, 6.64; p=0.000058, 1 d.f.). These differences were confirmed using DNA-based estimates for coefficients of inbreeding (inbreeding coefficients as means+/-standard error, cases: 0.058+/-0.007, controls: 0.022+/-0.003). CONCLUSIONS: Consanguinity rates are significantly elevated among Egyptian SZ patients in the Nile delta region. The associations are similar to those observed with BP1 in our earlier study. If replicated, the substantial risk associated with consanguinity raises public health concerns. They may also pave the way for gene mapping studies.

Consanguinity associated with increased risk for bipolar I disorder in Egypt.

We aimed to contrast rates of consanguinity among patients with bipolar I disorder (BP1) and controls in a population with customary consanguineous marriages (i.e., marriage between related individuals). Consanguinity increases risk for numerous monogenic and polygenic diseases. Whether the risk for BP1 increases with consanguinity has not been investigated systematically. Two independent studies were conducted in Egypt: (1) Case-control study 93 patients with BP1, 90 screened adult control individuals, and available parents. The inbreeding coefficient/consanguinity rate was estimated in two ways: using 64 DNA polymorphisms ("DNA-based" rate); and from family history data ("self report"); (2) Epidemiological survey: total of 1,584 individuals were screened, from whom self-reported consanguinity data were obtained for identified BP1 cases (n = 35) and 150 randomly selected, unaffected control individuals. DNA-based consanguinity rates showed significant case-control differences (P = 0.0039). Self-reported consanguinity rates were also elevated among BP1 patients in both samples (Study #1 OR = 2.66, 95% confidence intervals, CI: 1.34, 5.29; Study #2: OR = 4.64, 95% CI: 2.01, 10.34). In conclusion, two independent, systematic studies indicate increased consanguinity among Egyptian BP1 patients in the Nile delta region. Self-reported estimates of consanguinity are bolstered by DNA-based estimates, and both show significant case-control differences for BP1.