Hb H disease resulting from the association of an α0-thalassemia allele [-(α)20.5] with an unstable α-globin variant [Hb Icaria]: First report on the occurrence in Brazil

Hb H Disease is caused by the loss or inactivation of three of the four functional α-globin genes. Patients present chronic hemolytic anemia and splenomegaly. In some cases, occasional blood transfusions are required. Deletions are the main cause of this type of thalassemia ( α-thalassemia). We describe here an unusual case of Hb H disease caused by the combination of a common α0 deletion [-( α) 20.5 ] with a rare point mutation (c.427T > A), thus resulting in an elongated and unstable α-globin variant, Hb Icaria, (X142K), with 31 additional amino-acid residues. Very high levels of Hb H and Hb Bart's were detected in the patient's red blood cells (14.7 and 19.0%, respectively). This is the first description of this infrequent association in the Brazilian population

A rapid high-performance semi-automated tool to measure total kidney volume from MRI in autosomal dominant polycystic kidney disease.

OBJECTIVES: To develop a high-performance, rapid semi-automated method (Sheffield TKV Tool) for measuring total kidney volume (TKV) from magnetic resonance images (MRI) in patients with autosomal dominant polycystic kidney disease (ADPKD). METHODS: TKV was initially measured in 61 patients with ADPKD using the Sheffield TKV Tool and its performance compared to manual segmentation and other published methods (ellipsoidal, mid-slice, MIROS). It was then validated using an external dataset of MRI scans from 65 patients with ADPKD. RESULTS: Sixty-one patients (mean age 45 ± 14 years, baseline eGFR 76 ± 32 ml/min/1.73 m2) with ADPKD had a wide range of TKV (258-3680 ml) measured manually. The Sheffield TKV Tool was highly accurate (mean volume error 0.5 ± 5.3% for right kidney, - 0.7 ± 5.5% for left kidney), reproducible (intra-operator variability - 0.2 ± 1.3%; inter-operator variability 1.1 ± 2.9%) and outperformed published methods. It took less than 6 min to execute and performed consistently with high accuracy in an external MRI dataset of T2-weighted sequences with TKV acquired using three different scanners and measured using a different segmentation methodology (mean volume error was 3.45 ± 3.96%, n = 65). CONCLUSIONS: The Sheffield TKV Tool is operator friendly, requiring minimal user interaction to rapidly, accurately and reproducibly measure TKV in this, the largest reported unselected European patient cohort with ADPKD. It is more accurate than estimating equations and its accuracy is maintained at larger kidney volumes than previously reported with other semi-automated methods. It is free to use, can run as an independent executable and will accelerate the application of TKV as a prognostic biomarker for ADPKD into clinical practice. KEY POINTS: • This new semi-automated method (Sheffield TKV Tool) to measure total kidney volume (TKV) will facilitate the routine clinical assessment of patients with ADPKD. • Measuring TKV manually is time consuming and laborious. • TKV is a prognostic indicator in ADPKD and the only imaging biomarker approved by the FDA and EMA

Treatment seeking for alcohol and drug use disorders by immigrants to the Netherlands: Retrospective, population-based, cohort study

Background We compared risks of first contact with services for an alcohol use disorder (AUD) or drug use disorder (DUD) between the largest immigrant groups to the Netherlands and Dutch nationals. We tested the hypothesis that the ethnic pattern for DUD is similar to the previously demonstrated pattern for schizophrenia. Methods Retrospective, population-based cohort study of First Admissions to Dutch psychiatric hospitals during the period 1990-1996 (national data) and First Contacts with inpatient or outpatient centres in Rotterdam for treatment of AUD or DUD during the period 1992-2001 (Rotterdam data). Results In both datasets the risk of service contact for AUD was significantly lower in immigrants from Surinam, Turkey and Morocco than in Dutch nationals. The risk was lower or moderately higher in immigrants from western countries. Analysis of the national data showed that, compared with Dutch males, the risk of first hospital admission for DUD was higher for male immigrants from the Dutch Antilles (RR = 4.6; 95% CI: 4.0-5.3), Surinam (RR = 4.3; 3.94.7) and Morocco (RR = 23; 2.0-2.6), but not for male immigrants from Turkey (RR = 0.9; 0.7-1.1). A similar pattern was found with the Rotterdam data. Female immigrants from Surinam and the Dutch Antilles had a higher risk for DUD according to the national data, but a lower risk according to the Rotterdam data. Female immigrants from Turkey and Morocco had a lower risk (both datasets). Immigrants from western countries had a higher risk for DUD, but many had developed the disorder before emigrating. Conclusion Those immigrant groups in the Netherlands that are at increased risk of schizophrenia appear also at increased risk of developing DUD, but not AUD

Amelioration of Acute Kidney Injury in Lipopolysaccharide-Induced Systemic Inflammatory Response Syndrome by an Aldose Reductase Inhibitor, Fidarestat

Systemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism.Mice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney.Mortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation.AR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality

Sox6 Is Necessary for Efficient Erythropoiesis in Adult Mice under Physiological and Anemia-Induced Stress Conditions

BACKGROUND: Definitive erythropoiesis is a vital process throughout life. Both its basal activity under physiological conditions and its increased activity under anemia-induced stress conditions are highly stimulated by the hormone erythropoietin. The transcription factor Sox6 was previously shown to enhance fetal erythropoiesis together and beyond erythropoietin signaling, but its importance in adulthood and mechanisms of action remain unknown. We used here Sox6 conditional null mice and molecular assays to address these questions. METHODOLOGY/PRINCIPAL FINDINGS: Sox6fl/flErGFPCre adult mice, which lacked Sox6 in erythroid cells, exhibited compensated anemia, erythroid cell developmental defects, and anisocytotic, short-lived red cells under physiological conditions, proving that Sox6 promotes basal erythropoiesis. Tamoxifen treatment of Sox6fl/flCaggCreER mice induced widespread inactivation of Sox6 in a timely controlled manner and resulted in erythroblast defects before reticulocytosis, demonstrating that impaired erythropoiesis is a primary cause rather than consequence of anemia in the absence of Sox6. Twenty five percent of Sox6fl/flErGFPCre mice died 4 or 5 days after induction of acute anemia with phenylhydrazine. The others recovered slowly. They promptly increased their erythropoietin level and amplified their erythroid progenitor pool, but then exhibited severe erythroblast and reticulocyte defects. Sox6 is thus essential in the maturation phase of stress erythropoiesis that follows the erythropoietin-dependent amplification phase. Sox6 inactivation resulted in upregulation of embryonic globin genes, but embryonic globin chains remained scarce and apparently inconsequential. Sox6 inactivation also resulted in downregulation of erythroid terminal markers, including the Bcl2l1 gene for the anti-apoptotic factor Bcl-xL, and in vitro assays indicated that Sox6 directly upregulates Bcl2l1 downstream of and beyond erythropoietin signaling. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that Sox6 is necessary for efficient erythropoiesis in adult mice under both basal and stress conditions. It is primarily involved in enhancing the survival rate and maturation process of erythroid cells and acts at least in part by upregulating Bcl2l1

Uptake of health services for common mental disorders by first-generation Turkish and Moroccan migrants in the Netherlands

Abstract Background Migration and ethnic minority status have been associated with higher occurrence of common mental disorders (CMD), while mental health care utilisation by non-Western migrants has been reported to be low compared to the general population in Western host countries. Still, the evidence-base for this is poor. This study evaluates uptake of mental health services for CMD and psychological distress among first-generation non-Western migrants in Amsterdam, the Netherlands. Methods A population-based survey. First generation non-Western migrants and ethnic Dutch respondents (N = 580) participated in structured interviews in their own languages. The interview included the Composite International Diagnostic Interview (CIDI) and the Kessler psychological distress scale (K10). Uptake of services was measured by self-report. Data were analysed using weighting techniques and multivariate logistic regression. Results Of subjects with a CMD during six months preceding the interview, 50.9% reported care for mental problems in that period; 35.0% contacted specialised services. In relation to CMD, ethnic groups were equally likely to access specialised mental health services. In relation to psychological distress, however, Moroccan migrants reported less uptake of primary care services (OR = 0.37; 95% CI = 0.15 to 0.88). Conclusion About half of the ethnic Dutch, Turkish and Moroccan population in Amsterdam with CMD contact mental health services. Since the primary purpose of specialised mental health services is to treat "cases", this study provides strong indications for equal access to specialised care for these ethnic groups. The purpose of primary care services is however to treat psychological distress, so that access appears to be lower among Moroccan migrants

Animal models of cardiorenal syndrome: a review

The incidence of heart failure and renal failure is increasing and is associated with poor prognosis. Moreover, these conditions do often coexist and this coexistence results in worsened outcome. Various mechanisms have been proposed as an explanation of this interrelation, including changes in hemodynamics, endothelial dysfunction, inflammation, activation of renin-angiotensin-aldosterone system, and/or sympathetic nervous system. However, the exact mechanisms initializing and maintaining this interaction are still unknown. In many experimental studies on cardiac or renal dysfunction, the function of the other organ was either not addressed or the authors failed to show any decline in its function despite histological changes. There are few studies in which the dysfunction of both heart and kidney function has been described. In this review, we discuss animal models of combined cardiorenal dysfunction. We show that translation of the results from animal studies is limited, and there is a need for new and better models of the cardiorenal interaction to improve our understanding of this syndrome. Finally, we propose several requirements that a new animal model should meet to serve as a tool for studies on the cardiorenal syndrome

α-thalassaemia

Alpha-thalassaemia is inherited as an autosomal recessive disorder characterised by a microcytic hypochromic anaemia, and a clinical phenotype varying from almost asymptomatic to a lethal haemolytic anaemia