2P15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment

Elevated fetal hemoglobin (HbF) ameliorates the clinical severity of hemoglobinopathies such as β-thalassemia and sickle cell anemia. Currently, the only curative approach for individuals under chronic transfusion/chelation support therapy is allogeneic stem cell transplantation. However, recent analyses of heritable variations in HbF levels have provided a new therapeutic target for HbF reactivation: the transcriptional repressor BCL11A. Erythroid-specific BCL11A abrogation is now actively being sought as a therapeutic avenue, but the specific impact of such disruption in humans remains to be determined. Although single nucleotide polymorphisms in BCL11A erythroid regulatory elements have been reported, coding mutations are scarcer. It is thus of great interest that patients have recently been described with microdeletions encompassing BCL11A. These patients display neurodevelopmental abnormalities, but whether they show increased HbF has not been reported. We have examined the hematological phenotype, HbF levels, and erythroid BCL11A expression in 3 such patients. Haploinsufficiency of BCL11A induces only partial developmental g-globin silencing. Of greater interest is that a patient with a downstream deletion exhibits reduced BCL11A expression and increased HbF. Novel erythroid-specific regulatory elements in this region may be required for normal erythroid BCL11A expression, whereas loss of separate elements in the developing brain may explain the neurological phenotype

Risk propensity in the foreign direct investment location decision of emerging multinationals

A distinguishing feature of emerging economy multinationals is their apparent tolerance for host country institutional risk. Employing behavioral decision theory and quasi-experimental data, we find that managers’ domestic experience satisfaction increases their relative risk propensity regarding controllable risk (legally protectable loss), but decreases their tendency to accept non-controllable risk (e.g., political instability). In contrast, firms’ potential slack reduces relative risk propensity regarding controllable risk, yet amplifies the tendency to take non-controllable risk. We suggest that these counterbalancing effects might help explain observation that risk-taking in FDI location decisions is influenced by firm experience and context. The study provides a new understanding of why firms exhibit heterogeneous responses to host country risks, and the varying effects of institutions

Rapid detection of pathological mutations and deletions of the haemoglobin beta gene (HBB) by High Resolution Melting (HRM) analysis and Gene Ratio Analysis Copy Enumeration PCR (GRACE-PCR)

© 2016 The Author(s). Objectives: Inherited disorders of haemoglobin are the world's most common genetic diseases, resulting in significant morbidity and mortality. The large number of mutations associated with the haemoglobin beta gene (HBB) makes gene scanning by High Resolution Melting (HRM) PCR an attractive diagnostic approach. However, existing HRM-PCR assays are not able to detect all common point mutations and have only a very limited ability to detect larger gene rearrangements. The aim of the current study was to develop a HBB assay, which can be used as a screening test in highly heterogeneous populations, for detection of both point mutations and larger gene rearrangements. Methods: The assay is based on a combination of conventional HRM-PCR and a novel Gene Ratio Analysis Copy Enumeration (GRACE) PCR method. HRM-PCR was extensively optimised, which included the use of an unlabelled probe and incorporation of universal bases into primers to prevent interference from common non-pathological polymorphisms. GRACE-PCR was employed to determine HBB gene copy numbers relative to a reference gene using melt curve analysis to detect rearrangements in the HBB gene. The performance of the assay was evaluated by analysing 410 samples. Results: A total of 44 distinct pathological genotypes were detected. In comparison with reference methods, the assay has a sensitivity of 100 % and a specificity of 98 %. Conclusion: We have developed an assay that detects both point mutations and larger rearrangements of the HBB gene. This assay is quick, sensitive, specific and cost effective making it suitable as an initial screening test that can be used for highly heterogeneous cohorts

Body composition analysis by dual energy x-ray absorptiometry and anthropometry in adults with childhood-onset growth hormone (GH) deficiency before and after six months of recombinant GH therapy

Measurements of total body fat (BF) land fat free mass (FFM) obtained by anthropometry, using the Durnin and Womersley (DW) equations, and by total body dual energy x-ray absorptiometry (DXA) were compared in 8 adults with childhood-onset GH deficiency (GHD) and in 9 healthy subjects. The sensitivity of these two methods in detecting the changes in body composition produced by six months of GH therapy in patients with GHD was also compared. Anthropometric determination of percent BF was calculated from the sum of biceps, triceps, subscapular and suprailiac skinfolds, using the appropriate DW and Siri equations for body density and percent fat estimation. FFM was calculated by subtracting BF from body mass (BM). BF and FFM were also determined by DXA (QDR 1000W, Hologic Inc). The data obtained from the GHD patients were compared with those recorded in a control group of healthy males, matched for sex, age and physical activity. Body composition obtained by anthropometry: before GH treatment, significant differences existed between patients and controls in terms of BM (mean \ub1 SD: 45.8 \ub1 10.0 vs 71.7 \ub1 6.6 kg), percent BF (21.0 \ub1 3.2 vs 17.1 \ub1 3.7%) and FFM (36.0 \ub1 6.5 vs 59.3 \ub1 3.7 kg), while body mass index (BMI, kg/m2) values were similar in the two groups. Six months of GH therapy did not change BM and BMI, but caused a significant reduction of percent BF (from 21.0 \ub1 3.2 to 18.6 \ub1 4.0%) and a rise of FFM (from 36.0 \ub1 6.5 to 38.0 \ub1 6.7 kg). After treatment, no significant differences were found between percent BF values of patients and controls. Body composition obtained by DXA: BF (22.0 \ub1 3.9%) and FFM (37.2 \ub1 8.0 kg) of patients significantly differed from those of controls (16.8 \ub1 3.7% and 59.8 \ub1 3.7 kg) before treatment; after GH treatment, percent BF values (17.7 \ub1 4.9%) of patients were similar to those of controls. Anthropometry vs DXA: high correlation (p < 0.001-0.0001, R2 = 0.784-0.988) was found between the percent BF and FFM determined by anthropometry and by DXA for both patients, before and after treatment, and controls. It is noteworthy that, for both BF and FFM, most values were evenly distributed along the identity line, showing no systematic overestimation or underestimation by anthropometry. The relation between DXA and anthropometry was maintained even after GH treatment. These results indicate that body fat and FFM assessment by anthropometry are comparable to those by DXA. GH-induced changes in body composition in hypopituitary adults are detected with the same level of accuracy by the two techniques. The reliability, practicality and low cost of anthropometry favour its use for the assessment of body composition even in GHD patients

Lack of effects of circulating thyroid hormone levels on serum leptin concentrations.

Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur