Genomewide scans of red cell indices suggest linkage on chromosome 6q23

Background

The red cell indices quantify the size, number and oxygen‐carrying ability of erythrocytes. Although the genetic basis of many monogenic forms of anaemia is well understood, comparatively little is known about the genes responsible for variation in the red cell indices among healthy participants.

Objective

To identify quantitative trait loci (QTLs) responsible for normal variation in the red cell indices of 391 pairs of dizygotic twins who were measured longitudinally at 12, 14 and 16 years of age.

Results

Evidence suggesting linkage of red cell indices to haemoglobin concentration (LOD  = 3.03) and haematocrit (LOD  = 2.95) on chromosome 6q23, a region previously identified as possibly harbouring a QTL for haematocrit, was found. Evidence for linkage to several other regions of the genome, including chromosome 4q32 for red cell count and 7q for mean cell volume, was also found. In contrast, there was little evidence of linkage to the chromosomal regions containing the genes for erythropoietin (7q21) and its receptor (19p13.2), nor to the regions containing the genes for the haemoglobin α (16p13.3) and β chains (11p15.5).

Conclusion

Findings provide additional evidence for a QTL affecting haemoglobin and haematocrit on chromosome 6q23. In contrast, polymorphisms in the genes coding for erythropoietin, its receptor and the haemoglobin α and β chains do not appear to contribute substantially to variation in the red cell indices between healthy persons.The red cell indices describe the size, number and oxygen‐carrying capacity of erythrocytes. Haemoglobin concentration indicates the amount of oxygen‐carrying protein haemoglobin in a given volume of blood; red blood cell count (RBC), the concentration of erythrocytes; mean corpuscular volume (MCV), the average volume of each red cell; and haematocrit (HCT), the proportion of blood that consists of erythrocytes. Together, these indices assist in the differential diagnosis of anaemia and are risk factors for a number of clinical conditions. For example, a high haematocrit is associated with increased risk of cerebrovascular^1,2 and coronary artery diseases.¹Approximately 7% of the world''s population are carriers for different inherited disorders of haemoglobin, making them one of the most prevalent Mendelian diseases.³ Although the genetic basis of many of these haemoglobinopathies is well understood, comparatively little is known regarding the genetic causes of variation in the normal range of red cell values. Studies on twins have shown that a substantial proportion of the variation between persons is due to genetic factors with heritability estimates ranging from 20% to 96%.^4,5,6,7,8,9 A recent genomewide linkage study by Lin et al⁷ identified a locus on chromosome 6q23–24 linked to HCT, and a pleiotropic locus affecting haemoglobin and HCT on chromosome 9q.⁷ Interestingly, the authors found no evidence of linkage to regions containing the genes for the α and β haemoglobin chains (on chromosomes 16p13.3 and 11p15.5), nor erythropoietin and its receptor (on chromosomes 7q21 and 19p13.2), which have all been implicated in Mendelian forms of anaemia. The implication is that the quantitative trait loci (QTLs) responsible for normal variation in the red cell indices might differ from the loci which cause monogenic forms of anaemia.In a previous study, we reported that variation in the red cell indices was highly heritable, with genetic factors explaining between 61% and 96% of the phenotypic variance in our sample of adolescent twins.⁵ In this paper, we extend these results by performing a genomewide linkage scan of the 391 dizygotic twin pairs from that study. We measured the red cell indices of twins at 12, 14 and 16 years of age and performed univariate multipoint sib‐pair linkage analyses across the genome. Our study is the first to report linkage results for RBC and MCV, and will hopefully constitute the first stage in the identification and subsequent positional cloning of QTLs responsible for normal variation in the red cell indices.     

CD83 is a regulator of murine B cell function in vivo

The transmembrane glycoprotein CD83 has been described as a specific maturation marker for dendritic cells and several lines of evidence suggest that CD83 regulates thymic T cell maturation as well as peripheral T cell activation. Here we show for the first time that CD83 is involved also in the regulation of B cell function. CD83 is up-regulated on activated B cells in vivo, specifically in the draining lymph nodes of Leishmania major-infected mice. The ubiquitous transgenic (Tg) expression of CD83 interferes with Leishmania-specific T cell-dependent and with T cell-independent antibody production. This defect is restricted to the B cell population since the antigen-specific T cell response of CD83Tg mice to L. major infection is unchanged. The defective immunoglobulin (Ig) response is due to Tg expression of CD83 on the B cells because wild-type B cells display normal antigen-specific responses in CD83Tg hosts and CD83Tg B cells do not respond to immunization in a mixed wild-type/CD83Tg bone marrow chimera. Finally, the treatment of non-Tg C57BL/6 mice with anti-CD83 mAb induces a dramatic increase in the antigen-specific IgG response to immunization, thus demonstrating a regulatory role for naturally induced CD83 on wild-type B cells.     

The effect of a 6-month intradialytic exercise program on hemodialysis adequacy and body composition: a randomized controlled trial

Background/aim

End-stage kidney disease (ESKD) is strongly associated with factors that aggravate the physical activity level and body composition status of hemodialysis patients (HD). Even though exercise in HD patients have shown remarkable benefits on hemodialysis adequacy, it is yet inconclusive if exercise can positively affect body composition parameters or if dialysis adequacy may affect body composition status. This study aimed to investigate the effect of a 6-month intradialytic exercise training program on dialysis adequacy indices and body composition parameters in HD patients.

Study design

A total of 24 HD patients were randomly assigned into two equally sized groups. The exercise group (EX group) participated in a 6-month intradialytic moderate-intensity aerobic exercise training program at the beginning of the HD sessions, three times a week for 60 min, and maintained a Borg’s Rating of Perceived Exertion score between 13 and 14. The Control group (C group) remained untrained. At baseline, during, and at the end of the 6-month study, we assessed single-pool Kt/V, urea reduction ratio (URR), and body composition parameters, such as extracellular water (ECW)/ intracellular water (ICW) ratio, body mass index (BMI) and lean tissue mass (LTM). In all patients, the 6-min-walking test (6MWT) was performed as a marker of physical performance.

Results

A significant increase of both Kt/V (increase by 19%, p?=?0.01), and URR (increase by 7%, p?=?0.03) values has been observed in the EX group after the 6-month training program. Similarly, a statistically significant increase in 6MWT distance (from 442?±?67 m to 481?±?68 m, p?=?0.02) in the EX group has also been found, compared to the C group (from 393?±?59 m to 427?±?81 m, p?=?0.06). Neither EX nor C group has shown significant changes in body composition parameters. After training, linear regression analysis revealed a strong positive correlation between Kt/V and 6MWT changes (r?=?0.74, p?=?0.04) in the EX group.

Conclusions

Six months of intradialytic aerobic exercise might increase dialysis adequacy, by increasing Kt/V and URR, and physical performance, regardless of changes in body composition indices.

     

Potential role of hepatic progenitor cells expression in cases of chronic hepatitis C and their relation to response to therapy: a clinicopathologic study.

BACKGROUND: This study investigates the correlation of hepatic progenitor cells (HPC) expression with treatment response in patients with chronic hepatitis C. DESIGN: The study comprised 77 liver biopsies with chronic hepatitis C (HCV). All patients were PCR-HCV (+) and received antiviral therapy with interferon or pegylated interferon alpha-2b and ribavirin. Twenty-nine patients were assigned as responders (group A), 29 as nonresponders (group B) and 19 as relapsers (group C). Ten normal liver biopsies were used as controls. Liver paraffin sections were subjected (a) to immunohistochemistry using antibodies for cytokeratins 19 (CK19) and 7 (CK7), alpha-fetoprotein (AFP), leukocyte common antigen (LCA) and CD34 antigen (b) to in situ hybridization for AFP mRNA and (c) to immunohistochemistry+in situ hybridization. Results were expressed as % of positive cells following morphometric analysis. RESULTS: HPC expression was present in all 87 specimens. In the control biopsies, rare HPC were detected. In the CH cases and according to AFP mRNA expression, the grade for % HPC expression was: group B: 53.2+/-2.6> group C: 48.37+/-1.8> group A: 31.4+/-1.6 (group A vs B P<0.01, group A vs C P<0.01, group B vs C P>0.05. Double stain revealed that HPC coexpressed CK19/AFP mRNA, CK7/AFP mRNa and AFP protein/AFP mRNA. HPC-percentages were directly correlated with total HAI score (P<0.01), fibrosis stage (P<0.01), and transaminase values (P<0.05). CONCLUSIONS: This study demonstrates that in cases of chronic hepatitis C, the significant association of HPC expression with the severity of disease and more specifically with the response to treatment implies that HPC development and proliferation may provide additional prognostic information and predict prognosis in such cases.     

A systematic review of community pharmacies' staff diagnostic assessment and performance in patient consultations

BackgroundIncreases in patients seeking advice at pharmacies has led to pharmacy staff engaging in diagnostic behaviours. Approaches to diagnosis include using mnemonics and clinical reasoning.ObjectivesThe primary aim of this review was to assess the degree to which the criteria researchers use to evaluate diagnostic performance in pharmacy consultations, in studies that have simulated patients or vignettes, conform with a clinical reasoning and a mnemonic framework. A secondary aim of the review was to characterize staff performance in the studies, based on the authors' comments of their results.MethodsMEDLINE, EMBASE and Web of Science were searched between October 2016 and April 2017. Only peer-reviewed studies assessing pharmacy staff's diagnostic performance using simulated patients or vignettes were eligible for inclusion. Data were extracted about how each study's criteria conformed with clinical reasoning and mnemonic frameworks. A scoring system between 0 and 4 was devised to determine the degree to which studies aligned to these two approaches. Risk of bias was assessed using the NHI Study Quality Assessment Tools. The review was registered in PROSPERO with identification number CRD42017054827.ResultsSixty-eight studies (55 cross-sectional, 11 educational interventions and 2 RCTs) with sample sizes between 10 and 2700 were included in the review. Most studies were of poor or fair quality. Performance of pharmacy staff was overwhelmingly reported as poor by study authors. This was the case regardless of geography, scenario used, or assessment framework adopted. Scrutiny on how authors arrived at these conclusions revealed that mnemonic criteria were employed to assess pharmacy staff's diagnostic performance rather than a clinical reasoning approach.ConclusionsPotentially important aspects of the decision-making process, such as clinical reasoning, were left unexplored. The number and geographic distribution of the included studies is a strength of this review; however, a validated tool was not employed.     

Treatment with bortezomib‐based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, with poor outcome. Bortezomib‐based regimens (BBR) are highly effective in myeloma, but there is limited information about their efficacy and safety in PCL. Thus, we retrospectively collected data from 42 consecutive PCL patients (25 with primary PCL‐pPCL and 17 with secondary PCL‐sPCL) to explore the role of BBR in this entity. BBR were administered in 29 of 42 patients, while 6 of 25 patients with pPCL underwent autologous transplantation. Objective response (≥partial response) was significantly higher in patients treated with BBR versus conventional therapies (69% vs. 30.8%, P = 0.04); 27.5% of patients treated with BBR achieved at least very good partial response (vgPR). The highest ORR was observed in pPCL patients treated with BBR (88.9%; ≥vgPR: 33.3%). In BBR‐group, grade 3 of 4 hematological, neurological and renal toxicity and neutropenic infections were observed in 41.4%, 7%, 3.4%, and 31%, respectively. With a median follow‐up of 51 months, median overall survival (OS) for patients treated with BBR versus conventional therapies was 13 versus 2 months (P < 0.007). Median OS of patients with pPCL and sPCL treated with BBR was 18 and 7 months, respectively (P < 0.001). In the multivariate analysis normal PLTs, treatment with BBR and high quality response were the only powerful predictors for survival. Our study carrying the longest reported median follow‐up, demonstrated that treatment of PCL with BBR induces high response rates and prolongs survival over conventional therapies, regardless of additional autologous transplantation rescue or established high risk features, with manageable toxicity. Am. J. Hematol. 89:145–150, 2014. © 2013 Wiley Periodicals, Inc.     

Shortening the acquisition time of whole-body MRI: 3D T1 gradient echo Dixon vs fast spin echo for metastatic screening in prostate cancer

European Radiology - To compare 3D T1-weighted fast spin echo (FSE) and 3D T1-weighted gradient echo (GE) mDixon as morphologic sequences to complement diffusion-weighted imaging (DWI) for the...