Wolfgang Kühnau

Clozapine-induced weight gain: a study in monozygotic twins and same-sex sib pairs.

To assess the relative contribution of genetic factors in antipsychotic-induced weight gain, we explored the similarity in body mass index (BMI) (kg/m2) change under clozapine only (clozapine ΔBMI) and upon additional inclusion of BMI change under prior antipsychotic medication (total ΔBMI) of five monozygotic twins in comparison with seven same-sex sibs. Twin and sib pairs were identified by a telephone screening of 786 office-based psychiatrists. Measured data on weight and other clinical variables were obtained cross-sectionally and retrospectively from medical records. We found greater similarity in total ΔBMI in monozygotic twins (intrapair difference 2.78±3.41 kg/m2) than in same-sex sibs (5.55±4.35 kg/m2), resulting in heritability estimates of h2=0.8 and A=0.45 (ACE twin model). However, intrapair differences in clozapine ΔBMI were similar between twins (4.18±4.27 kg/m2) and sibs (4.68±4.88 kg/m2). We hypothesize that the weight plateau achieved under clozapine is influenced by genetic factors. The weight gain achieved during pretreatment with other antipsychotics seems to limit clozapine-induced weight gain, thus presumably explaining why heritability/similarity in monozygotic twins in comparison with same-sex sibs is greater for total ΔBMI than for clozapine ΔBMI. An important caveat is that, owing to the sample size, the heritability estimates have a large standard error and thus have to be interpreted with caution.

Body weight gain induced by atypical antipsychotics: an extension of the monocygotic twin and sib pair study

Background and objective:  In our original study based on five monozygotic twin pairs and seven same‐sex sib pairs, we previously showed that genetic factors contribute to body weight gain induced by the atypical antipsychotic clozapine. We aim to study this further by including patients treated with the atypical antipsychotics olanzapine or risperidone as well as opposite‐sex sib pairs.

Prevalence of primary adult lactose malabsorption in three populations of northern China

SummaryLactose absorption capacity was examined in 641 apparently healthy adolescents and adults (447 males and 194 females with an average age of 22.9 years and an age range of 16–46 years) using a field version of the lactose tolerance test with breath hydrogen determination. In the total sample, 89 lactose absorbers and 552 lactose malabsorbers were identified. Lactose malabsorption was most frequent in a subgroup of Han (Chinese) from northeastern China (229 of 248 subjects, 92.3%). Among 198 Mongols from Inner Mongolia, there were 174 lactose malabsorbers (87.9%). The frequency of lactose malabsorption was lowest in a group of Kazakhs, traditional herders from the northwestern region of Xinjiang (149 of 195 subjects, 76.4%). Reported symptoms of lactose intolerance were significantly more frequent in lactose malabsorbers. The findings in northern Han are similar to the reported lactose malabsorption frequency in southern (mainly overseas) Chinese, and correspond with the absence of animal milk from traditional Chinese diets. The relatively low prevalence of lactose malabsorption among the Kazakhs suggests that lactose persistence may be frequent in herding pastoralist populations of southwest Asia.

Twin study on heritability of activity, attention, and impulsivity as assessed by objective measures.

Objective: The purpose of this study was to assess heritability of activity, attention, and impulsivity by comparing young monozygotic (MZ) twins with dizygotic (DZ) twins using objective measures. Method: The OPTAx test is an infrared motion analysis to record the movement pattern during a continuous performance test. Seventeen MZ and 12 same sexed DZ twin pairs in the range of 6 to 12 years were tested. The zygosity was determined by DNA-fingerprinting. The measures under investigation were activity (microevents and spatial scaling), impulsivity (errors of commission), and attention (accuracy and variability). For statistical analyses, the classical model of Falconer and the ACE and ADE genetic model for twin data were applied in order to estimate the proportion of the variance in activity, impulsivity and attention that is due to genetic effects. Results: The respective coefficients of intraclass correlations in MZ twins ranged between .35 and .65 whereas for DZ twins the correlations were between .12 and .88. The heritability estimates resulting from both models were about 30% for 4 of the 5 measures, but none of these was significantly different from 0. Conclusion: We found no significant influence of genetic factors for activity, attention, and impulsivity. The authors conclude that further investigation of heritability of ADHD is necessary using larger sample sizes and objective measures.

Identification and clinical presentation of beta thalassaemia mutations in the eastern region of Saudi Arabia.

Editor—The autosomal recessive disease β thalassaemia is a common single gene disorder that poses a serious health problem in many parts of the world. According to the Human Gene Mutation Database (http://www.uwcm.ac.uk/uwcm/mg/hgmd.html) and the β-Globin Gene Server (http://globin.cse.psu.edu) about 300 sequence variants in the β globin gene have been identified up to the present. Mutations in the β globin gene have been found at carrier frequency rates ranging from 1% in some areas of Saudi Arabia to 15% in others.1 Both β° and β+ thalassemia have been reported.2 Studies on the molecular pathogenesis of β thalassaemia have shown that the mutations encountered in Arab countries close to the Mediterranean basin are the same as those reported in other Mediterranean populations.3 In the Gulf region, in Saudi Arabia, UAE, and Iraq, the Asian pattern of mutations seems to be prevalent.4 5 The precise genetic changes prevalent in the different regions of the large country of Saudi Arabia and analysis of the genotype/phenotype relationship of the disease in Saudi patients still remain inadequately studied. The present study aimed to investigate the mutational pattern of the β globin gene and to explore the relationship between these mutations and disease presentation in a group of patients with β thalassaemia major from the eastern region of Saudi Arabia. For this purpose, 31 children diagnosed with β thalassaemia major who over the past two years had regularly attended the paediatric clinics of Qatif Central Hospital or Dammam Maternity and Children Hospital were selected. Within this group of patients there were four pairs of sibs and one pair of first cousins. The whole β globin gene of all patients was amplified using standard PCR techniques and six specially designed different primers for …

Characterization of High-Avidity Cytomegalovirus-Specific T Cells with Differential Tetramer Binding Coappearing after Allogeneic Stem Cell Transplantation

CMV reactivation is a major complication after allogeneic stem cell transplantation (SCT). Immune reconstitution of CMV-specific CTLs (CMV-CTLs) is essential for virus control. During CMV-CTL monitoring using mutated HLA/CMV tetramers selectively detecting high-avidity T cells, we observed coappearance of CMV-CTLs with low (CMV tetlow CTLs) and high tetramer binding (CMV tethigh CTLs) in 53/115 CMV IgG+ patients stem cell transplanted from CMV IgG+ donors. However, the relevance of these coappearing differentially tetramer binding (“dual”) CMV-CTLs was unclear. In this study, we investigated the kinetics, properties, and clinical impact of coappearing CMV tetlow and tethigh CTLs after allogeneic SCT. Patients with dual CMV-CTLs had more CMV tethigh than tetlow CTLs. Chimerism analysis of isolated CMV tetlow and tethigh CTLs revealed their exclusive donor origin. CMV tetlow and tethigh CTLs had an identical effector memory CD45RA−CCR7− and CD45RA+CCR7− T cell distribution, equal differentiation, senescence, and exhaustion marker expression and were negative for regulatory CD8+ T cell markers. Isolated CMV tetlow and tethigh CTLs were equally sensitive to CMV peptides in IFN-γ release and cytotoxicity assays. However, CMV tethigh CTLs proliferated more in response to low CMV peptide concentrations than tetlow CTLs. TCR repertoire analysis revealed that CMV tetlow and tethigh CTLs use different TCRs. Finally, dual CMV-CTLs were not associated with CMV antigenemia. In conclusion, these data show for the first time, to our knowledge, that both CMV tetlow and tethigh CTLs are functional effector T cells differing by proliferation, numbers in peripheral blood, and probably by their precursors without increasing the CMV reactivation risk after allogeneic SCT.

Possible Impact of Cytomegalovirus-Specific CD8+ T Cells on Immune Reconstitution and Conversion to Complete Donor Chimerism after Allogeneic Stem Cell Transplantation

Complete donor chimerism is strongly associated with complete remission after allogeneic stem cell transplantation (allo-SCT) in patients with hematologic malignancies. Donor-derived allo-immune responses eliminate the residual host hematopoiesis and thereby mediate the conversion to complete donor chimerism. Recently, cytomegalovirus (CMV) reactivation was described to enhance overall T cell reconstitution, to increase graft-versus-host disease incidence, and to reduce the leukemia relapse risk. However, the link between CMV and allo-immune responses is still unclear. Here, we studied the relationship between CMV-specific immunity, overall T cell reconstitution, and residual host chimerism in 106 CMV-seropositive patients transplanted after reduced-intensity conditioning including antithymocyte globulin. In accordance with previous reports, the recovery of CMV-specific cytotoxic T cells (CMV-CTLs) was more frequent in CMV-seropositive recipients (R) transplanted from CMV-seropositive than from seronegative donors (D). However, once CMV-CTLs were detectable, the reconstitution of CMV-specific CTLs was comparable in CMV R+/D- and R+/D+ patients. CD3+ and CD8+ T cell reconstitution was significantly faster in patients with CMV-CTLs than in patients without CMV-CTLs both in the CMV R+/D- and R+/D+ setting. Moreover, CMV-CTL numbers correlated with CD3+ and CD8+ T cell numbers in both settings. Finally, presence of CMV-CTLs was associated with low host chimerism levels 3 months after allo-SCT. In conclusion, our data provide a first indication that CMV-CTLs in CMV-seropositive patients might trigger the reconstitution of T cells and allo-immune responses reflected by the conversion to complete donor chimerism.