The major histocompatibility complex region marked by HSP70-1 and HSP70- 2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat- shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.     

The circadian protein period 1 contributes to blood pressure control and coordinately regulates renal sodium transport genes

The circadian clock protein period 1 (Per1) contributes to the regulation of expression of the α subunit of the renal epithelial sodium channel at the basal level and in response to the mineralocorticoid hormone aldosterone. The goals of the present study were to define the role of Per1 in the regulation of additional renal sodium handling genes in cortical collecting duct cells and to evaluate blood pressure (BP) in mice lacking functional Per1. To determine whether Per1 regulates additional genes important in renal sodium handling, a candidate gene approach was used. Immortalized collecting duct cells were transfected with a nontarget small interfering RNA or a Per1-specific small interfering RNA. Expression of the genes for α-epithelial sodium channel and Fxyd5, a positive regulator of Na, K-ATPase activity, decreased in response to Per1 knockdown. Conversely, mRNA expression of caveolin 1, Ube2e3, and ET-1, all negative effectors of epithelial sodium channel, was induced after Per1 knockdown. These results led us to evaluate BP in Per1 KO mice. Mice lacking Per1 exhibit significantly reduced BP and elevated renal ET-1 levels compared with wild-type animals. Given the established role of renal ET-1 in epithelial sodium channel inhibition and BP control, elevated renal ET-1 is one possible explanation for the lower BP observed in Per1 KO mice. These data support a role for the circadian clock protein Per1 in the coordinate regulation of genes involved in renal sodium reabsorption. Importantly, the lower BP observed in Per1 KO mice compared with wild-type mice suggests a role for Per1 in BP control as well.     

Medicaid and privately financed orthodontic patients have similar occlusal and psychosocial outcomes

Objective: This study compares occlusal and psychosocial outcomes from comprehensive orthodontic treatment in Medicaid (MC) and privately financed (private pay, PP) patients. Methods: Two cohorts received comprehensive orthodontics: MC (n = 66); PP (n = 60). A calibrated, blinded examiner scored dental casts at baseline (pretreatment, T1) and after completing 2 years of treatment (posttreatment, T2) using the Peer Assessment Rating (PAR) and the Index of Complexity, Outcome, and Need (ICON). The prevalence of patients in the validated ICON categories for treatment need, complexity, and improvement were calculated. Questionnaires to assess body image (BI) and expectations/experiences were administered. Occlusal measures at T2 were compared after adjustment for baseline characteristics. Psychosocial measures were compared between and within groups. Occlusal and psychosocial associations were evaluated. Results: MC was 1.3 years younger (P < 0.001) and had worse malocclusions at baseline (PAR 32 versus 25; P < 0.001); (ICON 64 versus 56; P = 0.06). After adjustment for age and initial severity, estimated average differences between groups at T2 (MC‐PP) were slight: 1.5 [95 percent confidence interval (CI) ?2.9, 5.9] and 2.4 (95 percent CI ?4.4, 8.9) for PAR and ICON, respectively. More PP completed treatment under 2 years (85 percent versus 62 percent; P = 0.03). At baseline, both groups needed treatment, but MC malocclusions were more complex (P = 0.05). At T2, both groups were acceptable and there were no differences in ICON improvement categories. Group differences in psychosocial measures and associations between psychosocial and occlusal measures were evident in the “teeth” domain but weak or lacking elsewhere. Conclusions: Occlusal and psychosocial outcomes from orthodontics in MC and PP were comparable, despite worse MC malocclusions at baseline.     

Modality shift effects mimic multisensory interactions: an event-related potential study

A frequent approach to study interactions of the auditory and the visual system is to measure event-related potentials (ERPs) to auditory, visual, and auditory-visual stimuli (A, V, AV). A nonzero result of the AV ? (A + V) comparison indicates that the sensory systems interact at a specific processing stage. Two possible biases weaken the conclusions drawn by this approach: first, subtracting two ERPs from one requires that A, V, and AV do not share any common activity. We have shown before (Gondan and Röder in Brain Res 1073–1074:389–397, 2006) that the problem of common activity can be avoided using an additional tactile stimulus (T) and evaluating the ERP difference (T + TAV) ? (TA + TV). A second possible confound is the modality shift effect (MSE): for example, the auditory N1 is increased if an auditory stimulus follows a visual stimulus, whereas it is smaller if the modality is unchanged (ipsimodal stimulus). Bimodal stimuli might be affected less by MSEs because at least one component always matches the preceding trial. Consequently, an apparent amplitude modulation of the N1 would be observed in AV. We tested the influence of MSEs on auditory-visual interactions by comparing the results of AV ? (A + V) using (a) all stimuli and using (b) only ipsimodal stimuli. (a) and (b) differed around 150 ms, this indicates that AV ? (A + V) is indeed affected by the MSE. We then formally and empirically demonstrate that (T + TAV) ? (TA + TV) is robust against possible biases due to the MSE.     

The novel use of a biodegradable stent placed by percutaneous transhepatic cholangiography for the treatment of a hepaticojejunostomy biliary leak following an extended left hepatectomy and pancreaticoduodenectomy

A 61-year-old man presented with jaundice, and subsequently underwent an extended left hepatectomy and pancreaticoduodenectomy for a cholangiocarcinoma invading the head of the pancreas. The patient developed sepsis due to a biliary leak at the hepaticojejunostomy. We describe the original use of a biodegradable stent, deployed via percutaneous transhepatic cholangiography into the Roux limb, resulting in good drainage and resolution of sepsis. The chief benefit of this procedure is the lack of need for subsequent removal as well as purported reduced biofilm accumulation. We believe this to be the first reported case of this type and the literature surrounding the subject is also discussed.