Diplotypes of the human serotonin 1B receptor promoter predict growth hormone responses to sumatriptan in abstinent alcohol-dependent men.

BACKGROUND: Some studies have associated alcohol dependence (AD) with the human serotonin (5-HT)(1B) receptor (HTR1B). This investigation explored the functional responsivity of HTR1B in abstinent AD men using a sumatriptan challenge, while measuring genetic heterogeneity in the HTR1B promoter. METHODS: Abstinent AD men (n = 27) and abstinent men without any alcohol use disorder (n = 19) were administered 6 mg of sumatriptan succinate, subcutaneously. Plasma samples collected over the following 2 hours were assayed for growth hormone (GH) concentrations. His DNA was genotyped for the A-161T and T-261G polymorphisms of the HTR1B promoter and diplotypes determined. RESULTS: Integrated GH responses were predicted by interactions of AD and promoter diplotypes, as well as subject ethnicity. The final model accounted for nearly 35% of the variance in GH responses. Post hoc evaluation revealed that AD was associated with a blunting of GH secretion only among individuals with the most common HTR1B diplotype (TT/TT). CONCLUSIONS: A blunting of GH responses in abstinent AD men was observed only among those with the most common HTR1B promoter diplotype. Less common promoter diplotypes appeared protective. Controlling for genetic background is a useful augmentation of case-control pharmacological challenge strategies designed to elucidate the psychobiology of AD and other complex disorders.     

Bone loss detection in rats using a mouse densitometer.

Estrogen-depletion bone-loss studies often use ovariectomized (ovx) rats and measure bone mineral density in vivo or ex vivo using DXA. Recently, a portable densitometer (PIXImus) was developed for mouse research; however, its use in rats is unclear. This study compared the ability of PIXImus and a standard densitometer (DPXL) to detect ovx-induced bone loss in rats both in vivo and ex vivo. Additionally, instrument accuracy was assessed by comparing measured bone mass with ash weight. Finally, the use of two distal femur regions of interest (ROI) to detect ovx-induced bone loss was evaluated. Twenty-three 6-month-old nulliparous female Sprague-Dawley rats were randomly assigned to sham or ovx groups. Distal femur bone mineral density was assessed at baseline and at 1 and 2 months postoperatively, using a PIXImus and DPXL densitometer. At 3 months postoperatively, all animals were killed, and ex vivo femur scans obtained. Distal femur bone loss was demonstrable by 1 month post-ovx using either densitometer. With the PIXImus, a 4-mm ROI demonstrated greater bone loss (p < 0.05) than an 8-mm ROI. Using the 4-mm ROI, similar amounts of bone loss were detected by the PIXImus and DPXL: 22.2% and 22.4%, respectively, at 2 months post-ovx. Total femur bone mineral content was overestimated by the PIXImus but highly correlated with the DPXL measurement (r = 0.988) and ash weight (r = 0.998). Given its comparability to standard DXA plus its rapid scan speed and portability, the PIXImus is useful in evaluating ovx-induced osteopenia in rats.     

Electroencephalographic sleep measures in prepubertal depression.

Two nights of electroencephalographic (EEG) sleep recording were performed in a group of prepubertal subjects with major depressive disorder (MDD) (n = 36, mean age = 10.4, SD = 1.5) and age-matched normal control children (n = 18, mean age = 10.1, SD = 1.6). All subjects were medically healthy and free of medications at the time of the study. There were no significant group differences for any major sleep variable after the initial adaptation night in this study. One subgroup of MDD subjects (n = 8) showed reduced REM latency on both recording nights, decreased stage 4 sleep, and increased REM time; this subgroup had significantly higher severity scores for depression but did not otherwise appear to be clinically distinct from the rest of the MDD subjects. Overall, the results indicate that the EEG sleep changes associated with depression in adults occurred less frequently in prepubertal MDD subjects.     

Disposition of the neuroleptic zuclopenthixol cosegregates with the polymorphic hydroxylation of debrisoquine in humans

The pharmacokinetics of a single oral dose of the neuroleptic drug zuclopenthixol (10 or 6 mg) was studied in 6 extensive and 6 poor metabolizers of debrisoquine. The peak plasma concentrations of zuclopenthixol did not differ between the phenotypes, whereas the plasma elimination half-life was significantly longer in poor than in extensive metabolizers (29.9 +/- 6.6 vs 17.6 +/- 6.9 h). Accordingly, the total oral plasma clearance was lower in poor than in extensive metabolizers (0.78 +/- 0.27 vs 2.12 +/- 0.65 1/h/kg). Ten of the volunteers had previously participated in a similar study in which the kinetics of perphenazine, another neuroleptic drug, were studied in poor and in extensive metabolizers of debrisoquine. There was a significant correlation between the oral clearance of perphenazine and that of zuclopenthixol among these 10 subjects. The study indicates that the disposition of zuclopenthixol, as well as that of perphenazine, is related to the genetically determined capacity to hydroxylate debrisoquine. The significance of this polymorphism for the clinical use of neuroleptics is discussed.     

The Reactivity of Psychosis Rating Form (RPRF): background,development and psychometrics

The ICD-10 and DSM-IV classifications have both given low priority to “reactivity” to acute stress as a classificatory principle for functional psychoses. In Scandinavia, reactivity is still considered an important factor in the development of such psychoses. Reactivity is a complex concept, and its various components are historically examined. The Reactivity of Psychosis Rating Form (RPRF) was developed in order to operationalize reactivity. Seven of the 10 elements of RPRF can be rated reliably. Factor analysis of the RPRF yields three factors: stressor, onset and change, that also show high interrater reliability. Our results indicate that RPRF has both construct and discriminant validity. Further studies with the RPRF may elucidate the true status of reactivity in functional psychoses.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Serum TABM produced during anterior chamber-associated immune deviation passively transfers suppression of delayed-type hypersensitivity to primed mice

Injection of soluble protein antigen into the anterior chamber of the eye of primed mice induces anterior chamber-associated immune deviation (ACAID) which is manifested by suppression of delayed-type hypersensitivity (DTH) to the antigen. Recently, we found that ACAID induced in primed mice also results in a rapid rise in serum of soluble T lymphocyte-derived proteins specific for nominal antigen (TABM). Here, we demonstrate that serum TABM induced in primed mice during ACAID will transfer the suppression of DTH to mice primed to the same antigen. Sera from TNP-BSA-primed mice that received an anterior chamber injection of TNP-BSA, but not BSA alone, suppressed the DTH response to TNP when injected into other TNP-BSA-primed mice. Sera absorbed with Sepharose beads conjugated with either anti-TCR C(alpha), anti-TCR C(beta), anti-TABM or TNP-BSA did not contain TNP-specific TABM and did not transfer suppression of DTH. These results suggest that the antigen-specific, TCR C(alphabeta)+ TABM that appear in serum during ACAID are able to confer on or amplify the capacity of sensitized T cells to suppress DTH. We believe this to be the first demonstration of an in vivo immunologic function that is specifically associated with TABM produced in vivo.      

IL-10-driven immunoglobulin production by B lymphocytes from IgA-deficient individuals correlates to infection proneness

In search for a possible explanation of the phenotypic heterogeneity in IgA deficiency, we studied the function of B cells from IgA-deficient (IgAd) individuals. Two groups of IgAd individuals, one frequently infected and one clinically apparently healthy, as well as normal controls, were studied. Peripheral blood mononuclear cells (PBMC) and B cells from IgAd individuals and controls were cultured with Staphylococcus aureus Cowan I strain and with anti-CD40 MoAb presented on the CD32-transfected fibroblast cell line in the presence of IL-10. In this experimental system PBMC and B cells from the infection-prone IgAd individuals produced only minute amounts of IgA. In contrast, PBMC and B cells from healthy IgAd subjects secreted significantly more IgA1 and IgA2 in comparison with infection-prone IgAd patients (P < 0.05). These data suggest that the abnormalities of B cell differentiation in IgAd could be of heterogeneous origin. Thus, whereas in healthy IgAd subjects IgA production may be efficiently up-regulated in vitro by addition of IL-10 to CD40-activated B cell culture, the corresponding B cell differentiation does not occur in infection-prone IgAd patients. These observations provide a conceptual framework for phenotypic heterogeneity in IgAd subjects.     

Immunotherapy in patients allergic to cat and dog dander

Twenty-four asthmatics allergic to cat and/or dog dander were included in a study to examine the efficacy and safety of immunotherapy (IT) with partially purified, standardized extracts of cat or dog dander. In the first placebo controlled, double-blind part of the study, 10 patients were treated with extracts of both cat and dog, 12 with cat extracts and 2 with dog extracts. Fifteen patients received active IT and 9 placebo injections. Patients treated with both extracts received active extracts only, or placebo only. Bronchial allergen challenge after 5 months demonstrated a significant fall in sensitivity to cat (P = 0.04) in patients treated with cat extracts. No significant changes were found in sensitivity to dog after treatment with dog dander extract or in the placebo groups. During this period, bronchial sensitivity to histamine did not change significantly in any of the groups. To examine the effect of more prolonged IT, 19 patients allergic to cat (17) and/or dog (9) were treated for 12 months. Bronchial sensitivity to cat decreased further (P = 0.003), while no significant change was found in dog extract-treated patients. In cat extract-treated patients a significant decrease in bronchial histamine sensitivity developed (P = 0.02). Systemic side effects were few, but in some cases, local side effects were a dose-limiting factor. This study demonstrated that IT with cat extract may benefit cat-allergic asthmatics, whereas no influence of IT with dog extract was detected in dog-sensitive asthmatics.     

Analysis of the immune response to Mycobacterium avium subsp. paratuberculosis in experimentally infected calves

Johne's disease of cattle is widespread and causes significant economic loss to producers. Control has been hindered by limited understanding of the immune response to the causative agent, Mycobacterium avium subsp. paratuberculosis, and lack of an effective vaccine and sensitive specific diagnostic assays. The present study was conducted to gain insight into factors affecting the immune response to M. avium subsp. paratuberculosis. A persistent proliferative response to M. avium subsp. paratuberculosis purified protein derivative and soluble M. avium subsp. paratuberculosis antigens was detected in orally infected neonatal calves 6 months postinfection (p.i.) by flow cytometry (FC). CD4(+) T cells with a memory phenotype (CD45R0(+)) expressing CD25 and CD26 were the predominant cell type responding to antigens. Few CD8(+) T cells proliferated in response to antigens until 18 months p.i. gammadelta T cells did not appear to respond to antigen until 18 months p.i. The majority of WC1(+) CD2(-) and a few WC1(-) CD2(+) gammadelta T cells expressed CD25 at time zero. By 18 months, however, subsets of gammadelta T cells from both control and infected animals showed an increase in expression of CD25, ACT2, and CD26 in the presence of the antigens. Two populations of CD3(-) non-T non-B null cells, CD2(+) and CD2(-), proliferated in cell cultures from some control and infected animals during the study, with and without antigen. The studies clearly show multicolor FC offers a consistent reliable way to monitor the evolution and changes in the immune response to M. avium subsp. paratuberculosis that occur during disease progression.