Linkage analysis of candidate genes in autoimmune thyroid disease: 1. Selected immunoregulatory genes. International Consortium for the Genetics of Autoimmune Thyroid Disease

Graves' and Hashimoto's diseases are autoimmune thyroid diseases in which the genetic contribution is complex. For this reason, identification of necessary susceptibility genes has been difficult. However, a number of immunoregulatory genes have been implicated by association studies, including: CTLA-4, a recently described protein involved in antigen presentation, located on chromosome 2q33; the T-cell receptor V alpha and V beta gene complexes, located on 14q11 and 7q35, respectively; and the Ig gene complex (IgH), located on 15q11. We used polymorphic microsatellite markers located within these genes, or gene complexes, to test for linkage (rather than association), to each of these candidates. Using markers within the loci allowed us to assume a fixed recombination fraction of 0.01 in the tested model. Three hundred eight subjects from 48 multiplex families were studied, with 142 affected subjects. Using this set of families, we have previously shown evidence of linkage with a major susceptibility locus for Graves' disease (GD-1) on 14q24.3-31, with a maximum lod (logarithm + odds) score of 2.1, at a penetrance of 80% and with a dominant mode of inheritance. In the present study, we obtained consistently negative lod scores for each of the candidate genes, assuming either dominant or recessive modes of inheritance. These data, therefore, showed evidence against linkage with all the candidate genes. Unlike association studies, linkage analyses detect major genetic influences on disease susceptibility exerted by the linked loci. The lack of linkage for the immunoregulatory genes that were studied indicated, therefore, that they were not major contributors to disease etiology.     

Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sj?gren's syndrome

PURPOSE: Previous research has demonstrated that testosterone therapy causes a profound suppression of autoimmune disease in lacrimal glands of female mouse models of Sj?gren's syndrome. The aim of the present study was to determine whether other anabolic androgens, nonandrogenic steroids, or immunosuppressive agents might duplicate this hormonal effect. For comparative purposes, we also evaluated the influence of these various pharmacologic compounds on the tear volume, the magnitude of lymphocyte infiltration in the submandibular gland, and the extent of mucosal and peripheral lymphadenopathy. METHODS: Female MRL/MpJ-lpr/lpr mice were administered vehicle, steroids, or immunosuppressive compounds for 21 days after the onset of disease. Lacrimal glands and tears, as well as submandibular glands, spleens, and superior cervical and mesenteric lymph nodes were collected immediately before or after treatment and then processed for analysis. RESULTS: Our results showed that: (1) the immunosuppressive impact of testosterone on lymphocyte infiltration in lacrimal tissue was reproduced by the administration of 19-nortestosterone or cyclophosphamide, but not by therapy with 17 beta-estradiol, danazol, the experimental steroid Org 4094, cyclosporine A or dexamethasone; (2) treatment with testosterone, 19-nortestosterone, cyclophosphamide, or dexamethasone significantly reduced the extent of inflammation in salivary glands; (3) exposure to cyclophosphamide markedly diminished the size of lymphatic and splenic tissues, whereas glucocorticoid treatment only decreased the weight of superior cervical lymph nodes; and (4) administration of 17 beta-estradiol, Org 4094, or dexamethasone led to a significant decrease in tear volume. CONCLUSIONS: Overall, these results demonstrate that androgen or cyclophosphamide therapy may successfully ameliorate autoimmune expression in lacrimal and salivary glands of a female mouse model of Sj?gren's syndrome.     

Catch me if you can: are catechol- and indoleamine genes pleiotropic QTLs for common mental disorders?

The aim of this study was to determine the effect of a short-term ethinyl estradiol/levonorgestrel medication on blood flow in the uterine arteries in postmenopausal women in a prospective placebo-controlled double-blind study. Twenty-one healthy postmenopausal woman at least 2 years after menopause received 60 micrograms ethinyl estradiol (EE) for 14 days followed by 40 micrograms EE plus 125 micrograms levonorgestrel (LNG) for 12 days (total treatment period 26 days). Sonographically, uterine volume, endometrial thickness, and blood flow in the uterine arteries [as reflected by pulsatility (PI) and resistance indices (RI)] were measured. Uterine size increased from 44 to 80 mL (day 14, p < 0.001) and 87 mL (day 26, p = NS). Endometrium grew from 3 to 8 mm (day 14, p < 0.001) and 11 mm (day 26, p = NS). Uterine arterial PI fell from 2.76 to 1.37 (day 14, p < 0.001) and 1.34 (day 26, p = NS), whereas RI fell from 0.9 to 0.68 (day 14 and day 26, p < 0.001). In conclusion, short-term treatment with LNG does not antagonize the vascular effect of EE on the uterine arteries as reflected by PI and RI. This result might have clinical significance in the selection of the progestin used in hormonal replacement therapy.     

Oxygen mass transfer calculations in large arteries

Parkinsonism is characterised by overactive glutamatergic transmission in the cortico-striatal and subthalamo-medial pallidal pathways. Local blockade of glutamatergic transmission in these pathways can alleviate parkinsonian symptoms. The effectiveness of the treatment, however, is often limited by the simultaneous appearance of unwanted side-effects. These side-effects, including ataxia and dissociative anaesthesia, are particularly problematic when N-methyl-D-aspartate (NMDA) antagonists are used. In an attempt to overcome these problems we have attempted to manipulate excitatory amino acid (EAA)-mediated neurotransmission indirectly by targeting the NMDA receptor associated modulatory sites. We review evidence which demonstrates that antagonists for both the NMDA associated glycine and polyamine sites can reverse parkinsonian symptoms when injected intra-cerebrally in both MPTP-treated and bilateral 6-OHDA lesioned marmosets without eliciting unwanted side-effects. We further review preliminary data which suggest that ifenprodil, a polyamine site antagonist, has striking anti-parkinsonian actions in the marmoset. Potential mechanisms of action underlying these effects are discussed in terms of NMDA receptor subtypes and the neuroanatomical locus of action. The anti-parkinsonian efficacy of intra-striatally administered EAA antagonists leads us to question the view of dopamine acting in the striatum as a simple neuromodulator.     

Routine Highway Bridge Inspection Condition Documentation Accuracy and Reliability

Routine inspection is the most common form of highway bridge inspection to satisfy the requirements of the National Bridge Inspection Standards. The accuracy and reliability of documentation generated during these inspections are critical to the allocation of Department of Transportation construction, maintenance, and rehabilitation resources. Routine inspections are typically completed using only the visual inspection technique and rely heavily on subjective assessments made by bridge inspectors. In light of this, and given the fact that visual inspection may have other limitations that influence its reliability, the Federal Highway Administration initiated an investigation to examine the reliability of visual inspection as it is currently applied to bridges in the United States. This paper will summarize results from this study related to the accuracy and reliability of routine inspection documentation. A number of important conclusions were developed from the experimental study. Generally, it was found that all structural condition documentation is collected with significant variability. Specifically, 95% of primary element condition ratings for individual bridge components will vary within two rating points of the average and only 68% will vary within one point. Documentation generally collected to support condition ratings also has significant variability as exemplified by the number and types of field notes and photographs taken by inspectors. With respect to the use of element-level inspections, it was found that element usage was generally consistent with the Commonly Recognized Element Guide. However, there is significant variability in the condition state assignments of those elements and in some cases the condition states are not applied correctly to particular elements.     

Connections to cerebellar cortex (Larsell's HVI) in the rabbit: A WGA-HRP study with implications for classical eyeblink conditioning.

Conditioned eyeblink responses are presumably learned in the cerebellum and relayed to motoneurons by way of the red nucleus. Projections from the red nucleus to cerebellar cortex (Larsell's lobule HVI) could be important for shaping temporally adaptive features of the conditioned response. Rabbits that had pipettes containing wheat germ agglutinated horseradish peroxidase (WGA-HRP) implanted unilaterally into HVI showed retrograde labeling of neurons within subregions of the contralateral red nucleus implicated in eyeblink conditioning by lesioning and recording studies. Retrogradely labeled neurons were also observed in the pontine nuclei, inferior olive, and spinal trigeminal nucleus pars oralis. Projections to HVI provide a possible neural substrate for implementing time-derivative computational models of learning in the cerebellum. Time-derivative models are capable of describing the timing and topography of conditioned responses. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Outpatient group treatment of chronic pain: Effects of spouse involvement.

Evaluated the efficacy of outpatient group treatment of chronic pain and the effect of spouse involvement in treatment in chronic pain patients ranging in age from 23 to 69 yrs who were randomly assigned to couples group treatment (n?=?17), patient-only group treatment (n?=?14), or waiting-list controls (n?=?12). 29 Ss had low back pain; the remaining Ss reported pain in the knee, arm, leg, hip, head, and phantom limb. The Ss completed the MMPI—168 and measures of health-related psychosocial and physical dysfunction and marital satisfaction. Results indicate that the 16-hr cognitive-behavioral program produced reductions in pain, somatization, spouse-observed pain behavior, physical and psychosocial dysfunction, spouse-rated dysfunction, and utilization of health care resources. Depression was not affected by treatment. Spouse involvement did not facilitate response to treatment on any variables. Also, Ss in the individual condition only showed improved marital satisfaction. All treatment gains were maintained at 3-mo to 7-mo follow-ups. Results indicate that brief outpatient treatment can significantly ameliorate chronic pain problems, and spouse involvement is not essential for a positive response to treatment. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Creating profit with computers: my life as CEO of Bonner & Moore Associates

When Bonner & Moore was formed in 1956, few-if any-other firms were offering computer consulting services to private industry. Over the years, Bonner & Moore's software development and computer modeling projects took the company far and wide, from Texas oil refineries to the other side of the globe. Its computer services created a solid financial success.