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B Cox

Publications and source records attributed to B Cox.

At least 55 records · Page 3Linked to original sources

Cloning and expression throughout mouse development of mfat1, a homologue of the Drosophila tumour suppressor gene fat.

We present the entire sequence of the mouse Fat orthologue (mFat1), a protein of 4,588 amino acids with 34 cadherin repeats, 27 potential N-glycosylation sites, five EGF repeats and a laminin A G-motif in its extracellular domain. A single transmembrane region is followed by a cytoplasmic domain containing putative catenin-binding sequences. mFat1 shows high homology to human FAT and lesser homology to Drosophila Fat. The sequence of this giant cadherin suggests that it is unlikely to have a homophilic adhesive function, but may mediate heterophilic adhesion or play a signalling role. Expression analysis shows that the mfat1 gene is expressed early in pre-implantation mouse development, at the compact eight cell stage. Whole-mount and section in situ analyses show that transcripts are widely expressed throughout post-implantation development, most notably in the limb buds, branchial arches, forming somites, and in particular in the proliferating ventricular zones in the brain, being down-regulated as cells cease dividing. RT-PCR detects widespread expression in the adult suggesting a role in proliferation and differentiation of many tissues and cell types.

Amino Acid Sequence↗

MHC class II associations with autoantibody and T cell immune responses to the scleroderma autoantigen topoisomerase I.

Topoisomerase I (topo I) is a major autoantigen recognized by autoantibodies in about 30% of sera from patients with systemic sclerosis (SSc). Certain HLA-DRB1 and HLA-DQB1 alleles have been reported to be associated with autoantibody and T-cell responses to topo I suggesting a T-cell dependent process. We have examined the MHC class II allele associations with anti-topo I antibodies in 16 patients with SSc compared to 250 healthy controls. Furthermore, we have studied the T cell responses to a recombinant full-length topo I molecule purified from a baculovirus expression system in eight patients with SSc and eight controls (five healthy and three with autoimmune disease). HLA-DR5 was significantly increased in patients with anti-topo I antibodies (P< 0.02). Proliferative peripheral blood mononuclear cell (PBMC) responses to soluble topo I were present in nine of 16 individuals (four of eight with SSc and five of eight controls), including the three SSc patients with anti-topo I antibodies. Homozygosity for HLA DQB1:30:Y alleles was present in five of nine responders (P< 0.03) compared to none of the non-responders. Our findings support the notion that the MHC class II background influences the ability to generate an autoimmune response to intracellular autoantigens to which the immune system may not have been tolerized. Additional factors associated with the generation of autoantibodies appear to be more intimately associated with the development of SSc.

Alleles↗

Calcium channel blockers and pain therapy.

This review focuses on the advances in the development of N-type calcium channel blockers as analgesic agents over the last 2 years. Firstly, it highlights the clinical progress with SNX-111 (Ziconotide; Elan Pharmaceuticals, Smithfield, RI) and then secondly, it outlines the various approaches being taken by researchers to design orally active, selective, small molecule modulators without the perceived disadvantages associated with SNX-111.

Animals↗

Assessment of anxiety in older adults: a community-based survey and comparison with younger adults.

The reliability and validity of existing anxiety self-report scales in elderly adults has not been adequately established, and the phenomenology of anxiety in older adults is largely unknown. In the present study, three anxiety scales and measures of depression and somatization were used to compare symptoms between older (n = 84, mean age = 75.3) and younger (n = 48, mean age = 40.3) community-dwelling adults. Results showed that the anxiety scales demonstrated good internal consistency in both age groups, although the reliabilities of the Fear Questionnaire subscales ranged from poor to good. Convergent and divergent validity were found to be variable in the older group, but this may reflect differences in anxiety as it occurs in older persons rather than psychometric problems. Anxiety symptoms did not vary with age, and levels of anxiety also remained constant. However, gender differences were found only within the older age group, with women reporting more anxiety than men. Findings are discussed with respect to current conceptualizations of anxiety in older people, as well as implications for future research.

Adult↗

Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies.

Mixed lymphohematopoietic chimerism can be induced in mice with bone marrow transplantation (BMT) after a nonmyeloablative preparative regimen that includes cyclophosphamide, anti-T-cell antibody therapy, and thymic irradiation. These mixed chimeras are resistant to the induction of graft-versus-host disease (GVHD) after delayed donor leukocyte infusions (DLIs), despite a potent lymphohematopoietic graft-versus-host reaction that converts the mixed chimeric state to a full donor one. Based on this animal model, we initiated a trial of nonmyeloablative therapy with HLA-matched or -mismatched donor BMT and DLI for refractory hematologic malignancies. Twenty-one of 36 patients enrolled in this trial received a genotypically (n = 20) or phenotypically (n = 1) HLA-matched donor transplant; results reported here are for those patients only. Preparative therapy consisted of cyclophosphamide in doses of 150 to 200 mg/kg; peritransplant antithymocyte globulin; thymic irradiation (in patients who had not received previous mediastinal radiation therapy); and cyclosporine. Eighteen of 20 evaluable patients developed persistent mixed lymphohematopoietic chimerism as defined by >1% donor peripheral white blood cells until at least day 35 posttransplantation. Ten patients received prophylactic DLI beginning 5 to 6 weeks after BMT for conversion of mixed chimerism to full donor hematopoiesis and to optimize a graft-versus-leukemia effect. Fourteen of 20 evaluable patients (70%) achieved an antitumor response; 8 of these responses were complete, and 6 were partial. Of the 8 evaluable patients who received prophylactic DLI, 6 showed conversion to full donor chimerism. Five of the 9 evaluable patients (56%) who received prophylactic DLI achieved a complete response, compared with 3 of 11 patients (27%) who did not receive prophylactic DLI. Currently 11 patients are alive, and 7 of these are free of disease progression at a median follow-up time of 445 days (range, 105-548 days) posttransplantation. Transplantation-related complications included cyclophosphamide-induced cardiac toxicity in 3 of 21 patients (14%) and grade II or greater GVHD in 6 patients (29%). One patient (5%) died from a complication of BMT, and 1 patient (5%) died from GVHD after 2 prophylactic DLIs were given for conversion of chimerism. In summary, mixed lymphohematopoietic chimerism was reproducibly induced after a novel nonmyeloablative preparative regimen incorporating chemotherapy, peritransplant antithymocyte globulin, and thymic irradiation, allowing for early administration of DLI in 10 of 21 patients. After treatment, striking antitumor responses were observed in the majority of patients with chemotherapy-refractory hematologic malignancies.

Adult↗

Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine.

Retigabine is a novel anticonvulsant with an unknown mechanism of action. It has recently been reported that retigabine modulates a potassium channel current in nerve growth factor-differentiated PC12 cells (), however, to date the molecular correlate of this current has not been identified. In the present study we have examined the effects of retigabine on recombinant human KCNQ2 and KCNQ3 potassium channels, expressed either alone or in combination in Xenopus oocytes. Application of 10 microM retigabine to oocytes expressing the KCNQ2/3 heteromeric channel shifted both the activation threshold and voltage for half-activation by approximately 20 mV in the hyperpolarizing direction, leading to an increase in current amplitude at test potentials between -80 mV and +20 mV. Retigabine also had a marked effect on KCNQ current kinetics, increasing the rate of channel activation but slowing deactivation at a given test potential. Similar effects of retigabine were observed in oocytes expressing KCNQ2 alone, suggesting that KCNQ2 may be the molecular target of retigabine. Membrane potential recordings in oocytes expressing the KCNQ2/3 heteromeric channel showed that application of retigabine leads to a concentration-dependent hyperpolarization of the oocyte, from a resting potential of -63 mV under control conditions to -85 mV in the presence of 100 microM retigabine (IC(50) = 5.2 microM). In control experiments retigabine had no effect on either resting membrane potential or endogenous oocyte membrane currents. In conclusion, we have shown that retigabine acts as a KCNQ potassium channel opener. Because the heteromeric KCNQ2/3 channel has recently been reported to underlie the M-current, it is likely that M-current modulation can explain the anticonvulsant actions of retigabine in animal models of epilepsy.

Animals↗

Cutaneous malignant melanoma in New Zealand: trends by anatomical site, 1969-1993.

BACKGROUND: Site-specific trend analysis is probably the most effective method available for assessing how the long-term trend in melanoma rates relates to changes in sun exposure and behaviour. New Zealand has very high incidence of and mortality from melanoma and the fraction of melanoma cases and deaths with a site specified has been comparatively high. METHODS: Trends in incidence and mortality from melanoma in New Zealand were analysed between 1969 and 1993, by sex and body site. A graphical representation of the trend by birth-cohort and age-period-cohort modelling were used. RESULTS: For all sites combined, the annual increase in incidence was 6.7% (95% CI : 6.3-7.1%) in men and 3.1% (95% CI : 2.3-3.7%) in women. The increase was significantly greater at each site for males. The largest increases occurred for the upper limbs in males (7.3% a year) and the trunk in females (3.8% a year). Incidence rates slowed appreciably in the later years (currently about 26/100 000 for each sex) and no further increase in lifetime risk of melanoma was observed among post World War II generations. Mortality trends paralleled those for incidence with a 25-year gap, with a more modest rate of increase (2-3% per annum for each sex), essentially due to the increased risk among generations born up to 1919 or 1924. Age-standardized death rates have now stabilized in New Zealand at about 5.5/100 000 (men) and 3.2/100 000 (women). Trends between cohorts were the most marked for sites with a likely intermittent pattern of exposure, and were consistent overall for the trunk and the limbs. CONCLUSIONS: Results support the hypothesis that changes in lifestyle factors resulted in a pattern of carcinogenic exposures that explains both the upsurge in melanoma in the last few decades and the current levelling off in incidence.

Adult↗

Determination of glutamic acid decarboxylase 65 peptides presented by the type I diabetes-associated HLA-DQ8 class II molecule identifies an immunogenic peptide motif.

Particular HLA class II allelic sequences are associated with susceptibility to type I diabetes. To understand the mechanism, knowledge of the molecular nature of the specific TCR/peptide/class II interactions involved in the disease process is required. To this end, we have introduced the diabetes-associated human class II HLA-DQ8 allele (DQA1*0301/DQB1*0302) as a transgene into mice and analyzed T cell responses restricted by this molecule to an important Ag in human diabetes, human glutamic acid decarboxylase 65. Hybridomas were used to determine the particular peptides from this Ag presented by HLA-DQ8 to T cells and to map the core minimal epitopes required for T cell stimulation. Analysis of these core epitopes reveals a motif and relevant features for peptides that are immunogenic to T cells when presented by HLA-DQ8. The major immunogenic epitopes of glutamic acid decarboxylase 65 do not contain a negatively charged residue that binds in the P9 pocket of the HLA-DQ8 molecule. PBMC from HLA-DQ8+ diabetic and nondiabetic individuals respond to these peptides, confirming that the mouse model is a useful tool to define epitopes of autoantigens that are processed by human APC and recognized by human T cells.

Animals↗

Confirmatory factor analysis of the Fear Questionnaire in injured workers with chronic pain.

In an effort to extend the validity of the Fear Questionnaire (FQ) in a sample of patients with high levels of blood/injury phobia, the FQ responses of 255 injured workers with chronic pain were subjected to confirmatory factor analysis. Results indicated that an intercorrelated three-factor model of the FQ provided a better fit to the data than unidimensional, two-factor, hierarchical three-factor, or categorical three-factor models. These findings provide further support for the factorial validity of the FQ and the corresponding multidimensional theory of fear.

Accidents, Occupational↗

Treatment preference in hypochondriasis.

Promising cognitive-behavioral and medication treatments for hypochondriasis are in the early stages of evaluation. Little is known about the treatment preferences and opinions of individuals seeking help for this problem. In this exploratory study, 23 volunteers from the community with a DSM-IV diagnosis of hypochondriasis were recruited through a newspaper advertisement. Participants were presented with a survey which included balanced descriptions of both a medication and a cognitive-behavioral treatment for intense illness concerns (hypochondriasis). The brief descriptions of the treatments discussed the time commitment required as well as the major advantages and disadvantages of each. Results showed that, relative to medication treatment, cognitive-behavioral treatment was predicted to be more effective in both the short and long terms and was rated as more acceptable. Psychological treatment was indicated as the first choice by 74% of respondents, medication by 4%, and 22% indicated an equal preference. Forty-eight percent of respondents would only accept the psychological treatment.

Adult↗

Trends by anatomic site in the incidence of cutaneous malignant melanoma in Canada, 1969-93.

Trends in melanoma incidence by anatomic site were examined in Canada where ascertainment of cancer has been of a high standard. The analysis included 41,239 malignant melanomas registered between 1969 and 1993 and used an age, period and cohort modeling approach. The estimated annual increase was 4.8% for males and 3.1% for females but slowed appreciably in the later years. The lifetime risk of melanoma appeared to have peaked with women born about 1934 and men born about 1944. The age-standardized rates have now stabilized for women and are expected to plateau for men in the near future. The largest relative increases occurred for the upper limbs followed by the trunk for both sexes. Comparable generation effects were observed for intermittently exposed sites but the patterns of trend differed between sites for men and women. This supports effects due to sex- and site-specific pattern of sun exposure. The evidence, for the first time, of more favorable trends among post-World War II generations is thought to reflect reduced exposure to UV rays. This may possibly be the earliest signs of the impact of primary prevention programs, particularly if UV radiation also acts as a tumor promoter.

Adolescent↗

The value of basal serum follicle stimulating hormone, luteinizing hormone and oestradiol concentrations following pituitary down-regulation in predicting ovarian response to stimulation with highly purified follicle stimulating hormone.

The value of gonadotrophin and oestradiol concentrations following pituitary down-regulation with leuprolide acetate in predicting ovarian response to stimulation was evaluated in three groups of women undergoing ovarian stimulation for in-vitro fertilization with highly purified follicle stimulating hormone (FSH). Leuprolide acetate was started in the midluteal phase, and either stopped at menses (IVF-SL group, n = 3), or continued throughout stimulation (IVF-LL group, n = 38; oocyte donors, n = 58). Ovarian stimulation was started on cycle day 3, after blood was drawn for down-regulated FSH, luteinizing hormone (LH) and oestradiol. Higher down-regulated LH was predictive of higher oestradiol on day 5 of stimulation in both IVF groups, and of need for fewer ampoules in the IVF-LL group, but not of oestradiol on day of human chorionic gonadotrophin (HCG) administration or number of oocytes retrieved. Higher FSH after down-regulation predicted yield of fewer oocytes in the donor and IVF-LL groups, and higher oestradiol on day 5 of stimulation, need for fewer ampoules and a shorter duration of therapy in both IVF groups. Higher oestradiol after down-regulation was associated with higher oestradiol on day 5 of stimulation and on day of HCG administration, a shorter duration of therapy and need for fewer ampoules in all groups. Whereas these results do not ascribe any predictive significance to LH, they suggest that oestradiol and FSH concentrations after down-regulation are predictive of the pattern of ovarian response to stimulation and of oocyte yield.

Adult↗

Historical cohort study of a New Zealand foundry and heavy engineering plant.

OBJECTIVES: To investigate the mortality of workers who had been exposed to asbestos, machining fluids and foundry work in a foundry and heavy engineering plant in the railway rolling stock manufacturing industry in New Zealand. METHODS: Historical cohort study design. RESULTS: For the total workforce of 3522 men employed between 1945 and 1991, follow up was 90% of person-years to 31 December 1991. Significantly increased standardised mortality ratios (SMRs) were found for all causes of death combined (SMR 1.07; 95% confidence interval (95% CI) 1.01 to 1.14), all malignancies (SMR 1.15; 95% CI 1.01 to 1.31), circulatory (SMR 1.16; 95% CI 1.07 to 1.27) and musculoskeletal diseases (SMR 3.06; 95% CI 1.39 to 5.84), all digestive cancers (SMR 1.29; 95% CI 1.04 to 1.59), all respiratory cancers (SMR 1.34; 95% CI 1.08 to 1.65), cancer of the oesophagus (SMR 1.97; 95% CI 1.01 to 3.45), and mesothelioma of the pleura (SMR 6.58; 95% CI 1.24 to 19.49). Three deaths from pleural mesothelioma were recorded, with latency times of 51, 53, and 57 years. There were no dose-response relations between exposure to asbestos, machining fluids or foundry work, or by duration of employment in the plant, and any cause of death. CONCLUSIONS: This study found small increases in risk for several causes of death among foundry and heavy engineering workers; however, these increases were small and the possible effects of smoking and other lifestyle factors could not be excluded. There was evidence of asbestos related disease in those involved in engineering work in the past.

Aged↗