Effects of co-occurring disorders on employment outcomes in a multisite randomized study of supported employment for people with severe mental illness

Effects of co-occurring disorders on work outcomes were explored among individuals with severe mental illness who were participating in a multisite randomized study of supported employment. At seven sites, 1,273 people were randomly assigned to an experimental supported employment program or a control condition and followed for 2 years. Multivariate regression analysis examined work outcomes including earnings, hours worked, and competitive employment, as well as whether psychiatric disability was disclosed to coworkers and supervisors. Individuals with any comorbidity had lower earnings and were less likely to work competitively. Those with physical comorbidities had lower earnings, worked fewer hours, and were less likely to work competitively. Disclosure was more likely among those with both cognitive and physical comorbidities, as well as those with learning disabilities. Competitive employment was less likely among those with intellectual disability, visual impair ment, and human immunodeficiency virus/acquired immuno-deficiency syndrome. The experimental condition was positively related to all outcomes except disclosure. The results suggest that, with some exceptions, comorbidities affect employment outcomes, requiring tailored services and supports to promote vocational success.     

Clonal dysregulation of the antibody response to tetanus-toxoid after bone marrow transplantation

After bone marrow transplantation (BMT), a prolonged dysregulation of humoral immunity can be observed. In the present study, we investigated whether this is reflected in an abnormal production of specific antibodies (Ab) to the T-cell-dependent recall antigen tetanus-toxoid (TT). The study group consisted of children receiving transplants of an unmodified allogeneic graft and of adults receiving either a T-cell- depleted allogeneic or an unmodified autologous BM graft. Findings were compared with those in healthy controls. In pediatric graft recipients, who were routinely revaccinated early after BMT, the Ab response was quantitatively superior to that in adult graft recipients who did not receive early revaccination. In the majority of graft recipients, the time period after vaccination required to reach the peak level of antibodies was prolonged and the number of responding TT-specific B- cell clones was markedly decreased in comparison with controls. In controls, a low frequency of dominant B-cell clones may produce low quantities of homogeneous Ab components (H-Ab) against a heterogeneous background. However, in BM graft recipients, "overshooting" of Ab production by separate B-cell clones was observed, resulting in the development of H-Ab at a relatively high concentration. These abnormalities were present up to 10 years after BMT, irrespective of either the age of the recipient, the modulation of the graft, or the vaccination schedule used. It is hypothesized that the dysregulated Ab production is the consequence of activation of a restricted number of resting memory B cells, present in germinal centers, repopulating gradually after BMT. Our data show that routine revaccination early after BMT improves the humoral immune response. However, because of a clonally dysregulated Ab production, long-lasting qualitative defects may be present even after normalization of Ab titers.     

Negative selection of CD4+ CD8+ thymocytes by T-cell receptor peptide antagonists.

Antigen-induced activation of T cells can be specifically inhibited by antigen analogs that have been termed T-cell receptor peptide antagonists. These antagonists appear to act by inducing the formation of nonstimulatory or partially stimulatory complexes between T-cell receptors and the major histocompatibility complex molecules presenting the peptides. Herein, we have investigated the effect of T-cell receptor peptide antagonists on thymocyte negative selection. First, peptide antagonists were identified for the cytochrome c-specific T-cell clone AD10. These peptides were then tested for their ability to induce negative selection in an in vitro model system using thymocytes from mice transgenic for the AD10 T-cell receptor. Though unable to induce mature T-cell activation, the T-cell receptor peptide antagonists induced deletion of CD4+ CD8+ thymocytes. These results suggest that negative selection of CD4+ CD8+ thymocytes can be induced by T-cell receptor interactions of a lower affinity than those required for mature T-cell activation.     

Continuous combined oestrogen/progestin therapy is well tolerated and increases bone density at the hip and spine in post-menopausal osteoporosis

OBJECTIVES Although oestrogen/progestin therapy is effective prophylaxis against post-menopausal osteoporosis, its efficacy in the treatment of established disease is uncertain. In addition, cyclical oestrogen/progestin regimens are associated with low rates of patient acceptance. The present study assesses the acceptability of, and skeletal response to, continuous combined hormone replacement therapy in osteoporotic late post-menopausal women. DESIGN Retrospective, controlled study. PATIENTS One hundred and four osteoporotic late postmenopausal women treated with continuous combined hormone replacement therapy (5 mg medroxyprogester-one acetate daily and either 0·625 mg oral conjugated oestrogens or 50 μg transdermal oestradiol daily) were followed for an average of 1 year (range 2–38 months). Control subjects were 19 healthy normal women matched for menopausal age and weight. MEASUREMENTS Adverse effects and compliance rate were monitored. Baseline and 1-year measurements of lumbar spine bone mineral density (BMD) were performed using dual-energy X-ray absorptiometry in 51 women, 22 of whom also had measurements at 2 years. Twenty-eight women had proximal femur scans at baseline and 1 year. RESULTS Eighty-six per cent of women continued to take continuous combined hormone replacement therapy at the end of follow-up. Mastalgia (44%) and vaginal bleeding (29%), the most common side-effects, were minor and self-limiting in virtually all women. Spinal BMD increased by 7·1 ± 0·8% (mean±SEM P < 0·001) at 1 year and by 8·9 ± 1·5% (P < 0·001) at 2 years. In the proximal femur, BMD increased by 2·9 ± 0·9% at the femoral neck (P= 0·01) and by 2·5±0·9% (P= 0·001) at the trochanter at 1 year. BMD tended to decline in the control group. Among the women taking hormone replacement therapy, the increase in spinal BMD was similar in those treated with 0·3–0·44 mg/day of conjugated equine oestrogens to those receiving 0·45–0·625 mg/day. CONCLUSION Continuous combined hormone replacement therapy is an acceptable therapy to osteoporotic late post-menopausal women and produces substantial increases in lumbar spine and proximal femoral bone mineral density.     

Absence of intestinal synthesis of apolipoprotein B-48 in two cases of abetalipoproteinemia

Previous studies have reported that the absence of chylomicron, very-low-density lipoprotein, and low-density lipoprotein in abetalipoproteinemia is a consequence of apoprotein B (apo B) deficiency. Although the absence of apo B from the intestine has been shown by immunofluorescence, the antiserum used was raised against low-density lipoprotein apo B. Therefore, the precise nature of the underlying defect remains unknown, given that the postulated gene mutation could prevent the synthesis of the molecular form of apo B specific for chylomicrons, apo B-48, or produce an unstable aberrant form of apo B particle. This report concerns 2 girls aged 5.5 and 4.75 with well-documented clinical and biological manifestations of the disease in whom there was no immunologically detectable plasma apo B-48 and apo B-100. Their cultured jejunal explants incubated with [14C]palmitate showed slight decrease in the esterification of triglycerides, phospholipids, and cholesteryl esters. However, only traces of triglycerides and small amounts of cholesteryl esters were found in the culture medium in contrast to phospholipids, which were readily exported. Protein synthesis as assessed by [3H]leucine incorporation by explants was normal and only modestly diminished in the fat chylomicronlike fraction floated from the sonicated explants. However, there was no radioactivity at the electrophoretic position of apo B-100 and apo B-48. Immunologic confirmation of the absence of these two apoproteins was obtained by Western blots. These data confirm the hypothesis that in certain cases of abetalipoproteinemia the intestinal defect results from the lack of synthesis of apo B-48.     

Use of lispro insulin and quality of life in adolescents on intensive therapy

PURPOSE: This study examined the metabolic and quality-of-life effects of using lispro insulin in teenagers. METHODS: Teenagers on multiple daily injections who had not reached metabolic treatment goals were offered the opportunity to use lispro insulin as part of a larger ongoing study of intensive management in youth. Of the 51 who were eligible, 35 used lispro and were followed for 12 months; the remaining 16 had reached treatment goals, were not offered lispro, and comprised the control group. RESULTS: After 12 months, the teens who received lispro insulin achieved equivalent levels of metabolic control to those achieved by teens in the control group, without differences in total daily dose, insulin regimen, or adverse events. Those who received lispro found coping with diabetes less difficult than those who continued on regular insulin, and they reported less negative impact of diabetes on quality of life and fewer worries about diabetes. Both groups were equally satisfied with their diabetes treatment. CONCLUSIONS: Lispro insulin is a safe alternative for youth on intensive regimens, may assist youth in coping with diabetes, and may improve their quality of life.     

From the Cover: PNAS Plus: Comprehensive analysis of dengue virus-specific responses supports an HLA-linked protective role for CD8+ T cells

The role of CD8⁺ T cells in dengue virus infection and subsequent disease manifestations is not fully understood. According to the original antigenic sin theory, skewing of T-cell responses induced by primary infection with one serotype causes less effective response upon secondary infection with a different serotype, predisposing individuals to severe disease. A comprehensive analysis of CD8⁺ responses in the general population from the Sri Lankan hyperendemic area, involving the measurement of ex vivo IFNγ responses associated with more than 400 epitopes, challenges the original antigenic sin theory. Although skewing of responses toward primary infecting viruses was detected, this was not associated with impairment of responses either qualitatively or quantitatively. Furthermore, we demonstrate higher magnitude and more polyfunctional responses for HLA alleles associated with decreased susceptibility to severe disease, suggesting that a vigorous response by multifunctional CD8⁺ T cells is associated with protection from dengue virus disease.Dengue virus (DENV) is the etiologic agent of dengue fever (DF), the most significant mosquito-borne viral disease in humans. Disease can be caused by any of the four DENV serotypes (DENV1 to -4), which share 67–75% sequence homology with one another (1). DENV transmission occurs in more than 100 countries and is an increasing public health problem in tropical and subtropical regions (2). Demographic changes, urbanization, and international travel contribute to the expansion of geographical areas where transmission occurs, and all four DENV serotypes are now circulating in Asia, Africa, and the Americas (3, 4). Up to 100 million DENV infections occur every year (5), and severity can range from asymptomatic to an acute self-limiting febrile illness (DF). In a small proportion of patients, the disease can exacerbate and progress to dengue hemorrhagic fever (DHF) and/or dengue shock syndrome (DSS), characterized by severe vascular leakage, thrombocytopenia, and hemorrhagic manifestations (4).Although natural infection by any of the four DENV serotypes (primary infection) produces a lasting protective immunity against reinfection by the same serotype, it does not protect against infections with other serotypes (secondary infections) (6, 7). Epidemiologic studies have shown that the majority of individuals that develop DHF/DSS had been previously infected with a different serotype (8). Consequently, the development of DENV vaccines has been hampered by the potential risk of vaccine-related adverse events and the requirement to induce long-lasting protective immune responses against all four DENV serotypes simultaneously (9). The cause for the increased frequency of DHF following secondary infections has not been fully elucidated. One hypothesis is that serotype cross-reactive antibodies exacerbate disease by increasing infection of cells bearing Fcγ receptors, resulting in higher viral loads and more severe disease via this antibody-dependent enhancement (ADE) of infection (10, 11). Indeed, nonhuman primate and murine models have demonstrated that antibodies can lead to enhancement of DENV infection and disease in vivo (12–15).Another hypothesis postulates that T cells raised against the first infecting serotype dominate during a secondary heterologous infection in a phenomenon termed “original antigenic sin” (16, 17). This term was first applied to the humoral response to influenza epidemics (18) but has also been observed in CD8⁺ T-cell responses against lymphocytic choriomeningitis virus (19). This hypothesis postulates that, during secondary infection, expansion of preexisting lower avidity cross-reactive memory T cells dominate the responses over that of naïve T cells that are of higher avidity for the new DENV serotype. This expansion of low avidity T cells results in less efficient elimination of DENV-infected cells.A role for T cells in control of DENV infection is suggested by several studies that implicate HLA associations as a genetic component to variable susceptibility to DENV disease (20–26). However, it has not been addressed whether these associations might indicate a positive or detrimental role for T-cell responses. One major obstacle to the elucidation of the function of T cells is the lack of a comprehensive characterization of HLA-restricted DENV responses in the context of natural infection.Herein, we present a comprehensive analysis of functional T-cell memory against DENV and are able to correlate this with HLA alleles expressed in the very same donors. Collectively, the data suggest an HLA-linked protective role of CD8⁺ T-cell responses and do not support a causative role for CD8⁺ T cells in the induction of severe disease following secondary heterologous infection.     

PACAP stimulation of maturational gonadotropin secretion in goldfish involves extracellular signal-regulated kinase, but not nitric oxide or guanylate cyclase, signaling

In goldfish, nitric oxide synthase (NOS) immunoreactivity is present in gonadotropes and extracellular signal-regulated protein kinase (ERK) mediates GnRH stimulation of gonadotropin release and synthesis. In this study, we tested the possible involvement of nitric oxide (NO) and ERK in mediating PACAP-stimulated maturational gonadotropin (GTH-II) release from primary cultures of dispersed goldfish pituitary cells. In static incubation experiments, PACAP-induced GTH-II release was unaffected by two inhibitors of NOS synthase, AGH and 1400W; whereas addition of a NO donor, SNAP, elevated GTH-II secretion. In perifusion experiments, neither NOS inhibitors (AGH, 1400W and 7-Ni) nor NO scavengers (PTIO and rutin hydrate) attenuated the GTH-II response to pulse applications of PACAP. In addition, the GTH-II responses to PACAP and the NO donor SNP were additive while PTIO blocked SNP action. Although dibutyryl cGMP increased GTH-II secretion in static incubation, inhibition of guanylate cyclase (GC), a known down-stream target for NO signaling, did not reduce the GTH-II response to pulse application of PACAP. On the other hand, GTH-II responses to PACAP in perifusion were attenuated in the presence of two inhibitors of ERK kinase (MEK), U 0126 and PD 98059. These results suggest that although increased availability of NO and cGMP can lead to increased GTH-II secretion, MEK/ERK signaling, rather than NOS/NO/GC activation, mediates PACAP action on GTH-II release in goldfish.     

Evidence for a functional association between phosphatidylinositol 3-kinase and c-src in the spreading response of osteoclasts to colony-stimulating factor-1

Osteoclasts are bone-resorbing cells whose normal function depends in part upon their ability to migrate over the bone surface to initiate new sites of bone resorption. The growth factor/cytokine, colony-stimulating factor-1 (CSF-1), potently stimulates osteoclast motility, in a c-src-dependent fashion. The intracellular signaling molecules that participate with c-src in CSF-1-induced remodeling of the osteoclast cytoskeleton have not been identified. Here we demonstrate, using the inhibitors wortmannin and LY294002, that activation of phosphatidylinositol 3-kinase (PI3-K) is required for CSF-1-induced spreading in osteoclasts. After CSF-1 treatment of osteoclast-like cells, PI3-K activity associated with the CSF-1 receptor c-fms, is increased, and the 85-kDa regulatory subunit of PI3-K and c-src coimmunoprecipitate. CSF-1 induces redistribution of PI3-K to the periphery of the cell. The association between p85 and c-src is due in part to a direct interaction between the proline-rich sequences of p85 and the SH3 domain of c-src. In vitro, the c-src SH3 domain stimulates PI3-K activity. Taken together, the current data suggest that c-src, via its SH3 domain, may participate in CSF-1-induced activation of PI3-K and that PI3-K and c-src are in the signaling pathway that subserves CSF-1-induced cytoskeletal changes in osteoclasts.     

T-cell receptor antagonists induce Vav phosphorylation by selective activation of Fyn kinase

T cell receptor (TCR) antagonists inhibit antigen-induced T cell activation and by themselves fail to induce phenotypic changes associated with T cell activation. However, we have recently shown that TCR antagonists are inducers of antigen-presenting cell (APC)-T cell conjugates. The signaling pathway associated with this cytoskeleton-dependent event appears to involve tyrosine phosphorylation and activation of Vav. In this study, we investigated the role played by the protein tyrosine kinases Fyn, Lck, and ZAP-70 in antagonist-induced signaling pathway. Antagonist stimulation increased tyrosine phosphorylation and kinase activity of Fyn severalfold, whereas little or no increase in Lck and ZAP-70 activity was observed. Second, TCR stimulation of Lck(-), Fyn(hi) Jurkat cells induced strong tyrosine phosphorylation of Vav. In contrast, minimal increase in tyrosine phosphorylation of Vav was observed in Lck(hi), Fyn(lo) Jurkat cells. Finally, study of T cells from a Fyn-deficient TCR transgenic mouse also showed that Fyn was required for tyrosine phosphorylation and activation of Vav induced by both antagonist and agonist peptides. The deficiency in Vav phosphorylation in Fyn-deficient T cells was associated with a defect in the formation of APC-T cell conjugates when T cells were stimulated with either agonist or antagonist peptide. We conclude from these results that Vav is a selective substrate for Fyn, especially under conditions of low-affinity TCR-mediated signaling, and that this signaling pathway involving Fyn, Vav, and Rac-1 is required for the cytoskeletal reorganization that leads to T cell-APC conjugates and the formation of the immunologic synapse.