Plasma IL-6 levels correlate with clinical and ultrasound measures of arthritis in patients with systemic lupus erythematosus.

OBJECTIVE: The objective of this paper is to elucidate the role of specific cytokines in lupus (SLE) arthritis. METHODS: Fifty SLE and 40 RA patients had an ultrasound (US) scan of their hand as per standardized protocols. US scores were expressed per joint and as a total 'US activity' score, (sum of power Doppler (PD) and grey-scale synovial hypertrophy scores in all joints) and a total erosion score. SLE disease activity was assessed (BILAG and SELENA-SLEDAI). Plasma levels of IL-6, TNF-alpha and BLyS were measured using sandwich ELISA kits (Quantikine kits, R & D). RESULTS: On the basis of the US results SLE patients were divided into three groups: erosive arthritis (n = 20), non-erosive arthritis (n = 18) and those with a normal US scan (n = 12). Across the SLE groups plasma IL-6 levels correlated with CRP (p < 0.001), hand deformity scores (p = 0.005), BILAG musculoskeletal score (p = 0.009), wrist PD score (p = 0.01), the presence of tenosynovitis (p = 0.008) and total US activity score (p < 0.001) (which remained constant when corrected for total BILAG score). Neither TNF-alpha nor BLyS levels correlated with US or clinical measures of lupus arthritis; however, TNF-alpha correlated with total BILAG score (p < 0.001). CONCLUSION: This is the first study to examine levels of specific cytokines in a cohort of SLE patients stratified in terms of joint disease by US, where the most significant finding is that IL-6 levels correlated both with clinical and US measures of arthritis disease activity.

Re-evaluation of inhibin alpha subunit as a tumour suppressor in prostate cancer.

Inhibin is a member of the TGF-beta superfamily of growth and differentiation factors and a tumor suppressor. Consistent with the tumor suppressive function of the inhibin alpha subunit in prostate cancer, we reported a loss of gene expression due to DNA hypermethylation and loss of heterozygosity (LOH) as well as down regulation of inhibin alpha subunit immunoreactivity. Paradoxically, an expanded study to evaluate the prognostic significance of inhibin alpha subunit expression in men with prostate cancer resulted in a contradictory outcome, whereby an up-regulation of subunit expression was recorded. In seeking a more comprehensive explanation for all data sets, we offer a unifying hypothesis. We propose that the tumor suppressor activities of the inhibin alpha subunit dominate in non-malignant tissue, but its oncogenic activities emerge during tumorigenesis. An explanation such as this, involving a switch in gene function from being tumor suppressive to pro-oncogenic, may account for the discrepant findings in other types of cancer.

Epigenetic regulation of inhibin alpha-subunit gene in prostate cancer cell lines.

Inhibin was first identified as a gonad-derived regulator of pituitary FSH; however, it has subsequently been shown to be a tumour suppressor in the gonad and adrenal glands. Whereas non-malignant regions of human primary prostate carcinomas express inhibin alpha-subunit (INHA), malignant tissues lack INHA transcript and protein, which is consistent with epigenetic regulation of the inhibin alpha-subunit gene (INHA) promoter. This study investigated whether methylation of the INHA promoter was responsible for inactivation of INHA transcription and translation in the prostate cancer cell lines, LNCaP, DU145 and PC3. Methylation of the promoter was revealed by bisulphite genomic sequencing and use of inhibitors of methylation and histone deacetylation resulted in reactivation of the INHA transcription and translation. Significant (P<0.05) downregulation of a luciferase reporter gene downstream from a methylated INHA promoter compared with unmethylated INHA promoter occurred in vitro. The data demonstrate that promoter methylation is associated with downregulation of the INHA gene in prostate cancer cell lines, which is consistent with its tumour suppressive role. Therefore INHA has a significant role in prostate tumorigenesis.

Determinants of compliance with nasal continuous positive airway pressure treatment applied in a community setting.

Objectives: To assess determinants of nasal continuous positive airway pressure (CPAP) compliance when applied in a community setting.Background: One-third of obstructive sleep apnea patients eventually refuse CPAP therapy. Treatment outcomes may be improved by identifying predictors of CPAP failure, including whether management by primary care physicians without sleep consultation affects results.Methods: Polysomnogram, chart review, and questionnaire results for regular CPAP users (n=123) were compared with those returning the CPAP machine (n=26).Results: Polysomnographic data and the presence of multiple sleep disorders were only modestly predictive of CPAP compliance. Striking differences in questionnaire responses separated CPAP users from non-users, who reported less satisfaction with all phases of their diagnosis and management. Rates of CPAP use were not significantly different between patients managed solely by their primary care physician or by a sleep consultant.Conclusions: Polysomnographic findings are unlikely to identify eventual CPAP non-compliers in a cost-effective fashion. Improvements in sleep apnea management may result from addressing the role of personality factors and multiple sleep disorders in determining compliance. In this practice setting, management by primary care physicians did not significantly degrade CPAP compliance.

Activins as regulators of branching morphogenesis.

Development of glandular organs such as the kidney, lung, and prostate involves the process of branching morphogenesis. The developing organ begins as an epithelial bud that invades the surrounding mesenchyme, projecting dividing epithelial cords or tubes away from the site of initiation. This is a tightly regulated process that requires complex epithelial-mesenchymal interactions, resulting in a three-dimensional treelike structure. We propose that activins are key growth and differentiation factors during this process. The purpose of this review is to examine the direct, indirect, and correlative lines of evidence to support this hypothesis. The expression of activins is reviewed together with the effect of activins and follistatins in the development of branched organs. We demonstrate that activin has both negative and positive effects on cell growth during branching morphogenesis, highlighting the complex nature of activin in the regulation of proliferation and differentiation. We propose potential mechanisms for the way in which activins modify branching and address the issue of whether activin is a regulator of branching morphogenesis.

Seed Transmission of the High Plains virus in Sweet Corn.

The High Plains virus (HPV), which infects corn and other cereals, was first found in 1993 in the United States. Research was initiated in 1995 to investigate the potential for seed transmission of HPV. Sweet corn seeds of various cultivars harvested in 1994 to 1996 from 13 fields and research plots in southwestern Idaho, Colorado, and Nebraska were seeded in potting mix in the greenhouse. Leaf samples collected at the three- to six-leaf stage from both symptomatic and asymptomatic plants were tested by enzyme-linked immunosorbent assay (ELISA). Of the 46,600 seeds planted, 38,473 seedlings emerged, and three tested positive by ELISA, exhibited mosaic symptoms, and had the presence of HPV confirmed by an additional test. One of the positive plants was used for successful acquisition and transmission of HPV by the wheat curl mite to Westford barley. The other two plants were used to successfully transfer HPV to other corn plants by vascular puncture inoculation of seed. These results indicate that HPV can be seed transmitted at a very low frequency in sweet corn.

Effect of the androgen receptor CAG repeat polymorphism on transcriptional activity: specificity in prostate and non-prostate cell lines.

The action of androgens is essential for the development of benign prostatic hyperplasia and carcinoma of the prostate. The androgen receptor is a ligand-dependent nuclear transcription factor. The transcriptional activation domain of the androgen receptor gene contains a polymorphic CAG repeat sequence. A shorter CAG repeat sequence within the normal range has been reported to be associated with increased risk of prostate cancer and symptomatic benign prostatic hyperplasia. Here, we examine the in vitro transcriptional activity of the androgen receptor (AR) with different numbers of CAG repeats within the normal range in a number of different cell lines of prostatic (LNCaP, PC3) and non-prostatic (COS-1, MCF7) origin. We utilize a luciferase reporter driven by the rat probasin promoter (-286/+28) containing two androgen receptor binding sites. Transcriptional activation of the androgen responsive reporter was observed to be greater with the AR containing 15 vs 31 CAG repeats in COS-1 cells (123.2+/-16.6 vs 78.2+/-10.9, P value 0.01) and the well differentiated prostate cancer cell line LNCaP (103.4+/-17.7 vs 81.4+/-7.7, P value 0.045). No difference was observed in the poorly differentiated prostate cancer cell line, PC3 (106.9+/-21.9 vs 109. 6+/-21.4, P>0.5) or the breast cancer cell line MCF7 (120.4+/-39.4 vs 103.1+/-23.1, P value >0.5). Dose-response experiments with varying quantities of ligand (0.01, 0.1, 1 and 10 nM dihydrotestosterone) or AR cDNA did not demonstrate significant differences in transactivation of the androgen responsive reporter in PC3 cells by the different AR constructs. This suggests that the lack of influence of CAG number in this prostatic cell line is not related to dose of ligand or quantity of androgen receptor. Western immunoblot analysis of androgen receptor protein in transiently transfected COS-1 cells did not demonstrate a difference in the expression of the androgen receptor protein with different numbers of CAG repeats following incubation in the presence or absence of androgen. Gel shift assay did not demonstrate increased DNA binding by androgen receptor with a shorter CAG repeat sequence. These experiments using a relatively androgen- and prostate-specific reporter provide evidence for an inverse relationship between androgen receptor transcriptional activity and the number of CAG repeats in the transcriptional activation domain. The effect of CAG repeat number was cell specific suggesting the involvement of accessory factors expressed differentially between different cell lines.

The nurse who is the patient: a personal perspective.

The author, a registered nurse, describes her personal experience living with a chronic illness. The emotional turmoil she experienced as a patient with ulcerative colitis and later as a patient with a J-pouch heightened her awareness of the importance of learning self-management skills and the necessity of emotional support for all patients with a chronic illness. Implications for nurses are discussed throughout the article.

Diagnosis and treatment of sleep apnea within the community. The Walla Walla Project.

BACKGROUND: Patients with sleep disorders are common in primary care, yet most physicians lack training in the diagnosis and treatment of such patients. OBJECTIVES: To enhance recognition of sleep disorders by community physicians and transfer the diagnostic testing and care of such patients from tertiary care centers to the local community. To present our polysomnogram experience relevant to sleep apnea. METHODS: Sleep disorders specialists provided a community with education, diagnostic equipment, and ongoing support as sleep disorders expertise was established locally. Outcomes for a 2-year period were assessed by chart review, patient questionnaire, tabulation of polysomnographic data, and comparison with published reports from specialized centers. RESULTS: Referral for sleep testing increased by almost 8-fold in patients at the Walla Walla Clinic in Walla Walla, Wash, from 0.27% (2 of 752 cases reviewed) to 2.1% (294 of 14330 internal medicine patients). Data were collected from all community physicians for a 2-year period on 360 new patients who underwent polysomnogram testing. This resulted in the diagnosis of sleep-related breathing disorders in 81% and periodic leg movements of sleep in 18%. Nasal continuous positive airway pressure treatment was given to 228 patients (average baseline apnea index of 19.1), representing a higher volume of patients than at many traditional sleep centers, yet compliance with continuous positive airway pressure was comparable. CONCLUSIONS: Sleep apnea is significantly underrecognized by primary care physicians. As a result of the intervention, local sleep expertise was established and large numbers of patients were discovered and treated in the community. Thus, a significant public health problem is identified and a solution established.

Factors associated with dangerous behavior in forensic inpatients: results from a pilot study.

This study was designed to identify risk factors associated with violence within a forensic inpatient hospital setting. The primary purpose was to develop a screening tool to aid in the rapid identification of patients requiring high versus low security ward placement. Subjects included 232 consecutive admissions during a five-month period to a 300-bed forensic division within a public-sector psychiatric hospital. Demographic, historical, and current clinical variables were collected, and dangerous behaviors were documented by nursing staff on a daily basis. The associations between dangerous outcomes and various risk factors were examined using chi-square or t tests, as appropriate. Stepwise logistic regression analysis was performed to assess the contribution of each risk factor significantly associated with violent behavior. A strong association was found between 10 risk factors and the incidence of violence in our forensic population. These factors included current clinical factors (grossly inappropriate behavior observed on the ward, an assessment of current escape risk); historical factors (psychiatric hospitalization history, criminal history variables, and a self-report of prior violence); and one demographic variable (length of stay). Of the 10 risk factors then included in the stepwise regression analysis, four contributed significantly to the final predictive model. Grossly inappropriate behavior, patient self-report of prior violence, history of psychiatric hospitalization, and a history of 10 or more prior psychiatric hospitalizations were most predictive of a violent outcome. Although situational and environmental variables also must be incorporated into final assessments and decisions, the identified significant variables can provide an additional tool in the rapid assessment of violence potential.

An indirect radioimmunoassay for mouse casein using 125I-labeled antigen.

A new indirect radioimmunoassay was developed for detection of casein in mouse milk and in mammary tissue extract. Preincubation of rabbit gamma globulin to mouse milk casein (Ca2+-rennin precipitate) with unlabeled casein, milk, extracts of mammary tissues of late pregnancy and lactation, virtually blocked subsequent binding of 125I-labeled mouse milk casein to the antibody. Preincubation with mouse serum, bovine serum albumin, rennin, extracts of liver or immature mammary tissue had little effect on [125I]casein binding to the antibody. The inability of [125I]casein to bind to the antibody after preincubation with protein samples, which are likely to contain casein, is indicative of a specific antigen-antibody reaction. The assay is capable of detecting 0.2 mug casein, 1 mug milk proteins and 10 mug lactating mammary tissue extract. The application of the assay was also demonstrated using organ culture of the entire mammary gland. The glands treated with the lactogenic hormones, insulin + prolactin + cortisol, showed a saturation level of antibody-antigen reaction, indicating hormonal induction of casein; whereas, no reaction was observed with the non-treated gland.

Murine mammary gland RNA directed synthesis of casein in a heterologous cell-free protein synthesis system.

A cell-free protein synthesis system derived from Ehrlich ascites tumor cell ribosomes (S30) plus rabbit reticulocyte tRNA was developed and the activity of the system was dependent on rabbit reticulocyte ribosomal salt (0.5 M KC1) wash factors, The exogenous mRNAs from BALB/c mouse liver and the mammary gland were translated with a high efficiency in this heterologous cell-free system. Furthermore, the RNA from the lactating mammary gland faithfully directed the synthesis of casein. The presence of mouse casein in the reaction product was identified by radioimmunoprecipitation with mouse casein antiserum, co-electrophoresis of the reaction product and mouse casein the urea-polyacrylamide gel and by electrophoresis in sodium dodecyl sulfate (SDS) polyacrylamide gel. The major portion of the lactating mammary gland RNA directed synthesis of the milk protein in the cell-free system appeared to be analogous to alphas casein,