Regulator of G protein signaling 2 is a key regulator of pancreatic ß-cell mass and function.

Pancreatic ß-cell death and dysfunction contributes to the pathogenesis of both type 1 and type 2 diabetes. We aimed to examine whether the regulator of G protein signaling protein 2 (RGS2), a multifunctional inhibitor of G protein-coupled receptor (GPCR) signaling, impacts ß-cell death and function. Metabolic phenotypes, ß-cell secretory function, and glucose and insulin tolerance were measured in RGS2 knockout (RGS2-/-) mice and their wild-type (RGS2+/+) littermate controls. ß-Cell death was evaluated in RGS2-knockdown and -overexpressing ß cells and RGS2-/- islets by flow cytometry, western blot, ELISA, TUNEL staining, and apoptosis RT2 profiler PCR array analysis. ß-Cell mass was evaluated in pancreases from RGS2-/- and RGS2+/+ mice at 1 day, 4 weeks, and 25 weeks of age. Our data show that RGS2-/- islets secreted more insulin than RGS2+/+ islets when challenged with glucose or exendin-4. RGS2-knockdown cells are susceptible to hypoxia induced cell death while RGS2-overexpressing cells are protected from cell death. Depletion of RGS2 in islets alters expression of apoptosis-related genes and RGS2-/- islets are prone to apoptosis compared with RGS2+/+ islets. Ultimately, excessive insulin secretion and increased ß-cell apoptosis contributed to a 70% reduction in pancreatic ß-cell mass in RGS2-/- mice compared with RGS2+/+ mice at 25 weeks of age. RGS2 has critical roles in maintaining pancreatic ß-cell mass via modulating ß-cell function and apoptosis. It may serve as a druggable target to help prevent pancreatic ß-cell loss in the treatment of diabetes.

The evolution of regulators of G protein signalling proteins as drug targets - 20 years in the making: IUPHAR Review 21.

Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.

Depletion of the lipid raft constituents, sphingomyelin and ganglioside, decreases serotonin binding at human 5-HT7(a) receptors in HeLa cells.

AIM: The localization and function of several G protein-coupled receptors, including beta-adrenergic receptors and NK 1 receptors, are regulated via lipid rafts in the plasma membrane. These domains are enriched in cholesterol, gangliosides and sphingolipids, and play an important role in regulating signal transduction in most cell types. Serotonin (5-hydroxytryptamine, 5-HT), acting via 14 different receptors, regulates as diverse effects as mood, metabolism and smooth muscle contraction. 5-HT(7) receptors are involved in the regulation of depression, circadian rhythms, thermoregulation and vasodilatation. Ligand binding and signalling via the 5-HT(7) receptor are regulated by membranous cholesterol. Here we investigated the role of sphingomyelin and gangliosides on binding of 5-HT to 5-HT(7) receptors to further examine the role of lipid raft constituents on 5-HT(7) receptor function. METHODS: HeLa cells stably transfected with the human 5-HT(7) receptor were treated with Fumonisin B(1) or (+/-)-threo-1-Phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) to reduce sphingomyelin or ganglioside levels, respectively. The effects of these treatments were investigated by the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) viability assay, cholesterol analysis and [(3)H]5-HT binding studies on intact cells. RESULTS: Treatments with 20 mum Fumonisin B(1) for 24 h or with 10 mum PDMP for 48 h had no effects of total levels if 5-HT(7) receptors, but caused significant decreases in maximum [(3)H]5-HT binding to 5-HT(7) receptors. The effects were cholesterol-independent as levels of cholesterol remained unaffected by either treatment. CONCLUSION: These data demonstrate a role for sphingomyelin and gangliosides in regulating binding of [(3)H]5-HT to 5-HT(7) receptors. These observations further strengthen that actions of 5-HT via 5-HT(7) receptors are dependent upon lipid raft integrity.

Parkinson's disease and other basal ganglia or movement disorders in a large nationwide cohort of Swedish welders.

INTRODUCTION: Although it has been hypothesised that metal welding and flame cutting are associated with an increased risk for Parkinson's disease due to manganese released in the welding fume, few rigorous cohort studies have evaluated this risk. METHODS: The authors examined the relation between employment as a welder and all basal ganglia and movement disorders (ICD-10, G20-26) in Sweden using nationwide and population based registers. All men recorded as welders or flame cutters (n = 49,488) in the 1960 or 1970 Swedish National Census were identified and their rates of specific basal ganglia and movement disorders between 1964 and 2003 were compared with those in an age and geographical area matched general population comparison cohort of gainfully employed men (n = 489,572). RESULTS: The overall rate for basal ganglia and movement disorders combined was similar for the welders and flame cutters compared with the general population (adjusted rate ratio (aRR) = 0.91 (95% CI 0.81 to 1.01). Similarly, the rate ratio for PD was 0.89 (95% CI 0.79 to 0.99). Adjusted rate ratios for other individual basal ganglia and movement disorders were also not significantly increased or decreased. Further analyses of Parkinson's disease by attained age, time period of follow up, geographical area of residency, and educational level revealed no significant differences between the welders and the general population. Rates for Parkinson's disease among welders in shipyards, where exposures to welding fumes are higher, were also similar to the general population (aRR = 0.95; 95% CI 0.70 to 1.28). CONCLUSION: This nationwide record linkage study offers no support for a relation between welding and Parkinson's disease or any other specific basal ganglia and movement disorders.

Acute effects of exposure to vapours of dioxane in humans.

Information on the acute effects associated with the handling of 1,4-dioxane is sparse. Our aim was to evaluate the acute effects of 1,4-dioxane vapours. In a screening study, six healthy volunteers rated symptoms on a visual analogue scale (VAS), while exposed to stepwise increasing levels of 1,4-dioxane, from 1 to 20 ppm. The initial study indicated no increased ratings at any of the exposure levels; we decided to use 20 ppm (72 mg/m3) as a tentative no observed adverse effect level (NOAEL). In the main study, six female and six male healthy volunteers were exposed to 0 (control exposure) and 20 ppm 1,4-dioxane vapour, for 2 hours at rest. The volunteers rated 10 symptoms on VAS before, during, and after the exposure. Blink frequency was monitored during exposure. Pulmonary function, and nasal swelling, was measured before, and at 0 and 3 hours after exposure. Inflammatory markers in plasma (C-reactive protein, and interleukin-6) were measured before and at 3 hours after exposure. In conclusion, exposure to 20 ppm 1,4-dioxane for 2 hours did not significantly affect symptom ratings, blink frequency, pulmonary function, nasal swelling, or inflammatory markers in the plasma of the 12 volunteers in our study.

Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study.

OBJECTIVE: To study the association between silica exposure and rheumatoid arthritis and how it is modified by cigarette smoking. METHODS: Data were analysed from 276 male cases and 276 male controls aged 18 to 70 years, included in a Swedish population based study between May 1996 and June 2001. A case was defined as a person recently diagnosed with rheumatoid arthritis according to the ACR criteria. Controls were selected from the study base as a stratified random sample accounting for age, sex, and residency. Men with a self reported history of work with rock drilling, stone crushing, or exposure to stone dust in general were defined as silica exposed. Rheumatoid factor (RF) status among cases was recorded. RESULTS: Silica exposed men had increased risk of rheumatoid arthritis, with an odds ratio (OR), adjusted for age, residential area, and smoking, of 2.2 (95% confidence interval, 1.2 to 3.9) among men aged 18 to 70 years, and 2.7 (1.2 to 5.8) among those aged 50 to 70 years. Men who had worked with rock drilling or stone crushing (regarded as highly exposed) had a slightly greater increase in risk of rheumatoid arthritis than silica exposed men in general, with an OR of 3.0 (1.2 to 7.6). The joint effects of silica exposure and smoking were compatible with synergy between these two exposures in the development of rheumatoid arthritis but this was not conclusive. CONCLUSIONS: Silica exposure is associated with increased risk of developing rheumatoid arthritis. This association is not explained by smoking habits.

In the shadow of maternal depressed mood: experiences of parenthood during the first year after childbirth.

To study the period and point prevalence of maternal depressive mood at three occasions before and after childbirth, and the relationship to the parents' psychosocial conditions and experiences of parenthood during the first year after childbirth. In a longitudinal community-based study, 434 pregnant women were invited to complete the Edinburgh Postnatal Depression Scale (EPDS) (cut-off score 9/10) at three time points. The parents' psychosocial conditions and experiences of parenthood were enquired at two months and at one year after childbirth, when the form Experience of Motherhood/Fatherhood Questionnaire (EMQ/EFQ) was applied. Three times measurement responses from both men and women were analyzed using non-parametric statistical methods and path-analysis. About 75% of the parents responded to the questionnaires. The period prevalence was 28%, and the point prevalence found on the three time points was EPDS I 21%, EPDS II 17% and EPDS III 12%. Correlations between antenatal and postnatal depressive symptoms were found, r = 0.61 and r = 0.45, respectively. Women, who experienced financial worries, lack of social support and losses and strains after childbirth showed more symptoms of depressed mood. The maternal depressive mood influenced negatively on breastfeeding and experiences of motherhood, but not on experiences of fatherhood. The partners of depressed women were neither more involved in childcare nor did they utilize paternal leave more than the other men. Both men and women reported the sexual life as negatively influenced by the women's depressed mood.

Ischaemic heart disease among livestock and agricultural workers.

BACKGROUND: Agricultural workers are exposed to organic dust containing endotoxins, mites, and moulds. AIMS: To compare the occurrence of ischaemic heart disease (IHD) among male and female livestock and agricultural workers with gainfully employed men and women in Sweden. METHODS: Male and female livestock and agricultural workers were identified in the Swedish National Censuses of 1970 and 1990 and were followed until the end of 1995. The IHD mortality among the livestock and agricultural workers was compared with that of gainfully employed men and women. Information of smoking habits was gathered from a previous national survey. RESULTS: Male as well as female livestock workers had slightly higher standardised mortality ratios (SMR) regarding IHD compared with all gainfully employed men and women in Sweden. The SMR for male workers was 1.06 (95% CI 0.95 to 1.18). The SMR for female workers was 1.10 (95% CI 0.98 to 1.23). Agricultural workers had lower SMRs. Adjustments for smoking habits would further increase the SMRs by about 9% in male workers and about 5% in female workers. CONCLUSION: The present data suggest a slightly increased risk for IHD among both male and female livestock workers, which may be the result of organic dust exposure.

Physicians' attitudes and advice concerning pregnancy subsequent to the birth of a stillborn child.

The aim of this study was to identify physicians' approaches to pregnancy subsequent to the birth of a stillborn child. In a 48-question, cross-sectional survey performed in 1997 one specific question dealt with advice given to the women/parents about possible subsequent pregnancy. The present study analyzes the responses to that open-ended question. Fifty-eight out of 61 Swedish hospitals with departments of obstetrics and gynecology participated in the study. Of 594 physicians, 552 answered the open-ended question (93%) with 802 items of advice. The most frequent approach to subsequent pregnancy, expressed by a majority of physicians, was their own support to the couples (59%). Regarding gender differences the females were more likely to mention support strategies than their colleagues (p = 0.005). Significantly more female gynecologists than male (p = 0.005) recommended care during the new pregnancy at a special antenatal clinic. The statement that 'advice depends on diagnosis' was made by 27%, while 22% advocated that parents first work through the grief of the stillbirth (mentioned significantly more often by females, p = 0.014). A minority of physicians mention giving specific advice about the timing of next pregnancy. The study highlights physicians' concerns to support parents through a subsequent pregnancy whilst demonstrating that considerable variation exists in their advice, or lack of it, with regard to timing of another pregnancy.

Testosterone for male contraception during one year: attitudes, well-being and quality of sex life.

Men's attitudes, well-being, and sex life were studied during 1 year's use of testosterone contraception. A consecutive series of 25 men were followed by structured interviews at baseline, during the efficacy phase of oligo-azoospermia and after recovery. Open questions gave qualitative aspects on male contraception. Themes obtained were expectations about freedom and control over their reproduction (16/25) and an enhanced sex life (17/25). The method was rated to be as expected or better by the great majority. Health and most aspects of the men's sex life did not change, but the frequency of intercourse and the quality of sex life in general were higher (p = 0.001 and p = 0.006, respectively) during the efficacy phase compared to the recovery phase. The decrease during recovery phase may be explained by a pharmacological down-regulation of the androgen receptors. Eight of 22 men admitted slightly aggressive feelings during treatment. Five of 11 women reported the men as more self-assertive during the efficacy phase.

Effects on the nervous system in different groups of workers exposed to aluminium.

OBJECTIVE: To investigate possible neurotoxic effects in groups of aluminium pot room and foundry workers, aluminium welders, and a small group of workers exposed to aluminium in the production of flake powder. METHODS: Exposure to aluminium was evaluated with aluminium concentrations in blood and urine as well as a questionnaire. The groups exposed to aluminium were compared with a group of mild steel welders. Neurotoxic effects were studied with mood and symptom questionnaires and several psychological and neurophysiological tests. RESULTS: The pot room and foundry workers showed very low aluminium uptake as their aluminium concentrations in blood and urine were close to normal, and no effects on the nervous system were detected. The group of workers exposed to flake powder had high concentrations of aluminium in blood and urine, even higher than those of the aluminium welders. However, aluminium could not be shown to affect the functioning of the nervous system in flake powder producers. Although significant effects could not be shown in the present analysis of the data on welders, the performance of the welders exposed to high concentrations of aluminium was affected according to the analyses in the original paper from this group. CONCLUSIONS: For the pot room and foundry workers no effects related to the exposure to aluminium could be found. For the group of flake powder producers exposed for a short term no effects on the nervous systems were evident despite high levels of exposure. Due to the high concentrations of aluminium in the biological samples of this group, measures to reduce the exposure to aluminium are recommended, as effects on the central nervous system might develop after protracted exposures. However, this assumption needs to be verified in further studies.

Nitric oxide synthase inhibitor and IL-18 enhance the anti-tumor immune response of rats carrying an intrahepatic colon carcinoma.

The role of nitric oxide (NO) produced by adherent spleen cells in the systemic immunosuppression developing in tumor-bearing hosts was investigated. After therapeutic immunization of rats carrying an intrahepatic colon carcinoma, H1D2, the spleen cell antitumor immune responsiveness was analyzed. Compared to parallel immunized tumor-free rats, tumor-bearing rats (TB rats) had a greatly reduced proliferative T-cell response to wild-type tumor stimulator cells. The TB rats had a depressed proliferative response to anti-CD3 and to the superantigen SEA. TB rats with small tumors had a stronger response to IL-18-producing H1D2 stimulator cells than to wild type H1D2 cells. This was not the case with TB rats carrying larger tumors. Also the IFN-gamma production and cytotoxicity against the wild-type tumor cells and the NK sensitive YAC cells were depressed in spleen cells of TB rats after 5-day restimulation with wild-type tumor cells. A part of this immunosuppression was mediated by adherent spleen cells, mostly consisting of macrophages. An important mode of action appears to involve their production of an enhanced level of nitric oxide, since the competitive nitric oxide synthase (NOS) inhibitor L-NAME could partially counteract the suppression in vitro. We conclude that NOS inhibitors in combination with immunostimulatory cytokines, such as IL-18, could be useful tools to enhance anti-tumor immune responses in TB rats and therefore to increase the efficiency of immunotherapies.

Changes in personality pattern during the first pregnancy and lactation.

In order to study personality changes in first pregnancy and lactation, two groups of women (n = 161, mean age 26.8 years) completed the self-report inventory Karolinska Scales of Personality and a scale for emotional dependency during pregnancy and 3 or 6 months after delivery. The results were within normal limits when compared with the normative values. Analysis of variance showed that the subscales Muscular Tension, Somatic Anxiety, and Monotony Avoidance diminished significantly from pregnancy and to the test periods after delivery (all p values < 0.01). Impulsiveness showed the same trend (p = 0.1). The women who had breastfed for at least 8 weeks (91%) differed significantly from those who had not. They had lower scores on the Somatic Anxiety (p = 0.006), Muscular Tension (p = 0.003), Monotony Avoidance (p = 0.039), Suspicion (p = 0.03), Social Desirability (p = 0.045) and the Impulsiveness scale (p = 0.078) and higher scores on the Socialization scale (p = 0.001). Thus, we conclude that most personality traits are stable during first pregnancy and lactation, but some significant changes occur toward a lifestyle interpreted as more relaxed and tolerant to monotony.

Physicians' role and gender differences in the management of parents of a stillborn child: a nationwide study.

During spring 1997 all gynecologists working at gynecology departments in Sweden were sent a questionnaire regarding their role in, and attitudes to, the management of the parents of a stillborn child. Of 871 gynecologists approached, 761 answered the questionnaire (87%). The majority considered that the parents should hold the child (94%), that the child should be given a name (80%) and that the child should be photographed (92%). A smaller proportion considered that labor should be started within 24 h (40%) and that siblings should see the child (55%). A minority experienced guilt at what had happened (12%) and one-third were anxious about possible disciplinary measures (30%). The majority of the gynecologists stated that the need for guidance was urgent (90%) but that only a minority had received this (40%). Regarding gender differences, it emerged that the female gynecologists did not consider there was an age limit for siblings to see the child (p = 0.003), were less inclined to prescribe tranquilizers (p = 0.001) or to prolong the parents' sick-listing (p = 0.020). These differences remained after regression analysis was performed using background variables as covariates. In summary, this study demonstrates a great need for guidance; but that only a minority of the gynecologists get this. The lack of guidance/training may in the future increase the risk of this professional group becoming 'burnt out'.