GPR55 signalling promotes proliferation of pancreatic cancer cells and tumour growth in mice, and its inhibition increases effects of gemcitabine.

The life expectancy for pancreatic cancer patients has seen no substantial changes in the last 40 years as very few and mostly just palliative treatments are available. As the five years survival rate remains around 5%, the identification of novel pharmacological targets and development of new therapeutic strategies are urgently needed. Here we demonstrate that inhibition of the G protein-coupled receptor GPR55, using genetic and pharmacological approaches, reduces pancreatic cancer cell growth in vitro and in vivo and we propose that this may represent a novel strategy to inhibit pancreatic ductal adenocarcinoma (PDAC) progression. Specifically, we show that genetic ablation of Gpr55 in the KRASWT/G12D/TP53WT/R172H/Pdx1-Cre+/+ (KPC) mouse model of PDAC significantly prolonged survival. Importantly, KPC mice treated with a combination of the GPR55 antagonist Cannabidiol (CBD) and gemcitabine (GEM, one of the most used drugs to treat PDAC), survived nearly three times longer compared to mice treated with vehicle or GEM alone. Mechanistically, knockdown or pharmacologic inhibition of GPR55 reduced anchorage-dependent and independent growth, cell cycle progression, activation of mitogen-activated protein kinase (MAPK) signalling and protein levels of ribonucleotide reductases in PDAC cells. Consistent with this, genetic ablation of Gpr55 reduced proliferation of tumour cells, MAPK signalling and ribonucleotide reductase M1 levels in KPC mice. Combination of CBD and GEM inhibited tumour cell proliferation in KPC mice and it opposed mechanisms involved in development of resistance to GEM in vitro and in vivo. Finally, we demonstrate that the tumour suppressor p53 regulates GPR55 protein expression through modulation of the microRNA miR34b-3p. Our results demonstrate the important role played by GPR55 downstream of p53 in PDAC progression. Moreover our data indicate that combination of CBD and GEM, both currently approved for medical use, might be tested in clinical trials as a novel promising treatment to improve PDAC patients' outcome.

The influence of personality, measured by the Karolinska Scales of Personality (KSP), on symptoms among subjects in suspected sick buildings.

UNLABELLED: The aim was to study possible relationships between personality traits as measured by the Karolinska Scales of Personality (KSP), a self-report personality inventory based on psychobiological theory, and medical symptoms, in subjects with previous work history in suspected sick buildings. The study comprised 195 participants from 19 consecutive cases of suspected sick buildings, initially collected in 1988-92. In 1998-89, the KSP inventory and a symptoms questionnaire were administered in a postal follow-up study. There were 16 questions on symptoms, including symptoms from the eyes, nose, throat, skin, and headache, tiredness, and a symptom score (SC), ranging from 0 to 16, was calculated. The questionnaire also requested information on personal factors, including age, gender, smoking habits, allergy and diagnosed asthma. The KSP ratings in the study group did not differ from the mean personality scale norm scores, calculated from an external reference group. Females had higher scores for somatic anxiety (P < 0.01), muscular tension (P < 0.001), psychic anxiety (P < 0.01), psychasthenia (P < 0.05), indirect aggression (P < 0.05), and guilt (P < 0.05), while males scored higher on detachment (P < 0.001). Subjects with higher SC were found to display higher degree of somatic anxiety (P < 0.001), muscular tension (P < 0.001), psychic anxiety (P < 0.001), psychasthenia (P < 0.001), inhibition of aggression (P < 0.05), detachment (P < 0.05), suspicion (P < 0.01), indirect aggression (P < 0.01), and verbal aggression (P < 0.05). In addition, ocular, respiratory, dermal, and systemic symptoms (headache and tiredness) were significantly related to anxiety- and aggressivity-related scales. There were associations between personality scales and change of symptom score (SC) during the 9-year period. The associations between KSP personality traits and symptoms were more pronounced in females. In conclusion, there are gender differences in personality and SBS symptoms. Personality may play a role in the occurrence of symptoms studied in indoor environmental epidemiology. Our results support a view that measurement of personality could be of value in future studies and vulnerability to environmental stress. PRACTICAL IMPLICATIONS: Personality and personal vulnerability should be considered in both indoor environmental epidemiology and practical handling of building with suspected indoor problem, especially when the technical investigations fail to identify any obvious technical malfunction. Moreover, personality aspects should be considered among subjects with possible vulnerable personality exposed to environmental stress, and personality diagnosis can be a complementary tool useful when assessing 'sick building patients' in the medical services. We found no evidence of severe personality pathology in among those working in workplaces with environmental problems so called 'sick buildings'.

Nuclear export inhibitor leptomycin B induces the appearance of novel forms of human Mdm2 protein.

The nuclear export inhibitor leptomycin B (LMB) prevents the export of proteins from the nucleus to the cytoplasm, protects p53 from Mdm2-mediated degradation and is a very potent inducer of the p53 transcriptional activity. Here we suggest that LMB can also interfere with the degradation of human Mdm2. In the presence of this drug, we observed two novel forms of this protein: a slow mobility form and an amino-terminal fragment with an apparent molecular mass of 32 kDa. The presence of this 32 kDa band is abolished with proteasome inhibitors, indicating that its appearance could be because of limited processing by the proteasome. These results may be useful in understanding the mechanism of degradation of Mdm2 by the proteasome.

Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms.

Standardized diagnostic criteria determined by the International Restless Legs Syndrome Study Group were used to investigate the current prevalence of restless legs syndrome (RLS). Possible associations between RLS and neuropsychiatric and somatic complaints were also investigated. A random sample of 4,000 men living in central Sweden were sent a questionnaire that included questions about sleep habits, symptoms of sleepiness, and somatic and neuropsychiatric complaints. Four symptom questions accepted as minimal diagnostic criteria for RLS were also included. Odds (OR) ratios and 95% confidence interval (CI) for different variables were calculated by means of multivariate logistic regression; 5.8% of the men suffered from RLS. The prevalence of RLS increased with age. Sleep-related complaints were more frequent among the RLS sufferers. Complaints of headache at awakening and daytime headache were reported three to five times more frequently among RLS sufferers and there was a tendency toward reported social isolation related to RLS. Subjects with RLS more frequently reported depressed mood (OR, 2.6; 95% CI, 1.8-3.8), and complained more often of reduced libido (OR, 2.2; 95% CI, 1.4-3.3). RLS sufferers more frequently reported hypertension (OR, 1.5; 95% CI, 0.9-2.4) and heart problems (OR, 2.5; 95% CI, 1.4-4.3). Results show that restless legs syndrome is common among men. It is hypothesized that RLS may be associated with several somatic and neuropsychiatric symptoms.

Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo.

Mdm2 has been shown to promote its own ubiquitination and the ubiquitination of the p53 tumour suppressor by virtue of its E3 ubiquitin ligase activity. This modification targets Mdm2 and p53 for degradation by the proteasome. The p14ARF tumour suppressor has been shown to inhibit degradation of p53 mediated by Mdm2. Several models have been proposed to explain this effect of p14ARF. Here we have compared the effects of p14ARF overexpression on the in vivo ubiquitination of p53 and Mdm2. We report that the inhibition of the Mdm2-mediated degradation of p53 by p14ARF is associated with a decrease in the proportion of ubiquitinated p53. The levels of polyubiquitinated p53 decreased preferentially compared to monoubiquitinated species. p14ARF overexpression increased the levels of Mdm2 but it did not reduce the overall levels of ubiquitinated Mdm2 in vivo. This is unexpected because p14ARF has been reported to inhibit the ubiquitination of Mdm2 in vitro. In addition we show that like p14ARF, the proteasome inhibitor MG132 can promote the accumulation of Mdm2 in the nucleolus and that this can occur in the absence of p14ARF expression. We also show that the mutation of the nucleolar localization signal of Mdm2 does not impair the overall ubiquitination of Mdm2 but is necessary for the effective polyubiquitination of p53. These studies reveal important differences in the regulation of the stability of p53 and of Mdm2.

Restless Legs Syndrome among working-aged women.

A random sample of 200 women, aged 18-64 years, living in a county in mid-Sweden, was sent a questionnaire that included questions about sleep habits, symptoms of sleepiness and neuropsychiatric complaints. Standardized diagnostic criteria determined by the International Restless Legs Syndrome Study Group were used to investigate the prevalence of restless legs syndrome (RLS). Possible associations between RLS and neuropsychiatric complaints were also investigated. Odds ratios for different variables were calculated by means of multivariate logistic regression. 11.4% of the women suffered from RLS. Sleep-related complaints were more frequent among RLS sufferers than among nonsufferers. Complaints of daytime headache were reported 5 times more frequently among RLS sufferers, and there was a tendency towards social isolation related to RLS. Subjective problems in performing work due to sleepiness were ninefold among the women with RLS. These results indicate that RLS together with an association to neuropsychiatric symptoms is common among working-aged women.

The significance of neurobehavioral tests for occupational exposure limits: an example from Sweden.

The setting of OELs is part of risk management. It should, however, be kept in mind that not only scientific data affects the outcome of an OEL but also cost-benefit and technical feasibility. During the last decades, neurobehavioral methods have been used increasingly in human studies to investigate the effects of neurotoxic chemicals on the nervous system. Since exposure levels in the workplace are becoming lower and lower, traditional epidemiology will face difficulties in revealing any effects. Therefore authorities regulating chemicals must rely more and more on toxicological data and on results from experimental human studies. It will then be crucial that sound criteria for the validity of human neurobehavioral studies of neurotoxicity are established if the results from neurobehavioral studies are to be used in regulatory risk assessment. Because of the variation in individuals response to chemical exposures, exposure limits might not be possible to set with a view toward this range of susceptibility and the avoidance of any neuropathic effects. This paper discuss the Swedish experience when using neurobehavioral data in deciding effects on the nervous system as the critical effect.

Air and biological monitoring of solvent exposure during graffiti removal.

OBJECTIVE: The principal aim of the study was to estimate the level of exposure to organic solvents of graffiti removers, and to identify the chemicals used in different cleaning agents. A secondary objective was to inform about the toxicity of various products and to optimise working procedures. METHODS: Exposure to organic solvents was determined by active air sampling and biological monitoring among 38 graffiti removers during an 8-h work shift in the Stockholm underground system. The air samples and biological samples were analysed by gas chromatography. Exposure to organic solvents was also assessed by a questionnaire and interviews. RESULTS: Solvents identified were N-methylpyrrolidone (NMP), dipropylene glycol monomethyl ether (DPGME), propylene glycol monomethyl ether (PGME), diethylene glycol monoethyl ether (DEGEE), toluene, xylene, pseudocumene, hemimellitine, mesitylene, ethylbenzene, limonene, nonane, decane, undecane, hexandecane and gamma-butyrolactone. The 8-h average exposures [time-weighted average (TWA)] were below 20% of the Swedish permissible exposure limit value (PEL) for all solvents identified. In poorly ventilated spaces, e.g. in elevators etc., the short-term exposures exceeded occasionally the Swedish short-term exposure limit values (STEL). The blood and urine concentrations of NMP and its metabolites were low. Glycol ethers and their metabolites (2-methoxypropionic acid (MPA), ethoxy acetic acid (EAA), butoxy acetic acid (BAA), and 2-(2-methoxyethoxy) acetic acid (MEAA)) were found in low concentrations in urine. There were significant correlation between the concentrations of NMP in air and levels of NMP and its metabolites in blood and urine. The use of personal protective equipment, i.e. gloves and respirators, was generally high. CONCLUSIONS: Many different cleaning agents were used. The average exposure to solvents was low, but some working tasks included relatively high short-term exposure. To prevent adverse health effects, it is important to inform workers about the health risks and to restrict the use of the most toxic chemicals. Furthermore, it is important to develop good working procedures and to encourage the use of personal protection equipment.

Sleep-disordered breathing and occupational accidents.

OBJECTIVES: The relationship between a common type of sleep disturbance, sleep-disordered breathing, and the risk of becoming involved in an occupational accident was studied. METHODS: A 10-year retrospective comparison was made of occupational injuries reported to the Occupational Injury Statistics Division of the Swedish National Board of Occupational Safety and Health. The injury rates for 704 consecutive patients suffering from sleep-disordered breathing were compared with the rates for an employed, age-matched random sample of 580 subjects, drawn from the general population. RESULTS: The risk of being involved in an occupational accident was about 2-fold among male heavy snorers and increased by 50% among men suffering from obstructive sleep apnea syndrome (OSAS). For females the risk increased by at least 3-fold among heavy snorers and OSAS patients. Reduced vigilance and attention due to sleep-disordered breathing are the proposed mechanisms behind the results. CONCLUSION: The early identification and treatment of persons suffering from sleep-disordered breathing would not only have positive impact on individual health and well-being but also on occupational safety.

Adverse health effects among women living with heavy snorers.

Women living with heavy snorers were more frequently affected by symptoms of insomnia, morning headache, daytime sleepiness, and fatigue than women living with non-snorers. Questionnaire data were collected from 1,032 women 30 to 64 years of age residing in Dalarna county, in mid-Sweden. There were indications of a "dose-response relationship" between the conjectured sound exposure and reported symptoms, regardless of whether the female herself snored. Sleeping in separate bedrooms did not seem to give the women any alleviation. The results point to a possible contributory cause of disturbed sleep, morning headache, and daytime sleepiness among women living with a snoring spouse. The results also indicate that prevention and treatment of snoring are important issues for the couple as well as for the snorer.

Alkaline single cell gel electrophoresis and human biomonitoring for genotoxicity: a study on subjects with residential exposure to radon.

Based on theoretical estimates and various correlation studies, it has been suggested that ingestion of radon in drinking water represents an increased risk for cancer. Such a risk has never been conclusively shown in epidemiological or experimental animal studies, however, and it has been questioned whether the radon level in the drinking water is of any significance in terms of overall radon exposure. Using primary DNA damage as a biological marker for an ongoing exposure to ionising radiation, the present study was undertaken to investigate whether people with different types of residential radon exposures differed with regard to their levels of DNA damage in circulating lymphocytes. DNA damage was measured in coded blood samples from 125 residents living in 45 households with different levels of radon-222 in the drinking water (10-2410 Bq/l) and indoor air (35-1025 Bq/m3) using alkaline single cell gel electrophoresis (the 'Comet' assay). Increased levels of radon in indoor air (>200 Bq/m3) were found to be associated with an increased level of DNA damage in peripheral lymphocytes (P

The validity of reported musculoskeletal problems. A study of questionnaire answers in relation to diagnosed disorders and perception of pain.

The objectives of the present study were to evaluate the validity of answers given in a questionnaire on musculoskeletal pain and conditions by means of a clinical assessment, and to get some understanding of the subject's perception of reported pain. This was performed by using measures of sensitivity and specificity comparing data from the questionnaire with the clinical diagnoses of conditions in the neck, shoulders and thoracic spine. Subjective perception of pain was obtained by the use of visual analogue scale (VAS) and pain drawings. For the combination of neck and shoulders, both sensitivity (95%) and specificity (88%) were high for current pain. The results of the study confirm the validity of the subjective reports of the respondents. A 'pain assessment instrument' including a questionnaire, VAS and pain drawings may be useful to reveal conditions in the neck and shoulders and thoracic spine, common sites of work related musculoskeletal disorders.

Improvement of subjective work performance among obstructive sleep apnea patients after treatment with continuous positive airway pressure.

Obstructive sleep apnea syndrome (OSAS) is a significant problem for some patients presenting with snoring and excessive daytime sleepiness. The 'golden standard' therapy in OSAS is considered to be nasal continuous positive airway pressure (CPAP). The effects of CPAP on work performance in sleep apnoics has not been studied previously. One hundred and fifty-two patients with OSAS participated in an open label study. The patients were diagnosed as suffering from severe OSAS after they underwent overnight polysomnography showing that their apnea indexes were at least 20. The participants answered four questions concerning self-perceived work performance prior to and after using CPAP during 6 months. There were highly statistically significant decreases (P < 0.000001) in work performance difficulties as graded by the patient. The results of this study indicate that CPAP treatment improves subjective work performance in patients suffering from OSAS.

Cancer incidence in a cohort of Swedish sewage workers: extended follow up.

OBJECTIVES: To study the cancer incidence in a cohort of Swedish sewage workers. An increased incidence of cancer of the stomach, the kidney and the nervous system in this cohort was previously reported. This new analysis reports on 9 more years of follow up. METHODS: The study is an analysis of a cohort of all 711 employees at 17 Swedish sewage plants employed for at least for 1 year during the years 1965-86. Assessment of exposures was performed by classification of work tasks. Standardised incidence ratios (SIRs), and 95% confidence intervals (95% CIs) were calculated. RESULTS: The total cancer incidence was not significantly increased (SIR = 1.2, 95% CI 0.92 to 1.5) but the incidence of prostate cancer was (SIR = 1.6, 95% CI 1.0 to 2.5), and based on two cases only, there seemed to be a significant increase of cancer of the nose and the nasal sinuses (SIR = 12, 95% CI 1.5 to 44). The incidence of stomach cancer was also increased (SIR = 2.3, 95% CI 0.99 to 4.5). There was no relation between cancer incidence and level of sewage exposure. CONCLUSIONS: Sewage workers did not have an increased risk of cancer, and the increased risk estimates for some specific cancer sites were not conclusive.

Abdominal symptoms among sewage workers.

The objective of this cross-sectional study was to investigate the prevalence of abdominal symptoms and the abdominal medical history among sewage workers. 142 male sewage workers and 137 male referents in 11 Swedish municipalities were addressed with a questionnaire about abdominal symptoms, medical history, occupational history and life style factors. The sewage workers suffered less from nausea [adjusted odds ratio (adjOR) = 0.18, 95% confidence interval (Cl) 0.04-0.84] than the referents. There was no significant difference in the three months prevalence of diarrhoea (adjOR = 1.7, 95% Cl = 0.79-3.4), dyspepsia (adjOR = 0.85, 95% Cl = 0.49-1.5) or irritable bowel syndrome (adjOR = 1.4, 95% Cl = 0.53-3.5). The sewage workers were affected more often by peptic ulcers during their present jobs than the referents, although the increased risk was not significant (adjOR = 1.4, 95% Cl = 0.31-6.1). The odds ratios were adjusted for age, use of tobacco products and alcohol consumption. The conclusion of this study was that sewage workers are less affected by nausea than comparable referents.

[Reduced level of cadmium in the renal cortex. Due to less smoking or environmental improvement?]. / Kadmiumhalten i njurbark sjunker. En effekt av minskad tobaksrökning eller bättre miljö?

A cross-sectional study of the renal cortex cadmium concentrations in 171 cases of sudden death showed the levels to be lower than those quoted m a Swedish report published in 1976 the reduction being more than 50 per cent among the < or = 40-year-old age group. The reduction is probably attributable to reduced smoking among. Swedes during the past few decades, though there were indications of reduced cadmium levels in non-smoking as well.

Reduced cadmium levels in human kidney cortex in sweden.

Environmental pollution with the nephrotoxic metal cadmium is considered a potential health risk for the general population. In 1976 it was reported that the cadmium concentration in human kidney cortex in Sweden had increased in parallel with increasing levels in soil and grain during the twentieth century. Since the cadmium concentration in farming lands is still increasing, the present study was undertaken to further elucidate whether the cadmium concentration in the kidney is still increasing. Kidney cortex biopsies were collected at 171 autopsies of victims to sudden and accidental death during 1995 and 1996, and the cadmium concentrations were determined and compared with previously published Swedish data obtained from forensic autopsies. The geometric mean cadmium concentration in kidney cortex in subjects 40 years of age and younger was about 40% of the concentration found in the 1970s, while the reduction was less pronounced among older people. The highest individual concentration of cadmium was 41.5 microg/g wet weight (ww). The geometric mean concentration was less than 14 microg/g ww at ages around 50 years of age, when the cadmium concentration in kidney cortex is highest, as compared with approximately 20 microg/g ww in the 1970s. There was also a reduction in cadmium concentrations among nonsmokers; thus, a decrease in tobacco smoking in Sweden during the last decades is not the only explanation for the reduction of cadmium in the kidney cortex. Other reasons for this reduction could be changes in dietary habits and reduced cadmium contamination from Swedish industries.