The role of plasma microseminoprotein-beta in prostate cancer: an observational nested case-control and Mendelian randomization study in the European prospective investigation into cancer and nutrition.

BACKGROUND: Microseminoprotein-beta (MSP), a protein secreted by the prostate epithelium, may have a protective role in the development of prostate cancer. The only previous prospective study found a 2% reduced prostate cancer risk per unit increase in MSP. This work investigates the association of MSP with prostate cancer risk using observational and Mendelian randomization (MR) methods. PATIENTS AND METHODS: A nested case-control study was conducted with the European Prospective Investigation into Cancer and Nutrition (EPIC) with 1871 cases and 1871 matched controls. Conditional logistic regression analysis was used to investigate the association of pre-diagnostic circulating MSP with risk of incident prostate cancer overall and by tumour subtype. EPIC-derived estimates were combined with published data to calculate an MR estimate using two-sample inverse-variance method. RESULTS: Plasma MSP concentrations were inversely associated with prostate cancer risk after adjusting for total prostate-specific antigen concentration [odds ratio (OR) highest versus lowest fourth of MSP = 0.65, 95% confidence interval (CI) 0.51-0.84, Ptrend = 0.001]. No heterogeneity in this association was observed by tumour stage or histological grade. Plasma MSP concentrations were 66% lower in rs10993994 TT compared with CC homozygotes (per allele difference in MSP: 6.09 ng/ml, 95% CI 5.56-6.61, r2=0.42). MR analyses supported a potentially causal protective association of MSP with prostate cancer risk (OR per 1 ng/ml increase in MSP for MR: 0.96, 95% CI 0.95-0.97 versus EPIC observational: 0.98, 95% CI 0.97-0.99). Limitations include lack of complete tumour subtype information and more complete information on the biological function of MSP. CONCLUSIONS: In this large prospective European study and using MR analyses, men with high circulating MSP concentration have a lower risk of prostate cancer. MSP may play a causally protective role in prostate cancer.

Cannabis use and risk of schizophrenia: a Mendelian randomization study.

Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.

The Relationship between Body Mass Index and 10-Year Trajectories of Physical Functioning in Middle-Aged and Older Russians: Prospective Results of the Russian HAPIEE Study.

OBJECTIVE: To investigate the associations of overweight and obesity with longitudinal decline in physical functioning (PF) among middle-aged and older Russians. DESIGN: Prospective cohort study. SETTING: Four rounds of data collection in the Russian Health, Alcohol and Psychosocial factors In Eastern Europe study with up to 10 years of follow-up. PARTICIPANTS: 9,222 men and women aged 45-69 years randomly selected from the population of two districts of Novosibirsk, Russia. MEASUREMENTS: PF score (range 0-100) was measured by the Physical Functioning Subscale (PF-10) of the 36-item Short Form Health Survey (SF-36) at baseline and three subsequent occasions. Body mass index (BMI), derived from objectively measured body height and weight at baseline, was classified into normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), obesity class I (BMI 30.0-34.9), and obesity class II+ (BMI≥35.0). RESULTS: The mean annual decline in the PF score during the follow-up was -1.92 (95% confidence interval -2.17; -1.68) in men and -1.91 (-2.13; -1.68) in women. At baseline, compared with normal weight, obesity classes I and II+ (but not overweight) were associated with significantly lower PF in both sexes. In prospective analyses, the decline in PF was faster in overweight men (difference from normal weight subjects -0.38 [-0.63; -0.14]), class I obese men and women (-0.49 [-0.82; -0.17] and -0.44 [-0.73; -0.15] respectively) and class II+ obese men and women (-1.13 [-1.73; -0.53] and -0.43 [-0.77; -0.09] respectively). Adjustment for physical activity and other covariates did not materially change the results. CONCLUSIONS: PF decreased more rapidly in obese men and women than among those with normal weight. The adverse effect of high BMI on PF trajectories appeared to be more pronounced in men than in women, making more extremely obese Russian men an important target population to prevent/slow down the process of decline in PF.

Variants of ADRA2A are associated with fasting glucose, blood pressure, body mass index and type 2 diabetes risk: meta-analysis of four prospective studies.

AIMS/HYPOTHESIS: We quantified the effect of ADRA2A (encoding α-2 adrenergic receptor) variants on metabolic traits and type 2 diabetes risk, as reported in four studies. METHODS: Genotype data for ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 were analysed in >17,000 individuals (1,307 type 2 diabetes cases) with regard to metabolic traits and type 2 diabetes risk. Two studies (n = 9,437), genotyped using the Human Cardiovascular Disease BeadChip, provided 12 additional ADRA2A SNPs. RESULTS: Rs553668 was associated with per allele effects on fasting glucose (0.03 mmol/l, p = 0.016) and type 2 diabetes risk (OR 1.17, 95% CI 1.04-1.31; p = 0.01). No significant association was observed with rs10885122. Of the 12 SNPs, several showed associations with metabolic traits. Overall, after variable selection, rs553668 was associated with type 2 diabetes risk (OR 1.38, 95% CI 1.09-1.73; p = 0.007). rs553668 (per allele difference 0.036 mmol/l, 95% CI 0.008-0.065) and rs17186196 (per allele difference 0.066 mmol/l, 95% CI 0.017-0.115) were independently associated with fasting glucose, and rs17186196 with fasting insulin and HOMA of insulin resistance (4.3%, 95% CI 0.6-8.1 and 4.9%, 95% CI 1.0-9.0, respectively, per allele). Per-allele effects of rs491589 on systolic and diastolic blood pressure were 1.19 mmHg (95% CI 0.43-1.95) and 0.61 mmHg (95% CI 0.11-1.10), respectively, and those of rs36022820 on BMI 0.58 kg/m(2) (95% CI 0.15-1.02). CONCLUSIONS/INTERPRETATION: Multiple ADRA2A SNPs are associated with metabolic traits, blood pressure and type 2 diabetes risk. The α-2 adrenergic receptor should be revisited as a therapeutic target for reduction of the adverse consequences of metabolic trait disorders and type 2 diabetes.

Juvenile dermatomyositis with Sjögren's syndrome.

Juvenile dermatomyositis (JDM) is a rare disease, and Sjögren's syndrome (SS) is unusual in adolescents. We report the first case of biopsy-proven JDM and SS with pulmonary involvement. A 15-year-old adolescent boy presented with recurrent parotid gland hypertrophy, severe muscle weakness, pronounced skin rash and widespread lymphadenopathy. JDM was diagnosed by clinical examination, elevated muscle enzymes, electromyography and muscle biopsy; SS was diagnosed by xerostomia, anti-Ro (SS-A) positivity and histopathological analysis of salivary gland tissue. This case illustrates a systematic approach which we feel is especially important in the younger patient with a more plastic immune system.

A randomized, double-blind, placebo-controlled study of the efficacy of tetracaine gel (Ametop) for pain relief during topical photodynamic therapy.

BACKGROUND: Many patients find topical 5-aminolaevulinic acid (ALA) photodynamic therapy (PDT) painful. Local anaesthetics are not routinely used and their effect on PDT pain has not been examined. OBJECTIVES: To evaluate the efficacy of tetracaine gel (Ametop) for pain relief during and after PDT. METHODS: A prospective, double-blind, placebo-controlled study of 42 patients with lesions (< or =2 cm diameter) of superficial nonmelanoma skin cancer or dysplasia. Patients were randomized to either tetracaine (4% w/w) (n=22) or vehicle (n=20) gel under occlusion for 1 h pre-irradiation. Pain was assessed during and after irradiation using a visual analogue scale (VAS) and faces pain scale. RESULTS: Patients who received tetracaine gel experienced only slightly less pain during PDT (median VAS 4) compared with those who received placebo (median VAS 4.5) (95% confidence interval for difference 0-3, P=0.08). No significant difference in pain was experienced between the treatment groups immediately after irradiation or later. CONCLUSIONS: When compared with placebo, tetracaine gel did not significantly reduce pain during or after PDT for small lesions of superficial basal cell carcinoma, Bowen's disease or actinic keratosis.