The genetic architecture of mitochondrial dysfunction in Parkinson's disease.

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson's disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17-23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

Men with cancer change their health behaviour: a prospective study from the Danish diet, cancer and health study.

BACKGROUND: Health behaviour changes may improve the quality of life and survival among cancer survivors. We prospectively examined changes in health behaviour among and between men with prostate cancer (PC), men with cancers other than PC and cancer-free men. METHODS: We analysed data for 20 914 men (50-65 years), 426 with cancer, and 20 488 persons who were cancer-free between baseline (1993-1997) and follow-up (2000-2002) in multiple linear regression models to determine differences in changes in body mass index (BMI) and in alcohol and tobacco consumption. RESULTS: Body mass index and tobacco and alcohol consumption decreased significantly (P<0.001) between baseline and follow-up among both men with cancer and cancer-free men. Men with cancers other than PC significantly decreased their BMI (ß=-058; 95% confidence interval (CI): -0.77, -0.40) and tobacco consumption (ß=-1.36; 95% CI: -2.22, -0.49) compared with cancer-free men and were significantly more likely to quit smoking and lose weight. CONCLUSION: Men with cancers other than PC decreased their tobacco consumption and BMI significantly more than cancer-free men. Men with cancer do change their health behaviour; clinicians should take this into account in planning follow-up care for cancer survivors.

Use of non-prescription analgesics and male reproductive function.

We studied the association between intake of non-prescription analgesics and semen quality and male reproductive hormone levels in a cross-sectional study among 1493 men. The men provided one semen (n=1493) and blood sample (n=1056) and filled in questionnaires on use of non-prescription analgesics (paracetamol, NSAIDs and combination drugs (yes/no)). Adjusting for age, study and other covariates, we observed no association between intake of non-prescription analgesics and markers of semen quality. Adjusting for age and time of day of blood sampling, users of non-prescription analgesics had a 10.4% (95% confidence interval (CI) 4.0-17.1%) higher testosterone level than non-users. When we stratified by medication type, the association between analgesics and higher testosterone was observed between users of non-steroidal anti-inflammatory drugs (NSAIDs) and combination drugs but not paracetamol. This study suggests that use of non-prescription analgesics is associated with slightly higher serum testosterone levels than non-use.

Exercise gaming - a motivational approach for older adults with vestibular dysfunction.

Purpose The purpose of the study was to identify possible reasons for a modest level of exercise compliance during computer-assisted training for vestibular rehabilitation. Method Qualitative design and analysis of 14 semi-structured interviews with seven participants before and after a period with computer-assisted home training. The interviews evolved around themes, such as the elderly participants' self-efficacy, motivation and acceptance of the technology. Results Age was not an excuse for the modest exercise compliance. The participants were basically self-efficient and accepted the technology, but their knowledge and understanding of the training programme were insufficient. The participants asked for a greater variation in the exercises and asked for closer contact with the physiotherapist. When Mitii is used for vestibular rehabilitation, the system has some limitations. Conclusions The modest level of exercise compliance can be explained by (1) missing variety of exercise speed and duration and lack of introducing new exercises, (2) insufficient interaction with the physiotherapist regarding the participants' performance and lack of social contact with other patients and (3) desire for a deeper understanding of the training programme with supplying information on the parts of the vestibular system addressed by the training. Implications for Rehabilitation Computer-assisted technologies should generate feedback on the quality of user performance and inform the patient of the relevance of the exercise. The technology should support social contact among patients with the same diagnosis and establish contact with the physiotherapist at the hospital advice and feedback. Varity and adjustments to exercises are necessary to maintain motivation and exercise compliance.

Suriclone and diazepam in the treatment of neurotic anxiety. A double-blind cross-over trial.

Suriclone is a new anxiolytic drug belonging to the family of cyclopyrrolones. Although chemically entirely different from the benzodiazepines, it acts as a benzodiazepine agonist with very high affinity for the benzodiazepine receptors. In the present cross-over study, 33 out-patients with a diagnosis of neurotic anxiety were treated with suriclone (mean dose 2 mg/day) and diazepam (25 mg/day) in two 6-week periods. Both drugs had a significant anxiolytic effect, but diazepam appeared to have a better effect within the first 2 weeks of treatment, while no significant difference was seen after treatment, while no significant difference was seen after treatment for 6 weeks. Suriclone and diazepam had a different side effect profile: suriclone produced mainly dizziness, while diazepam caused sedation. This may reflect the fact that suriclone and benzodiazepines bind to distinct sites or different allosteric conformations of the benzodiazepine receptors.

Aneuploidy in sperm and exposure to fungicides and lifestyle factors. ASCLEPIOS. A European Concerted Action on Occupational Hazards to Male Reproductive Capability.

Fungicides include chemicals that are known aneugens. The purpose of the present study was to investigate whether occupational exposure to these and other agricultural pesticides induces aneuploidy in human sperm. The contribution of lifestyle factors (smoking and alcohol consumption) to the frequency of aneuploid sperm was evaluated as well. The effects of age and sperm concentration were analyzed as confounders. Spermatozoa from 30 healthy farmers were studied before and after exposure to fungicides, using fluorescence in situ hybridization (FISH). Ten thousand spermatozoa were scored per semen sample to determine the disomy and diploidy frequencies for chromosomes 1 and 7. Exposure to fungicides was not associated with sperm aneuploidy. Smoking was significantly associated with sperm carrying an extra chromosome 1 and with diploid sperm as well as with the aggregate frequency of aneuploid sperm. Alcohol consumption, sperm concentration, and age showed inconsistent results before and after the season of exposure to fungicides. For low-level exposures, such as occupational exposures, the sensitivity of the sperm-FISH method may not be sufficient. The present study supports earlier ones showing that smoking can increase aneuploidy in human sperm.

A longitudinal study of semen quality in pesticide spraying Danish farmers. The ASCLEPIOS Study Group.

It was hypothesized that occupational exposure to pesticides during a spraying season causes changes in semen quality that might be detected in a longitudinal study. We analyzed the within-person changes in semen quality and reproductive hormones across a spraying season in groups of farmers using and not using pesticides. A total of 248 men collected two semen samples (participation rate: 32%). The median sperm concentration declined significantly from the first to the second sample in both groups, but there was no statistical difference in the decline between the two groups, unadjusted or adjusted. Only minor changes were found in sperm morphology, vitality, motility, sperm chromatin denaturation (SCSA), and reproductive hormones, and the differences in changes between the two groups were nonsignificant, or, in the opposite direction to the expected. There was no relation between the changes in sperm parameters in relation to pesticide exposure variables. In conclusion, use of pesticides by Danish farmers is not a likely cause of short-term effects on semen quality and reproductive hormones.

Environmental semen studies--is infertility increased by a decline in sperm count?

The objective of the studies was to evaluate infertility according to sperm count shifts. The distribution of the sperm count of 1024 Danish men (median 56 million/ml) served as reference. The data were transformed with multiplicative or additive models to create alternative distributions with median sperm count values changed by 25-100%. Sperm-count-specific fecundabilities were provided from a follow-up of first-pregnancy planners in a Danish population. The estimated average fecundability of the 1024 Danish men was 16.9% [95% confidence interval (95% CI) 16.7-17.2], and the proportion of cohabiting men with spouses pregnant within 1 year was 86.0% (95% CI 84.1-87.8). Simulations of alternative sperm count distributions indicated that the relationship between sperm count shift and fertility strongly depends on the median level of the sperm count at onset and the type of shift, a dramatic decline from a high level in a multiplicative model indicating a marginal change and a minor decline from a low level in an additive model representing a strong decrease in fertility. In some cases sperm count, therefore, may be an early warning of changes in fertility.

Expectations and knowledge of pelvic examinations in a random sample of Danish teenagers.

The purpose of the study was to describe teenagers' expectations and knowledge of the pelvic examination (PE). The study was carried out as a cross-sectional postal questionnaire study. A total of 1500 women, aged 17 years, were selected at random from all Danish women of that age. The response rate was 76%, and 551 of these 1112 teenagers had experienced their first PE. Among the teenagers who had not had a PE, 48% thought the examination would be painful, 29% feared that the doctor would discover abnormal anatomy, 67% felt they would be embarrassed by exposing their genitals and 23% expected to be indisposed for the rest of the examination day. Among the teenagers who had not experienced a PE, only 17% felt that they had sufficient knowledge of the examination, compared to 68% in the group who had already experienced an examination. In the group who had not experienced a PE 33% knew what the doctor was able to inspect during the instrumental part of the examination, compared to 55% in the other group with experience. It is concluded that a considerable proportion of teenagers have negative expectations of the PE, and increased effort to improve teenagers' expectations and knowledge of the PE may be recommended.

[The first gynecologic examination. Indications, age and place]. / Første gynaekologiske undersøgelse. Indikation, alder og sted.

The purpose was to investigate age, place, and indication for 17 year-old women's first pelvic examination. A postal questionnaire was sent to 1500 randomly selected 17 years-old Danish women. The response rate was 76%. The median age at which such examinations first took place was 17 years and 10 months. The majority (86%) of examinations were performed by general practitioners and 72% were performed in relation to prescription of oral contraceptives. This indication has previously been a recommendation of the Danish National Board of Health, but changes have been announced, and indications for pelvic examinations of teenagers should be discussed.

[Age at menarche and first sexual intercourse. A cross-sectional study of 17-year old Danish women]. / Alder ved menarche og første samleje. Tvoersnitsundersøgelse af 17-årige danske kvinder.

The age at menarche and first intercourse was analyzed from data obtained from a questionnaire sent to 1500 17 year-old randomly selected Danish women (76% responded). The average age at menarche was 13.37 years (SD: 1.24). The median age at the time of the first intercourse was 16.6 years. Late sexual debut was observed for girls who were relatively old at menarche and for those with a higher level of education. Apparently the age at menarche and at first sexual intercourse has not changed significantly in recent years.

[Pesticides and time to pregnancy among Danish farmers]. / Pesticider og ventetid til graviditet hos danske landmaend. ASCLEPIOS Study Group.

The aim of this study was to examine time to pregnancy among farmers who used pesticides (traditional farmers) and farmers who did not (organic farmers). A total of 904 men, selected from the Danish Ministry of Agriculture lists of traditional and organic farmers, participated in telephone interviews. The participation rate was 84%. Information was collected on "time to pregnancy" for the youngest child, exposure to pesticides and potential confounders. Using the discrete analogue of the Cox Regression Model (including potential confounders: male and female smoking, female age, parity and contraceptive method), the fecundability ratio between traditional farmers using pesticides and organic farmers was 1.03 (95% CI: 0.75-1.40). In the group of farmers who sprayed with pesticides, none of the characteristics related to the use of pesticides could account for the variation in time to pregnancy. No overall effect of pesticides on male fecundability could be demonstrated in this retrospective study among Danish farmers.

[Ambulatory psychiatry--a follow-up after 1 year]. / Ambulant psykiatri--et års efterundersøgelsen.

This article describes the results of a one year follow-up investigation of patients suffering from psychiatric and mental diseases and psycho-social problems who were seen in general practice or by private practising psychiatrists and the psychiatric outpatient hospital clinic in a Danish county. 40-50% of the patients concluded treatment within the first year. The general practitioner and the private practising psychiatrist saw 10% of the patients more than 13 times. In the outpatient hospital clinic, 10% of the patients were seen more than 29 times. A psychotherapeutic approach to treatment was employed for 54-90% of the cases. Psychopharmacological medication was administered to 54-60% of the patients. Where patients in general practice and in the outpatient clinic were concerned, treatment in an emergency open unit and treatment in sheltered environments was required and supervision was necessary for 1/4 of the cases. The investigation demonstrates the role of the general practitioner in treatment and referral. After one year 25% of the patients were referred for other treatment. The general practitioner, private practicing psychiatrist and outpatient clinic treat different groups of psychiatric patients and work somewhat independently of one another.

[Sectorized psychiatry. Ambulatory psychiatry in a geographically defined region]. / Distriktspsykiatri. Ambulant psykiatri i et geografisk afgraenset område.

The article describes the psychiatric outpatient treatment service in the catchment area of the county of Roskilde in Denmark. Eighty-four general practitioners, ten private practising psychiatric specialists and the psychiatric outpatient service at Roskilde Amts Sygehus Fjorden participated in a prospective cohort study based on questionnaires. This includes 404 patients from general practice, 326 from the psychiatric specialists and 166 from the psychiatric hospital. The patients' social conditions, demographic data, psychosocial problems, psychosocial strain, diagnoses, and the treatment are presented. Psychotics constitute 52% of the patients from the outpatient treatment service corresponding to 25% from specialist practice and 12% from general practice. The most common diagnoses at specialist level are neuroses and crises, in general practice, in addition, psychosomatic illness and depression without psychoses. The treatment for most of the patients is psychotherapy or in combination with psychopharmacology. Further acute psychiatric service and supervision are required. One year follow-up has been accomplished. Follow-up reviews after five and ten years are planned.

The influence of type 2 diabetes on fibrin clot properties in patients with coronary artery disease.

Type 2 diabetes mellitus (T2DM) increases the risk of coronary thrombosis and both conditions are associated with altered fibrin clot properties. However, the influence of T2DM on fibrin clot properties in patients with coronary artery disease (CAD) remains unclear. We aimed to investigate the influence of T2DM on fibrin clot properties in patients with CAD. Fibrin clot structure and fibrinolysis were investigated in 581 CAD patients (148 with T2DM) using turbidimetric assays, confocal and scanning electron microscopy. Clots made from plasma and plasma-purified fibrinogen were studied, and plasma levels of inflammatory markers were analysed. T2DM patients had increased clot maximum absorbance compared with non-diabetic patients (0.36 ± 0.1 vs 0.33 ± 0.1 au; p=0.01), displayed longer lysis time (804 [618;1002] vs 750 [624;906] seconds; p=0.03) and showed more compact fibrin structure assessed by confocal and electron microscopy. Fibrinogen levels were elevated in T2DM (p< 0.001), but clots made from purified fibrinogen showed no differences in fibrin properties in the two populations. Adjusting for fibrinogen levels, T2DM was associated with C-reactive protein and complement C3 plasma levels, with the former correlating with clot maximum absorbance (r=0.24, p< 0.0001) and the latter with lysis time (r=0.30, p< 0.0001). Independent of fibrinogen levels, females had more compact clots with prolonged lysis time compared with males (all p-values< 0.001). In conclusion, T2DM is associated with prothrombotic changes in fibrin clot properties in patients with CAD. This is related to quantitative rather than qualitative changes in fibrinogen with a possible role for inflammatory proteins.

Reduced antiplatelet effect of aspirin is associated with low-grade inflammation in patients with coronary artery disease.

Inflammation has been proposed to modify platelet function. This may lead to increased platelet reactivity and reduced antiplatelet drug efficacy in patients with coronary artery disease (CAD). However, this hypothesis has not been investigated in stable CAD patients receiving aspirin as mono antiplatelet therapy. It was the objective of this study to investigate the association between platelet reactivity, the inflammatory markers high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6), and platelet activation. We performed a cross-sectional study on 524 stable high-risk CAD patients. Among these, 91% had a history of myocardial infarction, 23% had type 2 diabetes, and 13% had both. All patients received 75 mg aspirin daily as mono antiplatelet therapy. Platelet reactivity was assessed by multiple electrode aggregometry (Multiplate®, MEA) and VerifyNow®. Inflammation was evaluated by hs-CRP and IL-6. Platelet activation was assessed by soluble P-selectin (sP-selectin), and cyclooxygenase-1 inhibition was evaluated by measurement of serum thromboxane B2. Hs-CRP levels were significantly higher in upper platelet reactivity tertile patients than in lower platelet reactivity tertile patients (p≤0.02). Similar results were obtained with IL-6, though not statististically significant (p≥0.15). Platelet activation evaluated by sP-selectin was significantly higher in patients with MEA reactivity levels in the upper tertile than in the lower tertile (p=0.0001). Optimal compliance was confirmed by low serum thromboxane B2 levels in all patients. In conclusion, increased levels of hs-CRP were associated with augmented platelet reactivity in stable high-risk CAD patients receiving aspirin as mono antiplatelet therapy. These findings may suggest that chronic low-grade inflammation reduce the antiplatelet effect of aspirin.

Adenomyosis and junctional zone changes in patients with endometriosis.

OBJECTIVES: To evaluate image findings in the junctional zone (JZ) in patients with endometriosis and correlate with image findings of adenomyosis. To attempt a correlation of the degree of adenomyotic infiltration with the degree of infiltration and stage of endometriosis. STUDY DESIGN: Magnetic resonance imaging (MRI) of the uterus was performed in 153 women with suspected deeply infiltrating endometriosis and planned surgery, and in a reference group of 129 women without endometriosis, verified during hysterectomy. Changes in the JZ and endometriosis in the pelvis were described in detail. Diagnosis of adenomyosis at MRI was based on optimal criteria derived from the hysterectomy control group. The stage of endometriosis (AFS stage) was determined during surgery. RESULTS: In the group of women with endometriosis 34.6% had adenomyosis compared with 19.4% in the reference group (p<0.05). More women with endometriosis (39.9%) had an irregular JZ compared to 22.5% in the reference group (p<0.01). Among women with severe endometriosis (AFS stage IV) 42.8% had adenomyosis compared to 29.4% in the women with other stages of endometriosis (AFS stages I+II+III) (p=0.10). More women with severe endometriosis (AFS stage IV) had deeper wall invasion of adenomyosis (p>0.05) but the presence of deep infiltrative rectovaginal endometriosis and the size of infiltration were not correlated to adenomyosis or depth of infiltration of adenomyosis. CONCLUSIONS: In a group of young women with severe symptomatic endometriosis and planned surgery a systematic evaluation of the JZ revealed that one third had uterine adenomyosis, but the invasive potential of endometrial cells in the uterus and in the peritoneum corresponded only to a limited degree.

Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease.

BACKGROUND: Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin. OBJECTIVES: To investigate the impact of platelet turnover on the antiplatelet effect of aspirin in patients with stable coronary artery disease (CAD) and to identify determinants of platelet turnover. METHODS: Platelet turnover was evaluated by measurements of immature platelets and thrombopoietin in 177 stable CAD patients on aspirin monotherapy, including 85 type 2 diabetics and 92 non-diabetics. Whole blood platelet aggregation was determined using the VerifyNow(®) Aspirin test and multiple electrode aggregometry (MEA, Multiplate(®) ) induced by arachidonic acid (AA) (1.0 mm), adenosine diphosphate (ADP) (10 µm) and collagen (1.0 µg mL(-1) ). RESULTS: Immature platelet levels significantly correlated with MEA (r = 0.31-0.36, P-values < 0.0001) and the platelet activation marker sP-selectin (r = 0.19, P = 0.014). Contrary to the VerifyNow(®) test, MEA significantly correlated with variations in platelet count (r = 0.45-0.68, P-values < 0.0001). Among patients with residual platelet reactivity according to AA, there were significantly more diabetics (61% vs. 41%, P = 0.027) and higher levels of sP-selectin (77.7 ± 29 vs. 70.2 ± 25 ng mL(-1) , P = 0.070) and serum thromboxane B(2) (0.81 [0.46; 1.70] vs. 0.56 [0.31; 1.12] ng mL(-1) , P = 0.034). In a multivariate regression analysis, immature platelet levels were determined by thrombopoietin levels (P < 0.001), smoking (P = 0.020) and type 2 diabetes (P = 0.042). CONCLUSIONS: The antiplatelet effect of aspirin was reduced in CAD patients with an increased platelet turnover. Once-daily dosing of aspirin might not suffice to adequately inhibit platelet aggregation in patients with an increased platelet turnover.

Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus.

INTRODUCTION: Diabetes mellitus is complicated by accelerated atherosclerosis, resulting in an increased risk of coronary artery disease (CAD) and thrombosis. Despite the proven benefits of aspirin, previous studies indicate a reduced cardiovascular protection from aspirin in diabetic patients. We aimed to investigate whether diabetes mellitus influenced the platelet response to aspirin in patients with CAD. MATERIALS AND METHODS: Platelet aggregation and activation were evaluated during aspirin treatment in 85 diabetic and 92 non-diabetic patients with CAD. Adherence to aspirin was carefully controlled. All patients had CAD verified by coronary angiography and were taking 75 mg non-enteric coated aspirin daily. RESULTS: Diabetic patients showed significantly higher levels of platelet aggregation compared to non-diabetic patients evaluated by VerifyNow® Aspirin (p=0.03) and Multiplate® aggregometry using arachidonic acid (AA) 0.5 mM (p=0.005) and 1.0 mM (p=0.009). In addition, platelet activation determined by soluble P-selectin was significantly higher in diabetics compared to non-diabetics (p=0.005). The higher AA-induced aggregation was associated with higher levels of HbA(1c). Compliance was confirmed by low levels of serum thromboxane B(2) (below 7.2 ng/mL). Diabetics had significantly higher levels of serum thromboxane B(2) (p<0.0001). CONCLUSIONS: Diabetic patients with CAD had significantly higher levels of both platelet aggregation and activation compared to non-diabetic patients with CAD despite treatment with the same dosage of aspirin. These findings may partly explain the reduced cardiovascular protection from aspirin in diabetic patients.