Organic food consumption and the incidence of cancer in the Danish diet, cancer and health cohort.

PURPOSE: Expected beneficial health effects is a major reason why people purchase organically produced foods, although the existing evidence is limited. We investigated if organic food consumption, overall and by specific food groups, is associated with the incidence of cancer. METHODS: We used data from the Danish Diet, Cancer and Health cohort. Organic food consumption was reported for vegetables, fruits, dairy products, eggs, meat, and bread and cereal products. Consumption was summarized into an overall organic food score, evaluated as a continuous variable and in categories specified as never, low, medium, and high consumption. We followed 41,928 participants for a median of 15 years, during which 9,675 first cancer cases were identified in the Danish Cancer Registry. We used cox proportional hazard models adjusted for sociodemographic and lifestyle variables to estimate associations between organic food consumption and cancer incidence. RESULTS: No association was observed between intakes of organic foods and incidence of overall cancer. When compared to never eating organic foods, overall organic food consumption was associated with a lower incidence of stomach cancer (low: HR = 0.50, 95% CI: 0.32-0.78, medium: HR = 0.50, 95% CI: 0.32-0.80, high: HR = 0.54, 95% CI: 0.27-1.07, p-trend = 0.09), and higher incidence of non-Hodgkin lymphoma (low: HR = 1.45, 95% CI: 1.01-2.10, medium: HR = 1.35, 95% CI: 0.93-1.96, high: HR = 1.97, 95% CI: 1.28-3.04, p-trend = 0.05). Similar patterns were observed for the specific food groups. CONCLUSION: Our study does not support an association between organic food consumption and incidence of overall cancer. The scarce existing literature shows conflicting results with risk of specific cancers.

Managing persistent physical symptoms when being social and active is the norm: a qualitative study among young people in Denmark.

BACKGROUND: An increasing number of young people in Western countries report persistent physical symptoms (PPS). PPS may disturb everyday activities and they may have negative consequences for later adult mental and physical health. Still little is known about how young people handle PPS in their everyday lives. This study examines how young people with PPS attempt to manage their symptoms while staying engaged in their daily activities and what is at stake in these attempts. METHODS: This qualitative study involved semi-structured interviews with 11 young people with PPS. Photo-elicitation was used to capture the participants' experiences as they occurred in their everyday lives. The data material was analysed using a thematic analysis approach, as well as theory on subjectivity and social acceleration. RESULTS: The participants employed alleviating measures and tried to find patterns between their activities and the severity of their symptoms in order to adjust their activity level. Decisions not to participate in social activities were accompanied by feelings of missing out. The participants' attempts at adjusting their activity level was challenged by norms of being social and active, and they experienced difficulty prioritizing their activities and explaining their symptoms to others. CONCLUSION: PPS shaped the participants' sense of how to act towards their bodies and social relationships in interaction with societal norms. The participants' subject formation and symptom experiences should thus be seen as a biosocial process.

Organic food consumption is associated with a healthy lifestyle, socio-demographics and dietary habits: a cross-sectional study based on the Danish Diet, Cancer and Health cohort.

OBJECTIVE: To study the association between organic food consumption and lifestyle, socio-demographics and dietary habits. DESIGN: Cohort participants completed detailed questionnaires about organic food consumption, diet and lifestyle between 1999 and 2002. Polytomous logistic regression models were used to estimate the association between organic food consumption, and lifestyle, socio-demographics, and dietary habits. SETTING: This cross-sectional study uses data from the Danish Diet, Cancer and Health cohort. PARTICIPANTS: A total of 43 209 men and women aged between 54 and 73 years were included in the study. RESULTS: Overall, 15 % reported never consuming organic food, 39 % had low organic food consumption, 37 % had medium organic food consumption and 10 % had high organic food consumption. The relative risk of consuming organic food versus never consuming organic food was highest among women, persons with BMI < 25 kg/m2, persons with low alcohol intake, persons participating in sports, persons who did not smoke or were former smokers, and among persons who adhered to the Danish national dietary guidelines. Associations were more distinct with higher levels of organic food consumption. CONCLUSION: Based on a historical cohort of Danish adults, organic food consumption was associated with a generally healthy lifestyle, more favourable socio-demographics and dietary habits. These findings have to be considered in the adjustment strategy for future studies linking organic food consumption with health outcomes.

All-cause mortality and location of death in patients with established cardiovascular disease before, during, and after the COVID-19 lockdown: a Danish Nationwide Cohort Study.

BACKGROUND: On 13 March 2020, the Danish authorities imposed extensive nationwide lockdown measures to prevent the spread of the coronavirus disease 2019 (COVID-19) and reallocated limited healthcare resources. We investigated mortality rates, overall and according to location, in patients with established cardiovascular disease before, during, and after these lockdown measures. METHODS AND RESULTS: Using Danish nationwide registries, we identified a dynamic cohort comprising all Danish citizens with cardiovascular disease (i.e. a history of ischaemic heart disease, ischaemic stroke, heart failure, atrial fibrillation, or peripheral artery disease) alive on 2 January 2019 and 2020. The cohort was followed from 2 January 2019/2020 until death or 16/15 October 2019/2020. The cohort comprised 340 392 and 347 136 patients with cardiovascular disease in 2019 and 2020, respectively. The overall, in-hospital, and out-of-hospital mortality rate in 2020 before lockdown was significantly lower compared with the same period in 2019 [adjusted incidence rate ratio (IRR) 0.91, 95% confidence interval (CI) CI 0.87-0.95; IRR 0.95, 95% CI 0.89-1.02; and IRR 0.87, 95% CI 0.83-0.93, respectively]. The overall mortality rate during and after lockdown was not significantly different compared with the same period in 2019 (IRR 0.99, 95% CI 0.97-1.02). However, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during and after lockdown compared with the same period in 2019 (in-hospital, IRR 0.92, 95% CI 0.88-0.96; out-of-hospital, IRR 1.04, 95% CI1.01-1.08). These trends were consistent irrespective of sex and age. CONCLUSIONS: Among patients with established cardiovascular disease, the in-hospital mortality rate was lower and out-of-hospital mortality rate higher during lockdown compared with the same period in the preceding year, irrespective of age and sex.

Intake of whole grain and associations with lifestyle and demographics: a cross-sectional study based on the Danish Diet, Cancer and Health-Next Generations cohort.

PURPOSE: The aim was to analyze the intake of whole grain (WG) and associations with lifestyle and demographics in a newly established cohort of Danish adults. METHODS: Between 2015 and 2019, Danes were enrolled into The Diet, Cancer and Health-Next Generations cohort. A total of 38,553 persons were included in the current cross-sectional study, where all completed a 376-item food frequency questionnaire, a lifestyle questionnaire, and a physical examination in a study center where physical measurements and biological samples were collected. RESULTS: The median intake of WG was 79 g/10 mega joule (MJ) and 54% of the participants consumed the amount of WG recommended in Denmark, which is 75 g/10 MJ. The probability of consuming the recommended amount of WG was highest among men, persons < 30 years, students, persons with body mass index (BMI) < 25 kg/m2, persons participating in sports, who did not exceed the recommended maximum intake of alcohol and did not smoke. The probability of having a low intake of WG defined as < 25 g/10 MJ was highest among persons with short education, BMI ≥ 25 kg/m2, persons not participating in sports, persons having an alcohol intake above the recommended maximum level and persons being active smokers. CONCLUSION: The median intake of WG was 79 g/10 MJ. The probability of consuming at least 75 g WG/10 MJ was highest among persons who also adhered to healthy lifestyle measured by other factors. Only 6% of the cohort participants consumed < 25 g WG/10 MJ, these persons were more likely to have a general less healthy lifestyle.

Depression and anxiety symptoms in pregnant women in Denmark during COVID-19.

AIMS: Maternal mental distress in pregnancy can be damaging to the mother's and child's physical and mental health. This study aimed to provide an insight into mental well-being of pregnant women in Denmark during COVID-19 by assessing symptoms of depression and anxiety. METHODS: Data from two cohorts of pregnant women recruited from Danish general practice were compared. A COVID-19 lockdown cohort (N=330) completed questionnaires between 8 April and 6 May. Responses were compared to those from a control cohort of women from 2016 (N=1428). Mental well-being was measured with the Major Depression Inventory (MDI) and the Anxiety Symptom Scale (ASS). RESULTS: Questionnaires were returned by 83% of the COVID-19 lockdown cohort and by 93% of the control cohort. Multivariable analysis controlling for age, cohabitation status, occupation, smoking, alcohol use, chronic disease, fertility treatment, parity and children living at home showed no difference in depressive symptoms (MDI). Anxiety symptoms (ASS) were slightly worse in the COVID-19 lockdown cohort (mean difference=1.4 points), mainly driven by questions concerning general anxiety. The largest differences in anxiety were seen in first trimester (adjusted mean difference=4.0 points). CONCLUSIONS: Pregnant women questioned during the COVID-19 pandemic showed no change in symptoms of depression and only a modest elevation of anxiety when compared to pregnant women questioned during a non-pandemic period in 2016.

Use of alternative consultation forms in Danish general practice in the initial phase of the COVID-19 pandemic - a qualitative study.

BACKGROUND: Attempts to manage the COVID-19 pandemic have led to radical reorganisations of health care systems worldwide. General practitioners (GPs) provide the vast majority of patient care, and knowledge of their experiences with providing care for regular health issues during a pandemic is scarce. Hence, in a Danish context we explored how GPs experienced reorganising their work in an attempt to uphold sufficient patient care while contributing to minimizing the spread of COVID-19. Further, in relation to this, we examined what guided GPs' choices between telephone, video and face-to-face consultations. METHODS: This study consisted of qualitative interviews with 13 GPs. They were interviewed twice, approximately three months apart in the initial phase of the pandemic, and they took daily notes for 20 days. All interviews were audio recorded, transcribed, and inductively analysed. RESULTS: The GPs re-organised their clinical work profoundly. Most consultations were converted to video or telephone, postponed or cancelled. The use of video first rose, but soon declined, once again replaced by an increased use of face-to-face consultations. When choosing between consultation forms, the GPs took into account the need to minimise the risk of COVID-19, the central guidelines, and their own preference for face-to-face consultations. There were variations over time and between the GPs regarding which health issues were dealt with by using video and/or the telephone. For some health issues, the GPs generally deemed it acceptable to use video or telephone, postpone or cancel appointments for a short term, and in a crisis situation. They experienced relational and technical limitations with video consultation, while diagnostic uncertainty was not regarded as a prominent issue CONCLUSION: This study demonstrates how the GPs experienced telephone and video consultations as being useful in a pandemic situation when face-to-face consultations had to be severely restricted. The GPs did, however, identify several limitations similar to those known in non-pandemic times. The weighing of pros and cons and their willingness to use these alternatives shifted and generally diminished when face-to-face consultations were once again deemed viable. In case of future pandemics, such alternatives seem valuable, at least for a short term.

Taking no for an answer. Nurses' consultations with people with cardiac disease about rehabilitation: A qualitative study.

BACKGROUND: Research shows that many people with cardiac disease decline cardiac rehabilitation. There is little or no knowledge on how health professionals respond to these people. OBJECTIVES: To investigate how nurses respond to people who do not wish to participate in cardiac rehabilitation and what influences the nurses´ approach towards these people. DESIGN: A qualitative study involving interviews and video-recordings using an analysis inspired by ethnographic principles and categorisation theory. SETTING: A rehabilitation clinic at a large hospital in the Capital Region of Denmark. PARTICIPANTS: Five cardiac nurses and 28 people with cardiac disease. METHODS: We video-recorded the first consultation people with cardiac disease attended regarding cardiac rehabilitation, where the nurses followed up on these people's recovery, medication, lifestyle and need for rehabilitation. We conducted semi-structured interviews with the cardiac nurses. We asked the nurses about the purpose of the first rehabilitation consultation and how they handle people with cardiac disease who say no to rehabilitation. The nurses were shown video-clips with the people they had talked to in their consultation in order to facilitate a dialogue. RESULTS: When people with cardiac disease were reluctant to participate in rehabilitation, the nurses made an individual assessment of how much effort to put into motivating them, taking a complex range of factors into account. The effort among the nurses towards people with cardiac disease who decline rehabilitation was smaller in cases when the nurses believed an individual would benefit less from rehabilitation or have difficulty participating. It was important for the nurses to balance their motivational efforts with showing respect for people's autonomy. CONCLUSION: Even when nurses endorse rehabilitation, some people with cardiac disease decline rehabilitation. The nurses' recommendation of the rehabilitation programme is influenced by the knowledge they obtain about the people with cardiac disease during consultations.

Dysregulated iron metabolism in C. elegans catp-6/ATP13A2 mutant impairs mitochondrial function.

Mutations in the human ATP13A2 gene are associated with an early-onset form of Parkinson's disease (PD) known as Kufor Rakeb Syndrome (KRS). Patients with KRS show increased iron deposition in the basal ganglia, suggesting iron toxicity-induced neurodegeneration as a potential pathogenesis associated with the ATP13A2 mutation. Previously we demonstrated that functional losses of ATP13A2 disrupt the lysosomes ability to store excess iron, leading to reduce survival of dopaminergic neuronal cells. To understand the possible mechanisms involved, we studied a Caenorhabditis elegans mutant defective in catp-6 function, an ortholog of human ATP13A2 gene. Here we show that catp-6 mutant worms have defective autophagy and lysosomal function, demonstrate characteristic PD phenotypes including reduced motor function and dysregulated iron metabolism. Additionally, these mutants have defective mitochondrial health, which is rescuable via iron chelation or mitophagy induction.

Pre- and post-diagnostic intake of whole grain and dairy products and breast cancer prognosis: the Danish Diet, Cancer and Health cohort.

PURPOSE: Fiber rich foods and dairy products have been suggested to be associated with breast cancer prognosis, though existing research is limited and either report on pre- or post-diagnostic dietary intake in relation to breast cancer prognosis. We investigated the associations between intake of whole grain (WG) and dairy products assessed both pre- and post-diagnostically in relation to breast cancer prognosis. METHODS: A total of 1965 women from the Diet, Cancer and Health cohort who were diagnosed with breast cancer between baseline (1993-1997) and December 2013 were included and followed for a median of 7 years after diagnosis. During follow-up, 309 women experienced breast cancer recurrence and 460 women died, of whom 301 died from breast cancer. Dietary assessment by food frequency questionnaires was obtained up to three times, pre- and post-diagnostic, over a period of 18 years. Cox proportional hazard models were used to estimate hazard ratios. RESULTS: No associations were observed between pre- or post-diagnostic intake of total WG or total dairy products and breast cancer prognosis. A high pre-diagnostic intake of oatmeal/muesli was associated with lower all-cause mortality (HR 0.76, 95% CI 0.59-0.99), whereas high post-diagnostic intake of rye bread was associated with higher breast cancer-specific mortality (HR 1.29, 95% CI 1.02-1.63). A generally high intake of cheese was associated with a higher recurrence rate. CONCLUSION: Pre-diagnostic intake of oatmeal/muesli was associated with lower all-cause mortality, and post-diagnostic intake of rye bread was associated with higher breast cancer specific mortality.

Initiating Change: Negotiations of Subjectivity in a Danish Activation Programme for Young Adults with Psychosocial Problems and Common Mental Disorders.

An increasing number of young adults in Denmark experience difficulties in completing their education and holding down a job. Many of these young adults have psychosocial problems and common mental disorders. To retain public income support they must attend education and work-directed activities, known as 'activation programmes'. Based on ethnographic fieldwork, this study presents an analysis of how one such programme unfolds in practice and how the participants engaged with the activities and negotiated the underlying rationales. We argue that the activities involved in the programme constitute 'biographical techniques' that entail a configuration of the participants as being responsible for their own biographies and having the capability to solve their problems themselves. The participants challenged this configuration of subjectivity by recounting complex or immediate problems that could not be solved through biographical techniques and by refusing to deal with their life stories as a way of configuring their futures. Biographical techniques limited the possibilities for grappling with the complexity of the participants' problems. We conclude that the participants are therefore subjected to biographical coercion because forms of subjectivity other than biographical subjectivity are disregarded.

An inducible MAO-B mouse model of Parkinson's disease: a tool towards better understanding basic disease mechanisms and developing novel therapeutics.

Several studies have suggested that increases in astrocytic monoamine oxidase B (MAO-B) levels in conjunction with Parkinson's disease (PD) may contribute to subsequent neuropathology associated with the disorder. MAO-B inhibitors are currently widely used as symptomatic therapeutics for PD and, although somewhat controversial, these drugs may also exhibit disease-modifying properties. To obtain a better understanding of the potential role of MAO-B in disease neuropathology, we created an inducible astrocyte-specific transgenic MAO-B mouse model. Here, we summarize findings associated with this model, including neuropathological PD features associated with it.

Regulation of ATP13A2 via PHD2-HIF1α Signaling Is Critical for Cellular Iron Homeostasis: Implications for Parkinson's Disease.

We previously reported that pharmacological inhibition of a class of enzymes known as prolyl hydroxylase domain proteins (PHDs) has neuroprotective effects in various in vitro and in vivo models of Parkinson's disease (PD). We hypothesized that this was due to inhibition of the PHD2 isoform, preventing it from hydroxylating the transcription factor hypoxia inducible factor 1 α (HIF1α), targeting it for eventual proteasomal degradation. HIF1α itself induces the transcription of various cellular stress genes, including several involved in iron metabolism. Although all three isoforms of PHD are expressed within vulnerable dopaminergic (DAergic) substantia nigra pars compacta neurons, only select downregulation of the PHD2 isoform was found to protect against in vivo neurodegenerative effects associated with the mitochondrial neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. These findings were corroborated in induced pluripotent stem cell-derived neurons, providing validation in a pertinent human cell model. PHD2 inhibition was found to result in increased expression of ATP13A2, mutation of which is responsible for a rare juvenile form of PD known as Kufor-Rakeb syndrome. Knockdown of ATP13A2 expression within human DAergic cells was found to abrogate restoration of cellular iron homeostasis and neuronal cell viability elicited by inhibition of PHD2 under conditions of mitochondrial stress, likely via effects on lysosomal iron storage. These data suggest that regulation of ATP13A2 by the PHD2-HIF1α signaling pathway affects cellular iron homeostasis and DAergic neuronal survival. This constitutes a heretofore unrecognized process associated with loss of ATP13A2 function that could have wide-ranging implications for it as a therapeutic target for PD and other related conditions. SIGNIFICANCE STATEMENT: Reductions in PHD2 activity within dopaminergic neurons in vivo and in cultured human induced pluripotent stem cell-derived neurons protects against mitochondrial stress-induced neurotoxicity. Protective effects are dependent on downstream HIF-1α expression. Knockdown of ATP13A2, a gene linked to a rare juvenile form of Parkinson's disease and recently identified as a novel HIF1α target, was found to abrogate maintenance of cellular iron homeostasis and neuronal viability elicited by PHD2 inhibition in vivo and in cultured dopaminergic cells under conditions of mitochondrial stress. Mechanistically, this was due to ATP13A2's role in maintaining lysosomal iron stores. This constitutes a novel mechanism by which alterations in ATP13A2 activity may be driving PD-related neuropathology.

Sembragiline: A Novel, Selective Monoamine Oxidase Type B Inhibitor for the Treatment of Alzheimer's Disease.

Monoamine oxidase B (MAO-B) has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Increased MAO-B expression in astroglia has been observed adjacent to amyloid plaques in AD patient brains. This phenomenon is hypothesized to lead to increased production of hydrogen peroxide and reactive oxygen species (ROS), thereby contributing to AD pathology. Therefore, reduction of ROS-induced oxidative stress via inhibition of MAO-B activity may delay the progression of the disease. In the present study we report the pharmacological properties of sembragiline, a novel selective MAO-B inhibitor specifically developed for the treatment of AD, and on its effect on ROS-mediated neuronal injury and astrogliosis in MAO-B transgenic animals. Sembragiline showed potent and long-lasting MAO-B-selective inhibition and did not inhibit MAO-A at doses where full inhibition of MAO-B was observed. Such selectivity should translate into a favorable clinical safety profile. Indeed, sembragiline neither induced the serotonin syndrome when administered together with the serotonin precursor l-5-hydroxytryptophan in combination with antidepressants such as fluoxetine, nor potentiated the pressor effect of tyramine. Additionally, in experiments using a transgenic animal model conditionally overexpressing MAO-B in astroglia, sembragiline protected against neuronal loss and reduced both ROS formation and reactive astrogliosis. Taken together, these findings warrant further investigation of the potential therapeutic benefit of MAO-B inhibitors in patients with AD and other neurologic disorders.

Anti-Inflammatory and Neuroprotective Role of Natural Product Securinine in Activated Glial Cells: Implications for Parkinson's Disease.

Glial activation and subsequent release of neurotoxic proinflammatory factors are believed to play an important role in the pathogenesis of several neurological disorders including Parkinson's disease (PD). Inhibition of glial activation and inflammatory processes may represent a therapeutic target to alleviate neurodegeneration. Securinine, a major natural alkaloid product from the root of the plant Securinega suffruticosa, has been reported to have potent biological activity and is used in the treatment of neurological conditions such as amyotrophic lateral sclerosis, poliomyelitis, and multiple sclerosis. In this study, we explored the underlying mechanisms of neuroprotection elicited by securinine, particularly its anti-inflammatory effects in glial cells. Our results demonstrate that securinine significantly and dose-dependently suppressed the nitric oxide production in microglia and astrocytic cultures. In addition, securinine inhibited the activation of the inflammatory mediator NF-κB, as well as mitogen-activated protein kinases in lipopolysaccharide- (LPS-) stimulated BV2 cells. Additionally, securinine also inhibited interferon-γ- (IFN-γ-) induced nitric oxide levels and iNOS mRNA expression. Furthermore, conditioned media (CM) from securinine pretreated BV2 cells significantly reduced mesencephalic dopaminergic neurotoxicity compared with CM from LPS stimulated microglia. These findings suggest that securinine may be a potential candidate for the treatment of neurodegenerative diseases related to neuroinflammation.

Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin.

Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson's disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1α-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1α-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via upregulation of TFEB function. SIGNIFICANCE STATEMENT: Mutations in PARK2 are generally associated with loss in ability to interact with PINK1, impacting on autophagic initiation. Our data suggest that, in the case of at least one parkin mutation, Q311X, detrimental effects are due to inhibition at the level of downstream lysosomal function. Mechanistically, this involves elevations in PARIS protein levels and subsequent effects on PGC1α-TFEB signaling that normally regulates mitochondrial quality control. Treatment with rapamycin independently restores PGC1α-TFEB signaling in a manner not requiring parkin activity and abrogates subsequent mitochondrial impairment and neuronal cell loss. Taken in total, our data suggest that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via rapamycin.

Detrimental effects of oxidative losses in parkin activity in a model of sporadic Parkinson's disease are attenuated by restoration of PGC1alpha.

Loss of parkin E3 ligase activity as a result of parkin gene mutation in rare familial forms of Parkinson's disease (PD) has been shown to be detrimental to mitochondrial function and to contribute to ensuing neurodegeneration. This has been shown by ourselves and others to be in part due to reductions in parkin-mediated ubiquitination of the transcriptional repressor PARIS, limiting the protein's subsequent degradation by the proteasome. Subsequent elevations in PARIS protein levels result in reduced expression of the master mitochondrial regulator PGC-1α, impacting in turn on mitochondrial function. Here, we report that oxidatively-mediated reductions in parkin solubility and function in a mouse model of age-related sporadic PD coincides with increased PARIS levels and reduced PGC-1α signaling. Furthermore, restoration of PGC-1α expression was found to abrogate losses in mitochondrial function and degeneration of dopaminergic (DAergic) neurons within the substantia nigra pars compacta (SNpc) associated with this particular model. These findings suggest that the PGC-1α signaling pathway constitutes a viable therapeutic target for the treatment of not only familial PD, but also more common sporadic forms of the disorder.

Catecholamine metabolism drives generation of mitochondrial DNA deletions in dopaminergic neurons.

Accumulation of mitochondrial DNA deletions is observed especially in dopaminergic neurons of the substantia nigra during ageing and even more in Parkinson's disease. The resulting mitochondrial dysfunction is suspected to play an important role in neurodegeneration. However, the molecular mechanisms involved in the preferential generation of mitochondrial DNA deletions in dopaminergic neurons are still unknown. To study this phenomenon, we developed novel polymerase chain reaction strategies to detect distinct mitochondrial DNA deletions and monitor their accumulation patterns. Applying these approaches in in vitro and in vivo models, we show that catecholamine metabolism drives the generation and accumulation of these mitochondrial DNA mutations. As in humans, age-related accumulation of mitochondrial DNA deletions is most prominent in dopaminergic areas of mouse brain and even higher in the catecholaminergic adrenal medulla. Dopamine treatment of terminally differentiated neuroblastoma cells, as well as stimulation of dopamine turnover in mice over-expressing monoamine oxidase B both induce multiple mitochondrial DNA deletions. Our results thus identify catecholamine metabolism as the driving force behind mitochondrial DNA deletions, probably being an important factor in the ageing-associated degeneration of dopaminergic neurons.

Particulate Exposure at two Arkansas Racinos; Unsafe Environments?

The purpose of this pilot project was to initiate data collection on secondhand smoke (SHS) for two racinos (racetrack casinos) exempted from Arkansas' 2006 Clean Indoor Air Act. Air quality was assessed during regular hours in sites open to the public. All measurements of fine particulates (PM2.5) within both facilities exceeded maximal safe EPA standards for an equivalent 24-hour average exposure. The exemptions as they stand, fail to protect all interested citizens.

The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinson's disease.

In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 to explore its potential neuroprotective effects in models of Parkinson's disease and the potential mechanism(s) underlying such properties. Pre-treatment with D-512 in vitro was found to rescue rat adrenal Pheochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pre-treatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of MPTP, including losses in striatal dopamine, reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for Parkinson's disease.