James Gomes

Role of Hormonal and Other Factors in Human Prostate Cancer

American men have a lifetime risk of about 18% for prostate cancer diagnosis. Large international variations in prostate cancer risks and increased risks among migrants from low- to high-risk countries indicate important roles for environmental factors. Major known risk factors include age, family history, and country/ethnicity. Type 2 diabetes appears to reduce risk, while high birth weight and adult height are linked to increased risk of aggressive prostate cancer. Limited evidence supports an association with a history of sexually transmitted infections. A previous meta-analysis of eight cohort studies indicated no associations with plasma androgen, estrogen, or sex hormone binding globulin (SHBG) levels. However, there were dose-response relationships with baseline plasma testosterone levels in two studies that adjusted for other serum hormones and obesity. Finasteride (a drug that blocks testosterone activation) reduced prostate cancer risk by 25%. Low-frequency genes linked to familial prostate cancer only explain a small fraction of all cases. Sporadic cases were linked to relatively common polymorphisms of genes involved in (1) androgen synthesis, activation, inactivation and excretion, (2) hormone and vitamin D receptors, (3) carcinogen metabolism, and (4) DNA repair. Epidemiologic evidence supports protective roles for dietary selenium, vitamin E, pulses, tomatoes/lycopene, and soy foods, and high plasma 1,25-dihydroxyvitamin D levels. There is inadequate evidence that vegetables, fruit, carotenoids, and vitamins A and C reduce risk and that animal fat, α-linoleic acid, meat, coffee, and tea increase risk. Two major cohort studies found dose-response relationships with dietary calcium intake. Total dietary energy intake may enhance risk. Limited evidence supports a protective role for physical activity and elevated risk for farmers and other men with occupational pesticide exposure, particularly to organochlorine compounds and phenoxy herbicides. There is inadequate evidence for a relationship with alcohol or smoking. Most known or suspected external risk factors may act through hormonal mechanisms, but our review found little supporting evidence, and substantial further research is needed.

Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis

&NA; Although amyotrophic lateral sclerosis (ALS) was identified as a neurological condition 150 years ago, risk factors related to the onset and progression of ALS remain largely unknown. Monogenic mutations in over 30 genes are associated with about 10% of ALS cases. The age at onset of ALS and disease types has been found to influence ALS progression. The present study was designed to identify additional putative risk factors associated with the onset and progression of ALS using systematic review and meta‐analysis of observational studies. Risk factors that may be associated with ALS include: 1) genetic mutations, including the intermediate CAG repeat expansion in ATXN2; 2) previous exposure to heavy metals such as lead and mercury; 3) previous exposure to organic chemicals, such as pesticides and solvents; 4) history of electric shock; 5) history of physical trauma/injury (including head trauma/injury); 6) smoking (a weak risk factor for ALS in women); and 6) other risk factors, such as participating in professional sports, lower body mass index, lower educational attainment, or occupations requiring repetitive/strenuous work, military service, exposure to Beta‐N‐methylamino‐L‐alanin and viral infections. Risk factors that may be associated with ALS progression rate include: 1) nutritional status, including vitamin D deficiency; 2) comorbidities; 3) ethnicity and genetic factors; 4) lack of supportive care; and 4) smoking. The extent to which these associations may be causal is discussed, with further research recommended to strengthen the evidence on which determinations of causality may be based.

A meta-analysis of observational studies of the association between chronic occupational exposure to lead and amyotrophic lateral sclerosis.

Objective: The association between occupational exposure to lead and amyotrophic lateral sclerosis (ALS) was examined through systematic review and meta-analyses of relevant epidemiological studies and reported according to PRISMA guidelines. Methods: Relevant studies were searched in multiple bibliographic databases through September 2013; additional articles were tracked through PubMed until submission. All records were screened in DistillerSR, and the data extracted from included articles were synthesized with meta-analysis. Results: The risk of developing ALS among individuals with a history of exposure to lead was almost doubled (odds ratio, 1.81; 95% confidence interval, 1.39 to 2.36) on the basis of nine included case-control studies with specific lead exposure information, with no apparent heterogeneity across included studies (I2 = 14%). The attributable risk of ALS because of exposure to lead was estimated to be 5%. Conclusions: Previous exposure to lead may be a risk factor for ALS.

Systematic reviews of factors associated with the onset and progression of neurological conditions in humans: A methodological overview.

&NA; As a component of the National Population Health Study of Neurological conditions, systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 priority neurological conditions. Between 2011 and 2013, electronic databases and grey literature sources were searched to identify systematic reviews and primary studies reporting on the onset and progression of each condition. Inclusion was restricted to studies of humans reported in English or French. Additional condition‐specific eligibility criteria were also applied. Titles and abstracts were screened by one reviewer with excluded records verified by a second reviewer. Full‐text reports were screened independently by two reviewers. Disagreements were resolved by consensus or third party adjudication. Systematic reviews were quality appraised using the AMSTAR criteria, with only moderate and high quality reviews considered for inclusion. Primary studies were also sought to ensure that evidence from existing systematic reviews was supplemented with recent primary study findings (i.e., those published after the most recent systematic review). Evidence from primary studies was also considered if a systematic review was unavailable or of poor quality. Data were extracted using standardized forms. Where feasible, data were extracted independently by two reviewers. Otherwise, data were extracted by a single reviewer and independent data extraction by a second reviewer was conducted for a randomly selected sample of studies. An updated search was conducted in 2016 to identify systematic reviews published since the initial search in 2011–2013. A summary of the methodology used to conduct the systematic reviews is described. Illustrative results are provided for the risk of amyotrophic lateral sclerosis in relation to occupational exposure to lead and other heavy metals HighlightsFormal methods of systematic review were used to identify scientific publications on factors affecting the onset and progression of 14 priority neurological conditions according to pre‐defined search terms and appropriate inclusion/exclusion criteria.Distiller SR was used for data abstraction, and preparation of summary tables on the results of the systematic review.In cases where the volume of literature was large, results from pre‐existing high quality systematic reviews were updated.Where possible, meta‐analyses of multiple studies on the same risk factor were conducted.Syntheses of the findings across all 14 priority neurological conditions were also prepared.

Intermediate CAG repeat expansion in the ATXN2 gene is a unique genetic risk factor for ALS--a systematic review and meta-analysis of observational studies.

Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30–33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91–6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58–8.17) and sporadic ALS cases (OR = 3.16, 1.88–5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.

Risk factors associated with the onset and progression of Alzheimer’s disease: A systematic review of the evidence

&NA; A systematic review was conducted to identify risk factors associated with the onset and progression of Alzheimers disease (AD). Moderate and high quality systematic reviews were eligible for inclusion. Primary studies reporting on non‐genetic risk factors associated with neuropathologically or clinically confirmed AD were considered. Eighty one systematic reviews reporting on AD onset and 12 reporting on progression satisfied the eligibility criteria. Four hundred and thirty‐two relevant primary studies reporting on onset were identified; however, only those published between 2010 and 2012 (n = 65) were included in the qualitative synthesis. Several factors including statins, light‐to‐moderate alcohol consumption, compliance with a Mediterranean diet, higher educational attainment, physically and cognitively stimulating activities, and APOE &egr;2 appeared to be associated with a decreased risk of AD onset. The evidence was suggestive of an increased risk of AD associated with head injury in males, age, diabetes mellitus, conjugated equine estrogen use with medroxyprogesterone acetate, current smoking, and lower social engagement. With respect to genetic factors, APOE &egr;4 remained the strongest predictor of AD. Physical and cognitive activities were associated with a beneficial effect on cognitive function and other indicators of dementia progression while higher educational attainment was associated with faster cognitive decline. Although suggestive of an association, the current evidence for a majority of the identified putative factors for AD onset and progression was weak, at best due to conflicting findings across studies or inadequate evidence. Further research is required to confirm the etiological or protective role of a number of risk factors. HighlightsAlzheimers disease (AD) involves irreparable neuronal degeneration causing thinking ability and memory to deteriorate.Most AD cases are not inherited and are described as “sporadic”. Inherited or “familial” cases account for less than 5% of all cases of AD.Several factors including age, head injuries, smoking, lower social engagement, and APOE &egr;4 are associated with increased risk of AD.Factors including statins, light to moderate alcohol intake, physical and cognitive activities, and APOE &egr;2 are associated with decreased risk.A number of risk factors are potentially modifiable and may be targeted for prevention.

Oral exposure of male and female mice to formulations of organophosphorous pesticides: congenital malformations

Birth outcome was studied in pre-partum litters of mice exposed to oral doses of organophosphorous pesticides at low and high concentrations before mating. Exposed and unexposed pregnant dams were delivered by Caesarean section 1 day before partum, the fetuses were collected, counted and weighed, and the numbers of resorptions were recorded. Live litter sizes were non-significantly higher in all the exposed groups compared with the control group. The numbers of resorptions were significantly higher in all the exposed groups than in the comparison groups. The incidence of intra-uterine growth retardation was significantly higher in all the exposed groups than in the comparison groups. The incidences of congenital malformations were significantly higher in the exposed groups than in one or more of the comparison groups for the defects of the ears, eyes, jaws, brain, and tongue in all the exposed groups. Low set microtia, cataract or open eyelids, microcephaly or anencephaly, maxillary or mandibular hypoplasia, and protruding tongue were observed in all groups, but the numbers were significantly higher in the exposed groups compared with one or more of the comparison groups. Curled or missing tail and intra-auricular septal or intra-ventricular septal defects were observed in higher numbers in the groups in which both the males and the females were exposed than in the comparison groups. Male:female sex ratios were significantly higher in the groups in which males only and females only were exposed.

Genetic variation associated with the occurrence and progression of neurological disorders.

This paper presents an overview of genetic variation associated with the onset and progression of 14 neurological disorders, focusing primarily on association studies. The 14 disorders are heterogeneous in terms of their frequency, age of onset, etiology and progression. There is substantially less evidence on progression than onset. With regard to onset, the conditions are diverse in terms of their epidemiology and patterns of familial aggregation. While the muscular dystrophies and Huntingtons disease are monogenic diseases, for the other 12 conditions only a small proportion of cases is associated with specific genetic syndromes or mutations. Excluding these, some familial aggregation remains for the majority of cases. There is considerable variation in the volume of evidence by condition, and by gene within condition. The volume of evidence is greatest for Alzheimers disease, Parkinsons disease, multiple sclerosis and amyotrophic lateral sclerosis. As for common complex chronic diseases, genome wide association studies have found that validated genomic regions account for a low proportion of heritability. Apart from multiple sclerosis, which shares several susceptibility loci with other immune-related disorders, variation at HLA-DRB5 being associated both with Parkinsons disease and Alzheimers disease, and the association of the C9orf72 repeat expansion with ALS and frontotemporal degeneration, there was little evidence of gene loci being consistently associated with more than one neurological condition or with other conditions. With the exception of spina bifida, for which maternal MTHFR genotype is associated with risk in the offspring, and corroborates other evidence of the importance of folate in etiology, there was little evidence that the pathways influenced by genetic variation are related to known lifestyle or environmental exposures.

A systematic review of the risk factors associated with the onset and progression of primary brain tumours

&NA; The overall aim of this systematic review was to identify risk factors for onset and natural progression, which were shown to increase, decrease, or have a null association with risk of primary brain tumour. For onset, the project was separated into two phases. The first phase consisted of a systematic search of existing systematic reviews and meta‐analyses. Moderate to high methodological quality reviews were incorporated and summarized with relevant observational studies published since 2010, identified from a systematic search performed in phase 2. For natural progression, only the first phase was conducted. Standard systematic review methodology was utilized. Based on this review, various genetic variants, pesticide exposures, occupational farming/hairdressing, cured meat consumption and personal hair dye use appear to be associated with increased risk of onset amongst adults. The specific EGF polymorphsm 61‐A allele within Caucasian populations and having a history of allergy was associated with a decreased risk. For progression, M1B‐1 antigen was shown to increase the risk. High birth weight, pesticide exposure (childhood exposure, and parental occupational exposure) and maternal consumption of cured meat during pregnancy may also increase the risk of onset of childhood brain tumours. Conversely, maternal intake of pre‐natal supplements (folic acid) appeared to decrease risk. Children with neurofibromatosis 2 were considered to have worse overall and relapse free survival compared to neurofibromatosis 1, as were those children who had grade III tumours compared to lesser grades. HighlightsPrimary brain tumors (PBTs) originate in brain cells, nerves or glands in the brain, or the membranes around the brain (meninges).The annual incidence of PBTs is approximately 10.8 per 100,000.Genetic syndromes associated with PBTs include neurofibromatosis 1 and 2 (NF‐1, NF‐2), Li‐Fraumeni syndrome, Von Hippel‐Lindau (VHL) disease, tuberous sclerosis complex, Turcots syndrome, and Gorlins syndrome.Possible risk factors that could be targeted for prevention include birth weight >4000 g, maternal consumption of cured meats during pregnancy (for pediatric brain tumours), and pesticide exposure.

Determinants of neurological disease: Synthesis of systematic reviews

&NA; Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally. HighlightsWith population aging, the burden of neurological disease is increasing worldwide.Understanding the factors affecting the onset and progression of neurological disease through systematic review is essential for the development of strategies to reduce the burden of these diseases.Systematic review identified biological, demographic, environmental, genetic, lifestyle and pharmacological risk factors for specific neurological conditions.Several risk factors were associated with the onset of multiple conditions. Pesticides, for example, were associated with an increased risk of Alzheimers disease, amyotrophic lateral sclerosis, primary brain tumours, and Parkinsons disease.Helmet use was associated with a reduction in onset of neurotrauma, as well as all neurologic conditions for which head injury was a risk factor.The findings presented here should be viewed as provisional, pending a more in‐depth evaluation of the weight of evidence.Further research will also serve to fill current data gaps, particularly regarding risk factors for the progression of neurological disease.In the interim, the modifiable risk factors may be considered as potential candidates for the development of targeted interventions to reduce the burden of neurological disease in Canada and internationally.