Prevalence of Parkinson's disease across North America.

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

Passive smoking and Parkinson's disease in California Teachers.

INTRODUCTION: Tobacco smoking is consistently inversely associated with Parkinson's disease (PD) in men and women; recently this has been related to reverse causation, prompting questions as to whether similar patterns exist for passive smoke exposure. We used baseline and follow-up data from the California Teachers Study, a prospective cohort of women, to investigate whether timing, location and cumulative measures of intensity and duration of passive smoke exposure are associated with PD risk. METHODS: Using a nested case-control approach, we included 224 diagnostically validated cases (158 with no history of personal smoking) and selected 3230 age- and race-matched controls (1973 with no history of personal smoking). We estimated odds ratios(ORs) and 95% confidence intervals(CI) by fitting adjusted multivariable unconditional logistic regression models. RESULTS: Among lifelong non-smokers, passive smoke exposure combined across all settings and accumulated over a lifetime was not associated with PD risk (OR = 1.18, 95% CI 0.60, 2.30). Workplace exposure was also not associated with risk. Household exposure during adulthood but not childhood was inversely associated with PD (OR = 0.59, 95% CI 0.40, 0.87). Exposure to passive smoke in other social settings was positively associated with PD (OR = 1.62, 95% CI 1.11, 2.36). These contradictory results may be attributable to chance due to multiple comparisons in subgroup analyses. No pattern emerged to suggest that increasing years of passive smoke exposure, smokiness of the setting, or combined smokiness by exposure years was associated with lower PD risk. CONCLUSION: Results do not convincingly support a protective effect of passive smoking in PD.

[Heart failure provoked by a pacemaker lead-induced tricuspid stenosis]. / Insuffisance cardiaque par rétrécissement tricuspidien provoqué par une sonde d'électrostimulation. À propos d'un cas.

Tricuspid stenosis (TS) is an uncommon complication of ventricular pacemaker implantation. Mechanisms described by the literature are ventricular inflow obstruction by tricuspid vegetations (endocarditis) or multiple pacemaker leads and fibrosis secondary to mechanical trauma, accounting for perforation or laceration of the TV leaflets, or adherence between redundant loops and valve tissue. We present the case of iatrogenic tricuspid stenosis, observed in a 77-year-old man. Extrinsic tricuspid valve stenosis was detected by transthoracic echocardiography. Further investigations confirmed the intramyocardial lead position. Tricuspid valve stenosis due to transvenous leads are reported to be treated by surgical replacement, surgical valvuloplasty, or percutaneous balloon valvuloplasty.

Psychosocial stressors and lung function in youth ages 10-17: an examination by stressor, age and gender.

Background: Research on the impact of psychosocial stressors on child and adolescent lung function is uncommon, and has primarily relied either on parents' own stress measures or parent-reported stressors the child experienced, which may be a poor proxy for perceived stress in older children and adolescents. Methods: We performed multivariate linear regression of spirometry measures (FVC, FEV1 and FEF25-75) and psychosocial stressors in 584 adolescents in the Los Angeles Family and Neighborhood Survey. We examined family conflict, unsafe neighborhood or school, and the absence of a father in models stratified by gender, adjusting for PM2.5 and potential confounders. Results: We observed reductions in lung function in males related to the absence of a father in the house (FEV1: -176.2 ml, 95% CI -322.7, -29.7) and family conflict (FEV1: -156.2 ml, 95% CI -327.8, 15.5); associations were stronger in older males ages 15-17 years for each stressor (P for interaction of age and sex was 0.009 and 0.06, respectively). Conclusions: This research informs a very small literature on psychosocial stressors and lung function in adolescents. Our finding of differential vulnerability by age and gender warrants further exploration of adolescent psychosocial stressor response on lung function.

Fast food consumption in pregnancy and subsequent asthma symptoms in young children.

BACKGROUND: Recent cross-sectional studies suggested children's current fast food consumption to be related to frequency of asthma and allergies. Maternal prenatal diet has been suspected to contribute to children's asthma and atopic disease risks. OBJECTIVES: We hypothesized that maternal fast food intake during pregnancy increases offspring's risk for asthmatic symptoms. METHODS: We conducted a population-based study of 1201 mother/child pairs in Los Angeles, California. Detailed information about prenatal fast food intake and other dietary, lifestyle/environmental factors, and pregnancy was collected shortly after birth; further data were retrieved from birth certificates. Using the International Study of Asthma and Allergies in Childhood core questions, asthma and rhinitis symptoms were assessed, and doctor's diagnoses were recorded in offspring 3.5 years after birth. Poisson regression with robust error variance using a log link function was used to estimate relative risks (RRs). Models were adjusted using covariates or propensity scores. RESULTS: Maternal prenatal fast food consumption related to increased relative risks of their children for severe, and current asthma symptoms (wheeze last 12 months combined with doctor's diagnosis) in a dose-dependent manner: 'once a month': RR: 0.99 (95% CI: 0.36, 2.75), 'once a week': 1.26 (0.47, 3.34); '3-4 days a week': 2.17 (0.77, 6.12); and 'every day' 4.46 (1.36 14.6) compared to 'never', adjusting for potential confounders (p for trend = 0.0025). There was also suggestion of increased risks for rhinitis symptoms. CONCLUSIONS: These findings suggest that in utero exposure to frequent fast food through maternal diet may be a risk factor for asthmatic symptoms in young children.

Head injury, α-synuclein genetic variability and Parkinson's disease.

BACKGROUND AND PURPOSE: Head injury has been linked to Parkinson's disease (PD) in some but not all studies. Differences in the genetic and environmental susceptibility to PD between populations might be one explanation. The joint effects of head injuries and SNCA genetic variants were investigated. METHODS: From 2001 to 2012, 561 incident idiopathic PD cases and 721 population controls from central California were enrolled. Subjects reported on head injuries throughout their lifetime and were assessed for genetic variability in the SNCA 5' region (D4S3481; Rep1) and 3' untranslated region (rs356165). In unconditional logistic regression models adjusted for confounders, interactions between head injuries and genetic risk variants were investigated. RESULTS: Parkinson's disease risk in individuals with head injury who are carriers of at least one 263 bp allele in D4S3481 or rs356165 variants was 3-4.5-fold higher compared with non-carriers without head injuries. However, tests for interaction between head injury and SNCA D4S3481or rs356165 were not statistically significant. CONCLUSIONS: Our study finds some evidence that head injury and D4S3481 or rs356165 variants jointly increase the risk of PD but little evidence of interaction.

Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson's Disease: An Observational and Case-Control Study.

BACKGROUND/OBJECTIVES: The common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson's disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD. METHODS: For immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD. RESULTS: Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses. CONCLUSIONS: In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression.

Lifetime exposure to estrogens and Parkinson's disease in California teachers.

INTRODUCTION: Parkinson's disease (PD) is consistently observed to occur less frequently in women than men, prompting investigation into whether estrogen protects against neurodegeneration of dopaminergic neurons. METHODS: We used baseline data in the California Teachers Study, a prospective cohort of women, to investigate whether reproductive factors indicating higher long-term estrogen levels are associated with PD using a nested case-control approach. We identified 228 PD cases and 3349 unaffected controls frequency matched by age and race. RESULTS: Women who reported using combined estrogen/progesterone therapy or progesterone only formulations had a 57% increase in PD risk (OR = 1.57, 95% CI = 1.06, 2.34) compared to never having used HT. Compared to women with menopause at 50-52 years, menopause at younger (<35-46 years: OR = 0.59, 95% CI = 0.37, 0.94) and older ages (≥53 years: OR = 0.54, 95% CI = 0.36, 0.83) had lower PD risk. A derived composite estrogen summary score for women's exposure to both endogenous and exogenous estrogens throughout life indicated that women with presumed higher cumulative lifetime levels of estrogen (a score of 3-5) had a significantly reduced PD risk [(OR = 0.57, 95% CI = 0.35, 0.91) relative to those with lower lifetime estrogen exposure or a composite estrogen summary score of 0-1]. CONCLUSIONS: These results provide some support for the hypothesis that lifelong high estrogen is protective in PD, suggesting that the level and persistence of exposure over the long term may be important in PD risk reduction.

Reproductive factors and Parkinson's disease risk in Danish women.

BACKGROUND AND PURPOSE: Parkinson's disease is more common in men than women by a ratio of about 1.5:1 and yet there is no consensus to date as to whether female reproductive factors including hormone use affect Parkinson's disease risk. Our objective was to examine the relationship between Parkinson's disease and female reproductive factors in the largest population-based Parkinson's disease case-control study to date. METHODS: Seven hundred and forty-three female Parkinson's disease cases diagnosed between 1996 and 2009 were selected from the Danish National Hospital Register, diagnoses confirmed by medical record review, and the cases were matched by birth year to 765 female controls randomly selected from the Danish Civil Registration System. Covariate information was collected in computer-assisted telephone interviews covering an extensive array of topics including reproductive and lifestyle factors. RESULTS: After adjusting for smoking, caffeine and alcohol use, education, age, and family Parkinson's disease history, inverse associations between Parkinson's disease and early menarche (first period at ≤11 years), oral contraceptives, high parity (≥4 children) and bilateral oophorectomy were found; adjusted odds ratios and 95% confidence limits were respectively 0.68 (0.45-1.03) for early menarche, 0.87 (0.69-1.10) for oral contraceptives, 0.79 (0.59-1.06) for high parity and 0.65 (0.45-0.94) for bilateral oophorectomy. Little support for associations between Parkinson's disease and fertile life length, age at menopause or post-menopausal hormone treatment was found. CONCLUSIONS: Reproductive factors related to women's early- to mid-reproductive lives appear to be predictive of subsequent Parkinson's disease risk whereas factors occurring later in life seem less important.

[Platypnea-orthodeoxia syndrome: case report]. / Le syndrome de platydéoxie-orthopnée : à propos d'un cas.

We report the case of an 80-year-old woman with symptomatic postural hypoxaemia caused by a right-to-left shunt through a patent foramen ovale. The hypoxaemia was enhanced by the supine position and disappeared in upright position. Potential mechanisms underlying postural variations of the shunt seemed to be similar to those describe in platypnea-orthodeoxia syndrome. Patient became asymptomatic after shunt resolution.

Psychosocial risk factors, pre-motor symptoms and first-time hospitalization with Parkinson's disease: a prospective cohort study.

BACKGROUND AND PURPOSE: Experimental studies support a link between stress and development of parkinsonian symptoms, but prospective population studies are lacking. The aim of the current study is to determine the effects of several psychosocial factors on the risk of Parkinson's disease (PD), as well as to identify potential pre-motor symptoms for PD in a large prospective cohort study. METHODS: In 1991-1993, a total of 9955 women and men free of PD from the Copenhagen City Heart Study were asked about major life events, economic hardship, social network, impaired sleep and vital exhaustion. The participants were followed for first-time hospitalization with PD in nationwide registers until 2011. RESULTS: Vital exhaustion was associated with a higher risk of PD hospitalization in an exposure-dependent manner (P(trend) = 0.001), with high vs. low vital exhaustion being associated with a hazard ratio of 2.50 [95% confidence interval (CI): 1.28-4.89]. A slightly higher risk of PD hospitalization (hazard ratio = 1.49; 95% CI: 0.87-2.56) was suggested in participants with impaired sleep at baseline. No more than weak associations were observed for economic hardship, major life events or inadequate social network in the current study. CONCLUSIONS: Overall, the hypothesis that psychosocial risk factors affect the risk of PD is not supported. The results, however, suggest that vital exhaustion may be a pre-motor marker of the neurodegenerative process eventually leading to motor symptoms and clinical PD. Vital exhaustion may be useful for screening aimed at early detection and when considering disease-modifying therapies in people at high risk of clinical PD.

Major life events and development of major depression in Parkinson's disease patients.

BACKGROUND AND PURPOSE: Non-motor symptoms including depression are important features of Parkinson's disease (PD). We aim to address the relationship between major life events and depression amongst PD patients free of depressive symptoms at baseline. METHODS: New-onset PD patients from California were recruited in 2001-2007 and followed up for 3-4 years. The participants (n=221) were examined by neurologists and responded to comprehensive interviews that included major life events, social support, and coping measures from validated scales. Major depression was assessed using the Structured Clinical Interview for the DSM-IV depression module (SCID). RESULTS: More than half of all patients had experienced major life events since diagnosed with PD, and 22 patients developed a major depression. The number of life events was associated with risk of depression in an exposure-dependent manner, with each additional event being associated with a 56% higher risk of depression (95% CI: 1.23-1.98). Most individual life events were associated with a two- to eight-fold higher risk of depression. Patients with low social support or coping capacities seemed to be particularly susceptible to developing depression after experiencing major life events. CONCLUSIONS: Life events play an important role for onset of depression in patients with PD; an effect that seems to be modulated by social support and coping capacities and these factors may therefore be important to assess in order to identify patients with PD at high risk of depression and provide effective interventions.

Treatment for Helicobacter pylori infection and risk of Parkinson's disease in Denmark.

BACKGROUND AND PURPOSE: It has been speculated that gastrointestinal infection with Helicobacter pylori (HP) contributes to the development of Parkinson's disease (PD). We used nationwide Danish registers to investigate this hypothesis. METHODS: We identified 4484 patients with a first time PD diagnosis between 2001 and 2008 from the Danish National Patient Register (DNPR) and 22, 416 population controls from the Danish Civil Registration System (CRS). Information on drug use was obtained from the National Prescription Registry (NPR). We used logistic regression to compute odds ratios (OR) for the association between treatment for HP and risk of PD. RESULTS: Prescriptions for HP-eradication drugs and proton pump inhibitors (PPI) 5 or more years prior to the diagnosis of PD were associated with a 45% and 23% increase in PD risk, respectively. Hospitalizations and outpatient visits for gastritis and peptic/duodenal ulcers, however, were not associated with PD. CONCLUSIONS: Our population-based study suggests that chronic HP infections and/or gastritis contribute to PD or that these are PD-related pathologies that precede motor symptoms.

Association of DRD2 and DRD3 polymorphisms with Parkinson's disease in a multiethnic consortium.

OBJECTIVE: To examine genetic associations of polymorphisms in the dopamine receptor D2 (DRD2) and D3 (DRD3) genes with risk of Parkinson's disease (PD). METHODS: The study included 1325 newly diagnosed patients with PD and 1735 controls from a consortium of five North American case-control studies. We collected risk factor information by in-person or telephone interview. Six DRD2 and two DRD3 polymorphisms were genotyped using a common laboratory. Odds ratios were estimated using logistic regression. RESULTS: Among non-Hispanic whites, homozygous carriers of Taq1A DRD2 (rs1800497) polymorphism had an increased risk of PD compared to homozygous wildtype carriers (OR=1.5, 95% CI 1.0-2.3). In contrast, the direction of association for Taq1A polymorphism was opposite for African-Americans, showing an inverse association with PD risk (OR=0.10, 95% CI 0.2-0.7). Among white Hispanics who carried two alleles, the Ser9Gly DRD3 (rs6280) polymorphism was associated with a decreased risk of PD (OR=0.4, 95% CI 0.2-0.8). The inverse association of smoking with PD risk was not modified by any of the DRD2 or DRD3 polymorphisms. CONCLUSIONS: DRD2 polymorphisms are unlikely to be true disease-causing variants; however, three DRD2 polymorphisms (including Taq1A) may be in linkage disequilibrium with possible disease associated variants in the DRD2-ANKK1-NCAM1-TTC12 gene cluster.

Elevated blood levels of inflammatory monocytes (CD14+ CD16+ ) in patients with complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a chronic pain disorder. Although its pathophysiology is not completely understood, neurogenic inflammation is thought to play a significant role. Microglia and astrocytes are activated following tissue injury or inflammation and have been reported to be both necessary and sufficient for enhanced nociception. Blood-borne monocytes/macrophages can infiltrate the central nervous system (CNS) and differentiate into microglia resulting in hypersensitivity and chronic pain. The primary aim of this study was to evaluate the proportion of the proinflammatory CD14(+) CD16(+) monocytes as well as plasma cytokine levels in blood from CRPS patients compared to age- and gender-matched healthy control individuals. Forty-six subjects (25 CRPS, 21 controls) were recruited for this study. The percentage of monocytes, T, B or natural killer (NK) cells did not differ between CRPS and controls. However, the percentage of the CD14(+) CD16(+) monocyte/macrophage subgroup was elevated significantly (P<0·01) in CRPS compared to controls. Individuals with high percentage of CD14(+) CD16(+) demonstrated significantly lower (P<0·05) plasma levels on the anti-inflammatory cytokine interleukin (IL)-10. Our data cannot determine whether CD14(+) CD16(+) monocytes became elevated prior to or after developing CRPS. In either case, the elevation of blood proinflammatoty monocytes prior to the initiating event may predispose individuals for developing the syndrome whereas the elevation of blood proinflammatory monocytes following the development of CRPS may be relevant for its maintenance. Further evaluation of the role the immune system plays in the pathogenesis of CRPS may aid in elucidating disease mechanisms as well as the development of novel therapies for its treatment.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

Occurrence of depression and anxiety prior to Parkinson's disease.

OBJECTIVE: To assess the relationship between depression and anxiety and Parkinson's disease (PD). BACKGROUND: Many people with PD suffer from depression and anxiety prior to the onset of motor symptoms. Studies suggest these psychiatric conditions may be risk factors for PD or prodromal non-motor symptoms. METHODS: Using a population-based approach in three California counties, we recruited 371 incident PD cases, 402 population and 115 sibling controls. We recorded self-reports of lifetime depression/anxiety diagnoses and use of psychotropic medications. We adjusted for age, race, sex, pack-years of smoking, and education, and also conducted analyses after excluding (lagging) both diagnoses and medication use first occurring within 2, 5, 10, and 20 years of the index/diagnosis date. RESULTS: Cases were more likely to have received a diagnosis of depression or anxiety at any time prior to index date (OR 1.42, 95% CI 1.01, 2.00), but were not more likely to have been both diagnosed and treated (OR 1.11, 95% CI 0.77, 1.60). Male PD patients received diagnoses combined with treatment more often than population controls within 5 years of PD diagnosis (OR 2.21, 95% CI 1.21, 4.04; 2 year lag: OR 2.44, 95% CI 1.29, 4.61; 5 year lag: OR 1.67, 95% CI 0.80, 3.49). We did not see any differences for females. Results for cases compared to sibling controls were similar to those for population controls. CONCLUSION: These results suggest that depression and anxiety may be early symptoms during the prodromal phase of PD.

Familial associations of Alzheimer disease and essential tremor with Parkinson disease.

BACKGROUND: We constructed a cohort of first-degree relatives of participants in a population-based case-control study of Parkinson disease (PD) and compared the occurrence of Alzheimer disease (AD) and essential tremor (ET) in relatives of PD cases and controls. METHODS: We relied on proband interviews to assess family history in 372 probands with incident PD confirmed by a movement disorder specialist and 404 controls from three rural California counties. RESULTS: Overall, for the 2980 first-degree relatives of PD cases, the risk of AD was not increased compared with the 2981 relatives of controls. But relatives of younger onset PD cases (

Autoimmune disease and risk for Parkinson disease: a population-based case-control study.

OBJECTIVE: Inflammatory mediators are increased in autoimmune diseases and may activate microglia and might cause an inflammatory state and degeneration of dopaminergic neurons in the brain. Thus, we evaluated whether having an autoimmune disease increases the risk for developing Parkinson disease (PD). METHODS: A population based case-control study was conducted in Denmark of 13,695 patients with a primary diagnosis of PD recorded in the Danish National Hospital Register during the period 1986-2006. Each case was matched on year of birth and sex to 5 population controls selected at random from among inhabitants of Denmark who were alive at the date of the patient's diagnosis. The main exposure measure was a hospital diagnosis of 1 of 32 selected autoimmune diseases recorded 5 or more years before the index date in the files of the Danish Hospital Register. RESULTS: We observed no overall association between a diagnosis of autoimmune disease and risk for subsequent PD (odds ratio 0.96, 95% confidence interval 0.85-1.08). In a subgroup of patients with autoimmune diseases with systemic involvement, primarily rheumatoid arthritis, we saw a decrease in risk for PD of 30%. CONCLUSIONS: Our results do not support the hypothesis that autoimmune diseases increase the risk for Parkinson disease. The decreased risk observed among patients with rheumatoid arthritis might be explained by underdiagnosis of movement disorders such as Parkinson disease in this patient group or by a protective effect of the treatment with anti-inflammatory drugs over prolonged periods.