Early changes in tests of peripheral nerve function during oxaliplatin treatment and their correlation with chemotherapy-induced polyneuropathy symptoms and signs.

BACKGROUND AND PURPOSE: Assessment of the severity of chronic peripheral neuropathy during oxaliplatin treatment is based on symptoms. Efforts to adjust the total dose of oxaliplatin to prevent severe neuropathy can be complicated by the worsening of neuropathy symptoms following treatment. Objective measures of the structure and function of peripheral nerves during early phases of treatment may aid in determining the optimal oxaliplatin dose in individual patients. Intraepidermal nerve fibre density (IENFD) has been suggested as an early marker of peripheral neuropathy. METHODS: Sixty patients were examined before treatment and following 25% and 50% of the total planned oxaliplatin dose. Fifty-five of them were also examined at completion of chemotherapy and 6 months later. IENFD in skin biopsies from the distal leg, nerve conduction studies and quantitative sensory testing at the dorsum of the foot were performed. Forty-six healthy subjects were examined at baseline and after 6 and 52 weeks for comparison. RESULTS: Intraepidermal nerve fibre density was not reduced during treatment. Sural nerve amplitude and conduction velocity, vibration detection thresholds, mechanical detection threshold and cold detection threshold were significantly reduced during treatment. Compared to reference values and spontaneous changes in healthy subjects, the largest proportions of patients with deterioration were found for vibration detection thresholds followed by nerve conduction studies, mechanical detection threshold, cold detection threshold and IENFD. CONCLUSIONS: Significant changes were most pronounced for measures of large nerve fibre function, especially vibration sensation. Skin biopsies do not seem to provide a clinically relevant objective measure of peripheral nerve deterioration during oxaliplatin treatment.

Screening for late-onset Pompe disease in western Denmark.

OBJECTIVE: Late-onset Pompe disease (LOPD) is a rare autosomal recessively inherited metabolic myopathy caused by reduced activity of the lysosomal enzyme alpha-glucosidase. In a previous screening study at two large neuromuscular university clinics in Denmark, three patients with LOPD were identified out of 103 patients screened. No systematic screening has been performed at the other neurological departments in the western part of Denmark. Thus, patients with a diagnosis of unspecified myopathy were screened for LOPD. MATERIALS AND METHODS: At seven neurological departments in the western part of Denmark, medical records were evaluated for all patients registered with myopathy diagnosis codes (ICD 10 codes: G 71.0-71.9 and G 72.0-72.9) during the period January 1, 2002, to December 31, 2012. If no specific diagnosis has been reached, patients were invited for screening. Dried blood spot (DBS) test was used to analyze the activity of the enzyme alpha-glucosidase. RESULT: A total of 654 patients were identified. From the medical records, information was obtained concerning symptoms, family history, electromyography, muscle biopsy results and creatine kinase levels. Eighty-seven patients (13.3%) (males 61%) at a mean age of 53.3 years (SD 16.5) fulfilled the criteria for screening. A DBS test was performed in 47 (54%) patients. In all patients, the enzyme activity was within reference values. CONCLUSION: None of the screened patients had a reduced activity of the enzyme alpha-glucosidase. Although the cohort studied was small, our findings do not suggest that LOPD is underdiagnosed in patients with unspecified myopathy in western Denmark.

Incidence of intracranial bleeds in new users of low-dose aspirin: a cohort study using The Health Improvement Network.

Essentials Intracranial bleeds (ICB) are serious clinical events that have been associated with aspirin use. Incidence rates of ICB were calculated among new-users of low-dose aspirin in the UK (2000-2012). Over a median follow-up of 5.58 years, the incidence of ICB was 0.08 per 100 person-years. Our estimates are valuable for inclusion in risk-benefit assessments of low-dose aspirin use. SUMMARY: Background Low-dose aspirin protects against both ischemic cardiovascular (CV) events and colorectal cancer (CRC). However, low-dose aspirin may be associated with a slightly increased risk of intracranial bleeds (ICBs). Objectives To obtain the incidence rates of ICBs overall and by patient subgroups among new users of low-dose aspirin. Patients/Methods Using The Health Improvement Network (THIN) UK primary-care database (2000-2012), we identified a cohort of new users of low-dose aspirin aged 40-84 years (N = 199 079; mean age at start of follow-up, 63.9 years) and followed them for up to 14 years (median 5.58 years). Incident ICB cases were identified and validated through linkage to hospitalization data and/or review of THIN records with free-text comments. Incidence rates with 95% confidence intervals (CIs) were calculated. Results Eight hundred and eighty-one incident ICBs cases were identified: 407 cases of intracerebral hemorrhage (ICH), 283 cases of subdural hematoma (SDH), and 191 cases of subarachnoid hemorrhage (SAH). Incidence rates per 100 person-years were 0.08 (95% CI 0.07-0.08) for all ICBs, 0.04 (95% CI 0.03-0.04) for ICH, 0.03 (95% CI 0.02-0.03) for SDH, and 0.02 (95% CI 0.01-0.02) for SAH. The ICB incidence rates per 100 person-years for individuals with an indication of primary CV disease prevention were 0.07 (95% CI 0.06-0.07) and 0.09 (95% CI 0.08-0.10) for secondary CV disease prevention. Incidence rates were higher in men for SDH, and higher in women for ICH and SAH. Conclusions Our results provide valuable estimates of the absolute ICB risk for incorporation into risk-benefit assessments of low-dose aspirin use.

Statin use and risk of nonmelanoma skin cancer: a nationwide study in Denmark.

BACKGROUND: Evidence is conflicting regarding statin use and risk of basal cell (BCC) and squamous cell skin cancer (SCC). METHODS: Using Danish nationwide registries, we identified all patients with incident BCC/SCC during 2005-2009 and matched them to population controls. We computed odds ratios (ORs) for BCC and SCC associated with statin use. RESULTS: We identified 38,484 cases of BCC and 3724 cases of SCC. Statin ever use was associated with ORs of 1.09 (CI: 1.06-1.13) for BCC and 1.01 (CI: 0.91-1.11) for SCC. CONCLUSIONS: Statin use was not associated with risk of SCC. Residual confounding plausibly explains the marginally increased risk of BCC.

Myasthenia and risk of cancer: a population-based case-control study.

BACKGROUND AND PURPOSE: To evaluate the association between having non-thymoma myasthenia and the risk of extra-thymic cancer in a population-based setting. METHODS: A nationwide case-control study was conducted in Denmark based on medical registries. The study included all cases with a first time diagnosis of cancer during 2000-2009. Each case was matched by birth year and gender with eight population controls using risk set sampling. Subjects with myasthenia were identified through a validated register-based algorithm. Conditional logistic regression was used to compute crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs), for cancer associated with a prior diagnosis of myasthenia. RESULTS: In all, 233 437 cases and 1 867 009 controls were identified. A total of 80 cases and 518 controls had a prior diagnosis of myasthenia. Myasthenia was not associated with an increased risk of overall cancer (OR 1.1; 95% CI 0.9-1.4). Adjusted ORs for major cancer sites were also close to unity, whereas an elevated risk of lymphomas was observed (OR 2.0; 95% CI 0.8-5.5). Early-onset myasthenia was associated with a slightly increased OR for overall cancer (1.5; 95% CI 1.0-2.3); however, this estimate was based on small numbers. CONCLUSIONS: Non-thymoma myasthenia was not associated with an increased risk of overall cancer. Larger studies are necessary to evaluate the association between myasthenia and risk of lymphoma and the potential effect modification by age of myasthenia onset in relation to cancer risk.

Characterization and diagnostic evaluation of chronic polyneuropathies induced by oxaliplatin and docetaxel comparing skin biopsy to quantitative sensory testing and nerve conduction studies.

BACKGROUND AND PURPOSE: Chemotherapy-induced peripheral neuropathy negatively affects the quality of life for many patients treated with oxaliplatin or docetaxel for gastrointestinal cancer or breast cancer. Symptoms can persist long after treatment and often include neuropathic pain. Our objective was to characterize the neuropathies with regard to symptoms, neurological signs and objective evidence of damage to the structure and function of the peripheral nerves. Furthermore, the diagnostic values of skin biopsy, quantitative sensory testing (QST) and nerve conduction studies (NCS) were compared. METHODS: Patients complaining of neuropathy symptoms at least 3 months after completion of treatment with oxaliplatin (n = 20) or docetaxel (n = 20) were recruited from the Department of Oncology or using hospital records. Neuropathy scores were determined along with the intraepidermal nerve fibre density in skin biopsies from the proximal and distal parts of the leg, QST and NCS. RESULTS: Clinically only sensory functions were affected. In general, neuropathy scores were higher in the oxaliplatin-treated group. Both sensory and motor fibres were affected in the NCS, showing predominantly signs of axonal damage. Mechanical detection threshold was most often affected in the QST. NCS, QTS and skin biopsy were abnormal in 11, 13 and 17 and 7, 11 and 15 of the oxaliplatin-treated patients and docetaxel-treated patients, respectively. CONCLUSIONS: Chemotherapy-induced peripheral neuropathy after oxaliplatin or docetaxel treatment is a clinically sensory, axonal neuropathy affecting only small nerve fibres in some patients. NCS are often normal, whereas QST and skin biopsy have a higher diagnostic sensitivity.

Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine.

BACKGROUND AND PURPOSE: The association between use of azathioprine and risk of non-melanoma skin cancer (NMSC) in patients with myasthenia was evaluated in a nationwide setting. Treatment of autoimmune myasthenia frequently involves long-term exposure to immunosuppressants, including azathioprine. Use of azathioprine increases the risk of NMSC in organ recipients and probably also in patients with other autoimmune disorders. No previous study has specifically investigated the risk of NMSC in myasthenia patients treated with azathioprine. METHODS: This is a case-control study based on Danish population-based registries. Cases were myasthenia patients with a first time diagnosis of NMSC during 2004-2009. Age- and sex-matched controls were selected amongst myasthenia patients with no history of cancer using incidence density sampling. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for skin cancer associated with a high cumulative dose (≥150 g) or long-term use (≥5 years) of azathioprine, adjusted for confounders. RESULTS: Thirty NMSC cases and 360 matched controls were identified. Ever use of azathioprine was associated with a considerably increased risk of NMSC (OR 3.3, 95% CI 1.5-7.3) that was even more apparent in patients with high cumulative dose (OR 4.6, 95% CI 1.7-12.5) or long-term (OR 4.8; 95% CI 1.7-13.6) use of azathioprine. CONCLUSION: Azathioprine use in patients with myasthenia is associated with an increased risk of NMSC.

Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide case-control study in Denmark.

BACKGROUND AND PURPOSE: To evaluate the association between the use of azathioprine and risk of cancer in patients with non-thymoma myasthenia gravis (MG) in a nationwide setting. METHODS: Case-control study based on population-based registries. Cases were patients with MG with a first time diagnosis of cancer (except non-melanoma skin cancer) registered during 2000-2009, and controls were patients with MG with no history of cancer. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). We used unconditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for cancer associated with a high cumulative dose [≥ 1000 defined daily doses (DDD)] or long-term use (≥ 5 years) of azathioprine, compared with never use of the drug and adjusted for potential confounders. RESULTS: We identified 89 cases and 873 controls. The prevalence of ever use of azathioprine was similar among cases (39.3%) and controls (39.4%). We observed a slightly elevated OR for cancer overall associated with long-term use of azathioprine (1.22; 95% CI: 0.62-2.40, P = 0.56). The highest ORs were observed for use of 2000 DDD or more of azathioprine; however, these risk estimates were based on small numbers. CONCLUSIONS: Use of azathioprine in patients with non-thymoma MG may be associated with a slightly increased risk of cancer overall. Larger studies are necessary to address the risk of site-specific cancers.

Use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs and risk of glioma: a case-control study.

BACKGROUND: Few studies have examined the association between use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and risk of glioma and the results have been equivocal. We therefore investigated the influence of NSAID use on glioma risk in a nationwide setting. METHODS: We used national registries in Denmark to identify all patients aged 20-85 years with a first diagnosis of histologically verified glioma during 2000-2009. Each case was matched on birth year and sex to eight population controls using risk-set sampling. We used prescription data to assess NSAID use and classified exposure to low-dose aspirin or non-aspirin (NA) NSAIDs into ever use or long-term use, defined as continuous use for 5 years. Conditional logistic regression was used to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with NSAID use, adjusted for potential confounders. RESULTS: A total of 2688 glioma cases and 18,848 population controls were included in the study. Ever use of low-dose aspirin (OR=0.90; 95% CI: 0.77-1.04) or NA-NSAIDs (OR=1.05; 95% CI: 0.96-1.14) was not associated with glioma risk. Compared with never use, long-term use of low-dose aspirin or of NA-NSAIDs was associated with ORs of 0.80 (95% CI: 0.53-1.21) and 1.11 (0.57-2.17), respectively. We observed no clear patterns of risk in stratified analysis according to estimated doses of low-dose aspirin (≤ 100 mg, 150 mg). CONCLUSION: We did not find any apparent association between aspirin or NA-NSAID use and risk of glioma, although our results may be consistent with a slight reduction in glioma risk with long-term use of low-dose aspirin.

Use of statins and risk of glioma: a nationwide case-control study in Denmark.

BACKGROUND: Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting. METHODS: We conducted a nationwide case-control study in Denmark based on population-based medical registries. We identified all patients aged 20 to 85 years with a first diagnosis of histologically verified glioma during 2000-2009. These cases were matched on birth year and sex with population controls. Prior use of statins since 1995 was classified into short-term use (<5 years) and long-term use (5+ years). We used conditional logistic regression to compute odds ratios (ORs), with 95% confidence intervals (CIs), for glioma associated with statin use, adjusted for potential confounders. RESULTS: A total of 2656 cases and 18,480 controls were included in the study. The risk of glioma was reduced among long-term statin users (OR=0.76; 95% CI: 0.59-0.98) compared with never users of statins, and was inversely related to the intensity of statin treatment among users (OR=0.71; 95% CI: 0.44-1.15 for highest intensity). The inverse association between long-term statin treatment and glioma risk was more pronounced among men aged ≤ 60 years (OR=0.40; 95% CI: 0.17-0.91) compared with men aged 60+ years (OR=0.71; 95% CI: 0.49-1.03). An inverse association was also observed among women aged ≤ 60 years (OR=0.28; 95% CI: 0.06-1.25), but not among women over age 60 years (OR=1.23; 95% CI: 0.82-1.85). CONCLUSION: Long-term statin use may reduce the risk of glioma.

Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996-2009.

BACKGROUND: An increase in late-onset myasthenia gravis (MG) has been reported. There are few large population-based studies over longer periods of time reflecting recent developments in MG incidence. METHODS: We identified a nationwide cohort of patients with incident myasthenia in Denmark in 1996-2009. We used a validated algorithm to track subjects based on a combination of diagnosis and prescription (pyridostigmine) data from nationwide registers. Patients with myasthenia were classified into early onset (<50 years old) and late onset (50+ years). We calculated incidence rates (IRs) and corresponding 95% confidence intervals. RESULTS: We identified 693 patients (362 women) with incident MG in the study period corresponding to an IR of 9.2 per million person-years (8.5-9.9). Overall, 207 (29.9%) were classified as early-onset and 486 (70.1%) as late-onset MG. Women predominated in the early-onset group (70.5%), but not in the late-onset group (44.4%). The incidence rate of early-onset MG was 4.2 (3.6-4.8) and late-onset MG 18.9 (17.3-20.7) per million person-years and it did not vary over time in the study period (P-values for trend 0.54 and 0.15, respectively). CONCLUSION: Late-onset MG comprised a large proportion of all incident cases in Denmark, was more common in men than women, and occurred with a stable incidence in the 14-year study period. Therefore, we speculate whether previous reports of a rise in late-onset MG reflect a non-biological phenomenon, that is, a gradual improvement in the diagnosis of MG in this age group in previous years.

Early exposure to smoking and future fecundity among Danish twins.

Several studies have examined the effect of in utero exposure to smoking and fecundity among the offspring but the findings are contradictory. We therefore studied the waiting time to first pregnancy (TTP) and exposure to smoking in utero and childhood among Danish twins born between 1931 and 1952. Information about TTP, exposure to mothers smoking in pregnancy, exposure to smoking in childhood and current smoking among the male twins and smoking in their own pregnancy among female twins was collected by interview. Fecundability odds ratio (FOR) estimating the odds of conception in a cycle among exposed compared to the unexposed were calculated separately for female and male twins. A total of 1653 female and 1598 male twins reported a TTP. Female twins, exposed in utero, had reduced fecundability after control for confounders (FOR = 0.81; 95% CI 0.67-0.99). A nonsignificant increase in fecundity among male twins exposed to smoking in utero was found (FOR = 1.12; 95% CI 0.89-1.40). Among dizygotic twins of opposite sex sharing the same in utero exposures, the future fecundity of the male twin was unaffected by in utero exposure (FOR = 0.97; 95% CI 0.60-1.55) whereas the female twin had reduced fecundity (FOR = 0.65; 95% CI 0.47-0.91). This study supports that smoking is hazardous to the female fetus not only in the short term but also affects her future ability to conceive and makes it even more important to advise pregnant women to stop smoking.

Trends in utilization of antiepileptic drugs in Denmark.

OBJECTIVES: To describe utilization of antiepileptic drugs (AEDs) in Denmark during 1993-2002, with special emphasis on oxcarbazepine, and to assess probable indications for AED use. MATERIALS AND METHODS: We retrieved prescription data from Odense University Pharmacoepidemiological Database, in Funen County, Denmark (population in 2002: 472,869). Within each calendar year we estimated period prevalence, incidence rate and monotherapy rate. Based on co-medication we defined 'epilepsy' when only AEDs were prescribed, 'pain' with co-prescription of opioids, and 'mood disorder' with co-prescription of antipsychotics or antidepressants. RESULTS: We identified 15,604 AED users. The prevalence of using AED increased from 9.3 (95% CI, 9-9.5) to 12.1 (11.8-12.4)/1000 persons. The incidence rate increased from 1.4 (1.3-1.6) to 1.7 (1.6-1.9)/1000 personyears. The monotherapy rate was 79-82%. AED use for 'epilepsy' declined by 19.7%, whereas the proportion of 'pain' and 'mood disorder' treatment increased by 11.2% and 8.4% respectively. CONCLUSIONS: Antiepileptic drug utilization increased during the study period, the increase probably caused by expanding use in areas other than epilepsy.

Long-term effects of migraine on cognitive function: a population-based study of Danish twins.

OBJECTIVE: To investigate the cognitive functioning of migraineurs vs nonmigraineurs in a large population-based sample of middle-aged twins where headache diagnoses were established by neurologists. METHODS: Twins identified through the population-based Danish Twin Registry participated in face-to-face structured interviews, which included cognitive tests and two previously validated questions screening for migraine. Twins who screened positive for migraine and their co-twins were invited to participate in a telephone-based interview conducted by neurologists, who established headache diagnoses according to the International Headache Society criteria. Cognitive scores on fluency, digit span, delayed word recall, and symbol digit substitution test were compared between migraineurs and nonmigraineurs. Comparisons within monozygotic and dizygotic same sex twin pairs discordant for migraine were also performed. RESULTS: Of the 1,789 twins who were eligible for inclusion in the present study, 1,393 (77.8%) were interviewed. A diagnosis of migraine was established in 536 twins (migraine without aura n = 347; migraine with aura n = 157). Average scores on cognitive tests in twins with migraine or one of the migraine subtypes did not differ from those of nonmigraineurs in any of the tests. Comparisons within twin pairs discordant for migraine produced highly comparable results. Adjustment for possible confounders and stratification by cumulated number of lifetime attacks did not influence the results. CONCLUSIONS: A lifetime diagnosis of migraine was not associated with cognitive deficits in middle-aged subjects.

Appendicectomy has no beneficial effect on admission rates in patients with ulcerative colitis.

BACKGROUND AND AIMS: Those who have had an appendicectomy have a reduced risk of developing ulcerative colitis. However, the effect of appendicectomy on disease activity in patients with ulcerative colitis has not been established. METHODS: We used the Danish National Patient Registry to identify all incident cases of ulcerative colitis in Denmark during the period 1981 to 1999. Of these, 202 had an appendicectomy after their first admission with ulcerative colitis. In these patients, we compared the incidence rate of hospitalisations with ulcerative colitis as first diagnosis during the period between the onset of ulcerative colitis and appendicectomy, with the rate of such hospitalisations after appendicectomy. To adjust for the clinical course of ulcerative colitis unrelated to appendicectomy, we extracted a reference cohort (n = 808), matched to the index subjects with respect to age, sex, and year of first admission, but with an intact appendix. RESULTS: The rate of admission with ulcerative colitis as first diagnosis decreased by 47% after appendicectomy (rate ratio 0.53 (95% confidence interval (CI) 0.36-0.80)). However, the reference cohort showed a similar decline in admission rate (rate ratio 0.51). Thus appendicectomy had no apparent beneficial effect on admission rate after adjustment for the clinical course of disease unrelated to appendicectomy (adjusted rate ratio 1.05 (95% CI 0.67-1.67)). CONCLUSIONS: Appendicectomy had no significant beneficial effect on admission rates in patients with ulcerative colitis.

Frequency and heritability of depression symptomatology in the second half of life: evidence from Danish twins over 45.

BACKGROUND: Self-reported depressive symptoms among the elderly have generated considerable interest because they are readily available measures of overall well-being in a population often thought to be at special risk for mental disorder. METHOD: The heritability of depression symptoms was investigated in a sample of 2169 pairs of Danish twins (1033 MZ and 1136 same sex DZ) ranging in age from 45 to over 95. Twins completed an interview assessment that identified symptoms of depression, which were scored on Affective, Somatic and Total scales. RESULTS: Overall heritability estimates (a2) for the Affective (a2 = 0.27, (95% CI 0.22-0.32)). Somatic (a2 = 0.26, (0.21-0.32)), and Total (a2 = 0.29, (0.22-0.34)) scales were all moderate, statistically significant and similar to results from other studies. To assess possible variations in heritability across the wide age span, the sample was stratified into age groups in increments of 10 years. The magnitude of heritable influence did not vary significantly with age or sex. Somatic scale heritability tended to be greater for females than for males, though this difference was not statistically significant. The genetic correlation between the Affective and Somatic scales was 0.71, suggesting substantial common genetic origins. CONCLUSIONS: Though the frequency of self-reported depressive symptoms increased with age in this sample, their heritability did not.

Statins and risk of polyneuropathy: a case-control study.

BACKGROUND: Several case reports and a single epidemiologic study indicate that use of statins occasionally may have a deleterious effect on the peripheral nervous system. The authors therefore performed a population-based study to estimate the relative risk of idiopathic polyneuropathy in users of statins. METHOD: The authors used a population-based patient registry to identify first-time-ever cases of idiopathic polyneuropathy registered in the 5-year period 1994 to 1998. For each case, validated according to predefined criteria, 25 control subjects were randomly selected among subjects from the background population matched for age, sex, and calendar time. The authors used a prescription register to assess exposure to drugs and estimated the odds ratio of use of statins (ever and current use) in cases of idiopathic polyneuropathy compared with control subjects. RESULTS: The authors verified a diagnosis of idiopathic polyneuropathy in 166 cases. The cases were classified as definite (35), probable (54), or possible (77). The odds ratio linking idiopathic polyneuropathy with statin use was 3.7 (95% CI 1.8 to 7.6) for all cases and 14.2 (5.3 to 38.0) for definite cases. The corresponding odds ratios in current users were 4.6 (2.1 to 10.0) for all cases and 16.1 (5.7 to 45.4) for definite cases. For patients treated with statins for 2 or more years the odds ratio of definite idiopathic polyneuropathy was 26.4 (7.8 to 45.4). CONCLUSIONS: Long-term exposure to statins may substantially increase the risk of polyneuropathy.

Association of mutations in the hemochromatosis gene with shorter life expectancy.

BACKGROUND: To investigate whether the frequency of carriers of mutations in the HFE gene associated with hereditary hemochromatosis diminishes with age as an indication that HFE mutations are associated with increased mortality. It is of value in the debate concerning screening for hereditary hemochromatosis to determine the significance of heterozygosity. METHODS: Genotyping for mutations in exons 2 and 4 of the HFE gene using denaturing gradient gel electrophoresis in 1784 participants aged 45 to 100 years from 4 population-based studies: all 183 centenarians from the Danish Centenarian Study, 601 people aged 92 to 93 years from the Danish 1905 Cohort, 400 aged 70 to 94 years from the Longitudinal Study of Aging Danish Twins, and 600 aged 45 to 67 years from a study of middle-aged Danish twins. RESULTS: All participants (N=1784) were screened for mutations in exon 4, and a trend toward fewer heterozygotes for the C282Y mutation-the mutation most often associated with hereditary hemochromatosis-was found. This was significant for the whole population (P=.005) and for women (P=.004) but not for men (P=.26). A group of 599 participants was screened for mutations in exon 2, and there was no variation in the distribution of mutations in exon 2 in the different age groups. CONCLUSIONS: In a high-carrier frequency population like Denmark, mutations in HFE show an age-related reduction in the frequency of heterozygotes for C282Y, which suggests that carrier status is associated with shorter life expectancy.

Lipid-lowering drugs and risk of myopathy: a population-based follow-up study.

We conducted a population-based cohort study to estimate the risk of myopathy associated with use of lipid-lowering drugs. Using data from general practices in the United Kingdom in 1991 through 1997, we identified three cohorts of individuals 40 to 74 years of age. One cohort comprised 17,219 persons who had received at least one prescription for lipid-lowering drugs in the period; a second cohort consisted of patients with a hyperlipidemia diagnosis who had not been prescribed lipid-lowering drugs (N = 28,974); and a third cohort comprised 50,000 individuals from the general population with no diagnosis of hyperlipidemia. The incidence rate of myopathy in the cohort of users of lipid-lowering drugs was 2.3 per 10,000 person-years [95% confidence interval (95% CI) = 1.2-4.4], which exceeded the incidence rates observed in the nontreated hyperlipidemia cohort [0 per 10,000 person-years (95% CI = 0.0-0.4)] and the general population [0.2 per 10,000 person-years (95% CI = 0.1-0.4)]. The relative risks of myopathy in current users of fibrates and statins compared with nonusers were 42.4 (95% CI = 11.6-170.5) and 7.6 (95% CI = 1.4-41.3), respectively. Potential risk factors other than drug use could not explain our findings in the nested case-control analysis. We conclude that use of lipid-lowering drugs is associated with a substantially greater risk of myopathy, which is most pronounced for fibrates. The absolute risk of myopathy in users of lipid-lowering drugs is, however, small.

The Danish 1905 cohort: a genetic-epidemiological nationwide survey.

OBJECTIVES: The authors studied nonagenarians, a rapidly growing age group whose cognitive and physical abilities have yet to be investigated systematically. METHODS: All Danes born in 1905 were invited to participate in a home-based 2-hour multidimensional interview, including cognitive and physical performance tests and collection of DNA, carried out by lay interviewers. Population-based registers were used to evaluate representativeness. RESULTS: There were 2,262 participants. A total of 1,632 (72%) gave a DNA sample. Participants and nonparticipants were highly comparable with regard to marital status, institutionalization, and hospitalization patterns, but men and rural area residents were more likely to participate. Six months after the survey began, 7.2% of the participants and 11.8% of the nonparticipants had died. DISCUSSION: Despite the known difficulties of conducting surveys among the extremely old, it was possible to conduct a nationwide survey, including collection of DNA, among more than 2,000 fairly nonselected nonagenarians using lay interviewers.