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PubMed2001

Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are common diseases of the airways and lungs that have a major impact on the health of the population. The mainstay of treatment is by inhalation of medication to the site of the disease process. This can be achieved by a number of different device types, which have wide variations in costs to the health service. A number of different inhalation devices are available. The pressurised metered-dose inhaler (pMDI) is the most commonly used and cheapest device, which may also be used in conjunction with a spacer device. Newer chlorofluorocarbons (CFC)-free inhaler devices using hydrofluoroalkanes (HFAs) have also been developed. The drug is dissolved or suspended in the propellant under pressure. When activated, a valve system releases a metered volume of drug and propellant. Other devices include breath-actuated pMDIs (BA-pMDI), such as Autohaler and Easi-Breathe. They incorporate a mechanism activated during inhalation that triggers the metered-dose inhaler. Dry powder inhalers (DPI), such as Turbohaler, Diskhaler, Accuhaler and Rotahaler, are activated by inspiration by the patient. The powdered drug is dispersed into particles by the inspiration. With nebulisers oxygen, compressed air, or ultrasonic power is used to break up solutions or suspensions of medication into droplets for inhalation. The aerosol is administered by mask or by a mouthpiece. There has been no previous systematic review of the evidence of clinical effectiveness and cost-effectiveness of these different inhaler devices. OBJECTIVES: To review systematically the clinical effectiveness and cost-effectiveness of inhaler devices in asthma and COPD. METHODS: The different aspects of inhaler devices were separated into the most clinically relevant comparisons. Methods involved systematic searching of electronic databases and bibliographies for randomised controlled trials (RCTs) and systematic reviews. Pharmaceutical companies and experts in the field were contacted for further information. Trials that met the inclusion criteria were appraised and data extraction was under-taken by one reviewer and checked by a second reviewer, with any discrepancies being resolved through agreement. RESULTS--IN VITRO CHARACTERISTICS VERSUS IN VIVO TESTING AND CLINICAL RESPONSE: There is evidence that when comparative testing is performed on inhaler devices using the same methods, there is some correlation between particle size measurements and clinical response. However, the measurements are dependent upon the methods used, and a single measure of a device in isolation is of limited value. Also, there is little data on comparing devices of different types. There is currently insufficient data to verify the ability of in vitro assessments to predict inhaler performance in vivo. RESULTS--EFFECTIVENESS OF METERED-DOSE INHALERS FOR THE DELIVERY OF CORTICOSTEROIDS IN ASTHMA: The review of three trials in children and 21 trials in adults demonstrated no evidence to suggest clinical benefits of any other inhaler device over a pMDI in corticosteroid delivery. RESULTS--EFFECTIVENESS OF METERED-DOSE INHALERS FOR THE DELIVERY OF BETA-AGONISTS IN STABLE ASTHMA: In children, 11 studies were reviewed, of which seven compared the Turbohaler with the pMDI. One study found a significant treatment difference in peak expiratory flow rate, although there were differences in the patients' baseline characteristics. In adults, a review of 70 studies found no demonstrable difference in the clinical bronchodilator effect of short-acting b2-agonists delivered by the standard pMDI compared with that produced by any other DPI, HFA-pMDI or the Autohaler device. The finding that HFA-pMDIs may reduce treatment failure and oral steroid requirement in beta-agonist delivery needs further confirmatory research in adequately randomised clinical trials. RESULTS--EFFECTIVENESS OF NEBULISERS VERSUS METERED-DOSE INHALERS FOR THE DELIVERY OF BRONCHODILATORS IN STABLE ASTHMA: In children, three included trials compared different devices with a nebuliser and demonstrated no evidence of clinical superiority of nebulisers over inhaler devices in bronchodilator delivery. A total of 23 studies in adults found no equivalence for the main pulmonary outcomes and no evidence of difference in other outcomes. RESULTS--EFFECTIVENESS OF METERED-DOSE INHALERS FOR THE DELIVERY OF BETA-AGONISTS IN COPD: Only two studies were included in this review. No evidence of clinical difference was found in beta-agonist delivery. RESULTS--EFFECTIVENESS OF NEBULISERS VERSUS METERED-DOSE INHALERS FOR THE DELIVERY OF BRONCHODILATORS IN COPD: Evidence from 14 trials demonstrated equivalence for the main outcomes of pulmonary function. For other outcomes there was no evidence of treatment difference in bronchodilator delivery. RESULTS--PATIENTS' ABILITY TO USE METERED-DOSE INHALERS: Differences among studies and the heterogeneity of the results make it difficult to draw conclusions about inhaler technique differences between device types. The review of technique after teaching the correct technique suggests that there is no difference in patients' ability to use DPI or pMDIs. RESULTS--ECONOMIC ANALYSIS: The total number of NHS prescriptions for inhaler therapy for asthma in 1998 was over 31 million, with a net ingredient cost in excess of 392 million GB pounds. This economic assessment uses decision analysis to estimate the relative cost-effectiveness of inhaler devices for the delivery of bronchodilator and corticosteroid inhaled therapy. Overall, there were no differences in patient outcomes among the devices. On the assumption that the devices were clinically equivalent, pMDIs were the most cost-effective devices for asthma treatment. CONCLUSIONS: This systematic review examined the evidence from clinical trials evaluating the clinical effectiveness of different inhaler devices in the delivery of inhaled corticosteroids and beta2-bronchodilators for patients with asthma and COPD. The evidence from the published clinical literature demonstrates no difference in clinical effectiveness between nebulisers and alternative inhaler devices compared to standard pMDI with or without a spacer device. The cost-effectiveness evidence therefore favours pMDIs (or the cheapest inhaler device) as first-line treatment in all patients with stable asthma unless other specific reasons are identified. Patients can use pMDIs as effectively as other inhaler devices as long as the correct inhalation technique is taught. CONCLUSIONS--RECOMMENDATIONS FOR RESEARCH: Further clinical trials are required to demonstrate any differences in the clinical effectiveness and cost-effectiveness of inhaler devices and nebulisers compared with pMDIs. These should be of sufficient statistical power and methodological rigour to demonstrate any clinical benefit. Trials should be undertaken in community settings to ensure the generalisability of results. Outcome measures should be more patient-centred and report adverse effects more completely. Reporting of data from trials should be improved.

Adolescent↗
PubMed2000

How well are randomized controlled trials reported in the dermatology literature?

OBJECTIVE: To assess the methodological quality of the design and reporting of randomized controlled trials published in one major dermatology specialty journal. DESIGN AND DATA SOURCES: In a survey of all published parallel group randomized controlled trials, we found 73 reports with allocation described as randomized from all issues of Clinical and Experimental Dermatology from its inception in 1976 through 1997. MAIN OUTCOME MEASURES: Direct and indirect measures of the adequacy of randomization, trial sample size, baseline comparisons, and intention-to-treat analysis. RESULTS: Hand searching identified 73 randomized controlled trials, but only 31 of these were found by searching MEDLINE for the publication type clinical trials. Of the 73 randomized controlled trials, 68 contained sufficient information to include in the analysis. Only 1 study (1%) reported the method of random sequence generation, and only 5 studies (7%) reported adequate concealment of allocation. Among 38 trials that used simple randomization, the sample sizes in the comparison groups were identical in 22 occasions, raising the possibility that simple randomization might not have been adequately generated or concealed. Most trials (88%) excluded some randomized participants from their analysis. The median sample size was 23 per trial. Only 1 trial reported sample size and statistical power considerations and had an a priori main hypothesis. CONCLUSIONS: Hand searching is important for locating all relevant trials. There is the need for higher methodological quality in clinical trial reporting in dermatology journals. The adoption of the CONSORT (Consolidated Standards of Reporting Trials) statement and checklist for the reporting of trials should enhance the validity of and strengthen the evidence from clinical trials reports.

Data Collection↗
PubMed2003

Time trends and familial risks in squamous cell carcinoma of the skin.

OBJECTIVES: To study time trends and familial clustering of invasive and in situ squamous cell skin cancers (SCC), with particular reference to sun-exposed and covered sites of the body. DESIGN: Epidemiologic follow-up study of the whole population. SETTING: The Swedish Family-Cancer Database from the year 2000, to cover individuals born after 1931 with their biological parents, totaling 10.2 million persons. PATIENTS: Cancer data were obtained from the Swedish Cancer Registry from 1961 through 1998 and included 1907 invasive SCCs in offspring and 12,702 and 7167 in fathers and mothers, respectively. The numbers of patients affected by in situ SCC were 2666, 13,739, and 13,321, respectively. MAIN OUTCOME MEASURES: Standardized incidence ratios and 95% confidence intervals were calculated for SCC in offspring when parents had SCC. Incidence rates were calculated for the population in the Database. RESULTS: Incidence trends showed a large increase in reported cases of SCC and particularly of in situ SCC. Among invasive cases, the increase was largest among covered sites. A clear cohort effect was observed particularly for SCC on covered sites. Familial standardized incidence ratios for offspring combining invasive and in situ SCC were 2.25 (95% confidence interval, 1.93-2.59) for concordant exposed sites and 2.60 (95% confidence interval, 1.38-4.20) for concordant covered sites, suggesting no difference between the body parts within the present statistical power. CONCLUSIONS: The higher increase in incidence on covered sites and the strong cohort effect suggest a contribution by intentional tanning. The observed equal increase in the familial effect on exposed and covered sites suggests that familial risk increases proportionately to the background rate.

Adolescent↗
PubMedDate not supplied

Massage therapy for osteoarthritis of the knee: a randomized controlled trial.

BACKGROUND: Massage therapy is an attractive treatment option for osteoarthritis (OA), but its efficacy is uncertain. We conducted a randomized, controlled trial of massage therapy for OA of the knee. METHODS: Sixty-eight adults with radiographically confirmed OA of the knee were assigned either to treatment (twice-weekly sessions of standard Swedish massage in weeks 1-4 and once-weekly sessions in weeks 5-8) or to control (delayed intervention). Primary outcomes were changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and functional scores and the visual analog scale of pain assessment. The sample provided 80% statistical power to detect a 20-point difference between groups in the change from baseline on the WOMAC and visual analog scale, with a 2-tailed alpha of .05. RESULTS: The group receiving massage therapy demonstrated significant improvements in the mean (SD) WOMAC global scores (-17.44 [23.61] mm; P < .001), pain (-18.36 [23.28]; P < .001), stiffness (-16.63 [28.82] mm; P < .001), and physical function domains (-17.27 [24.36] mm; P < .001) and in the visual analog scale of pain assessment (-19.38 [28.16] mm; P < .001), range of motion in degrees (3.57 [13.61]; P = .03), and time to walk 50 ft (15 m) in seconds (-1.77 [2.73]; P < .01). Findings were unchanged in multivariable models controlling for demographic factors. CONCLUSIONS: Massage therapy seems to be efficacious in the treatment of OA of the knee. Further study of cost effectiveness and duration of treatment effect is clearly warranted. .

Aged↗
PubMed1997

Association between migraine and stroke in a large-scale epidemiological study of the United States.

OBJECTIVE: To examine the association between stroke and migraine in an epidemiological study. DATA SOURCES AND DESIGN: The National Health and Nutrition Examination Survey baseline and first follow-up data were used to investigate cross-sectional and longitudinal associations between headache/migraine and stroke. SETTING: Study participants from a national probability sample of the civilian noninstitutionalized population of the United States. MAIN OUTCOME MEASURE: Self-reported physician diagnosis of stroke. RESULTS: After controlling for established risk factors for stroke (hypertension, diabetes, heart disease, and gender), both migraine and severe nonspecific headache were associated with a significantly increased risk for stroke reported at follow-up. The risk for stroke associated with migraine decreased as the age at stroke increased. CONCLUSIONS: Our results strengthen previous evidence regarding a nonrandom association of both headache and migraine with stroke, particularly among young women. To our knowledge, this is the first systematic examination in a large-scale prospective epidemiological study of men and women with sufficient statistical power to test the association between migraine and stroke in women. Severe headache and migraine should be considered as risk factors for the development of stroke, particularly in the absence of other well-established stroke risk factors. Further investigation is required to identify the putative mechanisms underlying comorbidity of migraine and stroke.

Adult↗
PubMed2004

Genetic polymorphisms in Parkinson disease subjects with and without hallucinations: an analysis of the cholecystokinin system.

BACKGROUND: Hallucinations in patients with Parkinson disease (PD), occurring in about one third of those receiving long-term dopaminergic therapy, contribute to morbidity and mortality. In matched Chinese PD subjects with and without hallucinations, the presence of the -45 C/T locus in the cholecystokinin (CCK) gene, particularly when combined with the CCK receptor, CCKAR (cholecystokinin A receptor), C polymorphism, was associated with increased hallucination risk. Because CCK gene polymorphisms vary across ethnic groups, the presence of similar associations in white PD subjects merits investigation. OBJECTIVE: To determine whether polymorphisms of CCK and CCK receptor genes are associated with hallucinations in white PD subjects. DESIGN: Case-control study of PD subjects with and without chronic hallucinations matched for age and dopaminergic medication. Genomic DNA was analyzed for CCK, CCKAR, and CCKBR (cholecystokinin B receptor) polymorphisms by polymerase chain reaction. Genotype distributions and allele frequencies were compared between groups and in matched pairs. RESULTS: Comparing matched pairs, we found more frequent representation of the CCK T allele in hallucinating PD subjects, although this finding was not statistically significant (P =.06). Of 5 cases with both CCK T and CCKAR C alleles, 4 were hallucinators. Cases and controls did not differ in CCKAR or CCKBR polymorphisms. CONCLUSIONS: Our study supports a previous association of hallucinations in PD subjects with the CCK T allele and the combined CCK T and CCKAR C allele, suggesting that the CCK system may influence the development of hallucinations in PD subjects. The lower representation of the T allele in our white sample limited our statistical power. Further assessment of the T allele as a risk factor for hallucinations would include longitudinal study of nonhallucinators to detect the evolution of hallucinations relative to T allele frequency.

Aged↗
PubMed1992

Accounting for the correlation between fellow eyes in regression analysis.

Regression techniques that appropriately use all available eyes have infrequently been applied in the ophthalmologic literature, despite advances both in the development of statistical models and in the availability of computer software to fit these models. We considered the general linear model and polychotomous logistic regression approaches of Rosner and the estimating equation approach of Liang and Zeger, applied to both linear and logistic regression. Methods were illustrated with the use of two real data sets: (1) impairment of visual acuity in patients with retinitis pigmentosa and (2) overall visual field impairment in elderly patients evaluated for glaucoma. We discuss the interpretation of coefficients from these models and the advantages of these approaches compared with alternative approaches, such as treating individuals rather than eyes as the unit of analysis, separate regression analyses of right and left eyes, or utilization of ordinary regression techniques without accounting for the correlation between fellow eyes. Specific advantages include enhanced statistical power, more interpretable regression coefficients, greater precision of estimation, and less sensitivity to missing data for some eyes. We concluded that these models should be used more frequently in ophthalmologic research, and we provide guidelines for choosing between alternative models.

Adolescent↗
PubMed2000

Impact of tonsillectomy and adenoidectomy on child behavior.

OBJECTIVE: To measure the impact of tonsillectomy and adenoidectomy (T&A) on children's behavioral and emotional problems using a standardized assessment. DESIGN: Prospective study. SETTING: Tertiary care children's hospital. PATIENTS: Thirty-six children, aged 2 through 18 years, with symptoms of nighttime snoring, observed apneas, and daytime mouth breathing and physical examination results demonstrating 3+ or 4+ tonsils scheduled for T&A. INTERVENTION: Parents completed a standard survey of their children's symptoms of sleep apnea and a standardized measure of children's competencies and problems, the Child Behavior Checklist for ages 2 through 3 years or 4 through 18 years, before T&A and 3 months postoperatively. MAIN OUTCOME MEASURE: The Child Behavior Checklist total problem score. RESULTS: The preoperative Child Behavior Checklist total problem score was consistent with abnormal behavior for 10 children (28%). After T&A (n = 15), only 2 scores were abnormal, but the change was not statistically significant. In contrast, the mean total problem score was 7.5 points lower after surgery (95% confidence interval, 5.1-9.7), indicating a significant decrease (P<.001, matched t test). CONCLUSIONS: This pilot study demonstrates a high prevalence (28%) of abnormal behavior in children undergoing T&A for chronic upper airway obstruction. Scores on a standardized measure of behavior improve following T&A, but larger studies with increased statistical power are needed to clarify the degree of improvement and its clinical importance.

Adenoidectomy↗
PubMed1992

Third-generation cephalosporins in the treatment of acute pneumococcal otitis media. An animal study.

There is concern that third-generation cephalosporins may not be effective in the treatment of acute otitis media due to Streptococcus pneumoniae. Using the chinchilla animal model, we compared two third-generation cephalosporins, cefixime (Suprax) and ceftibuten (investigational), with ampicillin and saline controls in an investigator-blinded, randomized trial. Whereas the saline controls performed worse than all other groups, no significant differences were detected among the three antibiotics regarding the time required to sterilize the middle ear cleft, or the prevalence of positive cultures after 10 days of therapy. The statistical power of the comparisons of cefixime and ceftibuten with ampicillin were 98% and 67%, respectively. The results of this in vivo animal study fail to support the contention that the two third-generation cephalosporins investigated are not effective in the treatment of pneumococcal acute otitis media. Caution is advised when extrapolating these results to the general clinical setting.

Acoustic Impedance Tests↗
PubMed2001

Relationship between positive and negative symptoms of schizophrenia and schizotypal symptoms in nonpsychotic relatives.

BACKGROUND: Continuous rather than categorical measures of psychopathology may provide greater statistical power to detect susceptibility loci for schizophrenia. However, it has not been established that the dimensions of schizophrenic symptomatology and personality traits in nonpsychotic individuals share etiological factors. We therefore sought to clarify the relationship between positive and negative symptoms of schizophrenic probands and dimensions of schizotypy in their first-degree relatives. METHODS: In the Roscommon Family Study, we examined the ability of positive and negative symptoms in probands to predict 7 factors of schizotypy in nonpsychotic relatives using regression analysis. These consisted of positive, negative, and avoidant symptoms; odd speech; suspicious behavior; social dysfunction; and symptoms of borderline personality disorder. We examined 3 proband groups: schizophrenia (n = 127); schizophrenia, simple schizophrenia, and schizoaffective disorder (n = 178); and all nonaffective psychoses (n = 216), and their nonpsychotic relatives (n = 309, 477, and 584, respectively). RESULTS: Positive symptoms in all nonaffective psychoses probands predicted positive schizotypy (beta = 0.1972, P =.0004), social dysfunction (beta = 0.0719, P =.0489), and borderline personality disorder symptoms (beta = 0.1327, P =.0084) in relatives, while negative symptoms predicted negative schizotypy (beta = 0.2069, P =.0002), odd speech (beta = 0.2592, P =.0001), suspicious behavior (beta = 0.2749, P =.0001), and social dysfunction (beta =.2398, P =.0002). Proband negative symptoms and borderline personality disorder symptoms in relatives in the schizophrenia, simple schizophrenia, and schizoaffective disorder group were inversely related (beta = -0.1185, P =.05). CONCLUSIONS: Positive and negative symptoms in schizophrenia predict corresponding schizotypal symptoms in relatives. This provides evidence that these schizophrenic symptom factors (1) are etiologically distinct from each other and (2) occur on an etiological continuum with their personality-based counterparts.

Borderline Personality Disorder↗
PubMed2003

P300 and genetic risk for schizophrenia.

BACKGROUND: We assessed the suitability of event-related potential frontal and temporoparietal P300 changes as intermediate phenotypes in genetic studies of schizophrenia. We applied a principal component analysis approach based on the notion that P300 abnormalities in siblings of schizophrenic patients may involve a widespread network of relatively weak cortical generators and because an earlier, smaller study that used a topographic analysis of covariance model did not show that localized P300 changes predict risk for schizophrenia. METHODS: P300 changes in 66 schizophrenic patients, 115 healthy siblings of schizophrenic patients, and 89 unrelated controls were studied during a standard auditory oddball paradigm. Principal components were calculated across electrodes, revealing frontal and temporoparietal components for latency and amplitude, respectively. For the frontal and temporoparietal P300 amplitude and latency components, the intraclass correlations (ICCs) between sib-pairs (pairs of unaffected siblings and schizophrenic index patients) and the relative risk ratios (lambda) were determined. RESULTS: Compared with controls, schizophrenic patients and their unaffected siblings showed significant reductions in the temporoparietal P300 amplitude component. Both groups were also characterized by a significantly higher frontal P300 amplitude component. Significant ICCs and increased relative risk ratios were found for the frontal (ICCU = 0.18; P =.04; lambda = 3.4) and temporoparietal (ICCU = 0.24; P =.01; lambda = 1.7) P300 amplitude components. CONCLUSIONS: Temporoparietal P300 amplitude reduction and frontal P300 amplitude increase seem to be quantitative phenotypes associated with increased risk of schizophrenia. Both measures may be useful for increasing the statistical power of genetic studies of schizophrenia.

Adolescent↗
PubMed2006

Antidepressants and the risk of suicide, attempted suicide, and overall mortality in a nationwide cohort.

BACKGROUND: It is unknown if antidepressant treatment is associated with either increased or decreased risk of suicide. OBJECTIVE: To estimate the risk of suicide, attempted suicide, and overall mortality during antidepressant treatments in a real-life setting with high statistical power. DESIGN AND SETTING: A cohort study in which all subjects without psychosis, hospitalized because of a suicide attempt from January 1, 1997, to December 31, 2003, in Finland, were followed up through a nationwide computerized database. PARTICIPANTS: A total of 15 390 patients with a mean follow-up of 3.4 years. MAIN OUTCOME MEASURES: The propensity score-adjusted relative risks (RRs) during monotherapy with the most frequently used antidepressants compared with no antidepressant treatment. RESULTS: In the entire cohort, fluoxetine use was associated with the lowest risk (RR, 0.52; 95% confidence interval [CI], 0.30-0.93), and venlafaxine hydrochloride use with the highest risk (RR, 1.61; 95% CI, 1.01-2.57), of suicide. A substantially lower mortality was observed during selective serotonin reuptake inhibitor use (RR, 0.59; 95% CI, 0.49-0.71; P<.001), and this was attributable to a decrease in cardiovascular- and cerebrovascular-related deaths (RR, 0.42; 95% CI, 0.24-0.71; P=.001). Among subjects who had ever used any antidepressant, the current use of medication was associated with a markedly increased risk of attempted suicide (39%, P<.001), but also with a markedly decreased risk of completed suicide (-32%, P=.002) and mortality (-49%, P<.001), when compared with no current use of medication. The results for subjects aged 10 to 19 years were basically the same as those in the total population, except for an increased risk of death with paroxetine hydrochloride use (RR, 5.44; 95% CI, 2.15-13.70; P<.001). CONCLUSIONS: Among suicidal subjects who had ever used antidepressants, the current use of any antidepressant was associated with a markedly increased risk of attempted suicide and, at the same time, with a markedly decreased risk of completed suicide and death. Lower mortality was attributable to a decrease in cardiovascular- and cerebrovascular-related deaths during selective serotonin reuptake inhibitor use.

Adolescent↗
PubMed1998

Effects of sucralfate vs antacids on gastric pathogens: results of a double-blind clinical trial.

BACKGROUND: Unblinded studies suggested that sucralfate prophylaxis for stress ulcers is associated with a lower rate of nosocomial pneumonia than acid-reducing approaches. We performed a randomized, double-blind, double-sham clinical trial comparing the exact microbial effects of each treatment. METHODS: One hundred forty patients entered this study before major elective surgery, allowing baseline cultures of gastric and pulmonary secretions to be obtained intraoperatively. Postoperatively, the patients were treated with standard doses of either sucralfate or antacids, plus a sham of the other drug. Cultures were repeated twice daily for 3 days. Molecular epidemiological typing was used to track the appearance of specific microbes and their transmission from site to site, and clinical end points were compared. The number of patients chosen was for sufficient statistical power to detect differences in the microbial measures, as detecting differences in clinical measures would have required increasing the sample size by an order of magnitude. RESULTS: Gastric pH was affected by the form of stress ulcer prophylaxis throughout the study, and this pH effect affected the number of new gastric organisms appearing in the 2 different groups. Colonization of the airway with new gastric organisms occurred more frequently in the antacid than in the sucralfate group, and colonization of the airway with organisms of gastric origin was associated with occurrence of postoperative pneumonia. CONCLUSIONS: Both sucralfate and antacids offered safe and effective stress ulcer prophylaxis in this double-blind clinical trial of postoperative patients in an intensive care unit. In association with the drug's effects on gastric pH, more new pathogens appeared in the gastric contents of antacid-treated than sucralfate-treated patients.

Antacids↗
PubMed2000

Risk of breast cancer with oral contraceptive use in women with a family history of breast cancer.

CONTEXT: Oral contraceptive (OC) use is weakly associated with breast cancer risk in the general population, but the association among women with a familial predisposition to breast cancer is less clear. OBJECTIVE: To determine whether the association between OC use and risk of breast cancer is influenced by family history of the disease. DESIGN AND SETTING: Historical cohort study of 426 families of breast cancer probands diagnosed between 1944 and 1952 at the Tumor Clinic of the University of Minnesota Hospital. Follow-up data on families were collected by telephone interview between 1991 and 1996. PARTICIPANTS: A total of 394 sisters and daughters of the probands, 3002 granddaughters and nieces, and 2754 women who married into the families. MAIN OUTCOME MEASURE: Relative risk (RR) of breast cancer associated with history of OC use by relationship to proband. RESULTS: After accounting for age and birth cohort, ever having used OCs was associated with significantly increased risk of breast cancer among sisters and daughters of the probands (RR, 3.3; 95% confidence interval [CI], 1.6-6.7), but not among granddaughters and nieces of the probands (RR, 1.2; 95% CI, 0.8-2.0) or among marry-ins (RR, 1.2; 95% CI, 0.8-1.9). Results were essentially unchanged after adjustment for parity, age at first birth, age at menarche, age at menopause, oophorectomy, smoking, and education. The elevated risk among women with a first-degree family history of breast cancer was most evident for OC use during or prior to 1975, when formulations were likely to contain higher dosages of estrogen and progestins (RR, 3.3; 95% CI, 1.5-7.2). A small number of breast cancer cases (n = 2) limited the statistical power to detect risk among women with a first-degree relative with breast cancer and OC use after 1975. CONCLUSIONS: These results suggest that women who have ever used earlier formulations of OCs and who also have a first-degree relative with breast cancer may be at particularly high risk for breast cancer. Further studies of women with a strong family history who have used more recent lower-dosage formulations of OCs are needed to determine how women with a familial predisposition to breast cancer should be advised regarding OC use today. JAMA. 2000;284:1791-1798.

Adult↗
PubMed1997

Lack of association between bipolar disorder and tyrosine hydroxylase: a meta-analysis.

Tyrosine hydroxylase (TH) is a candidate gene extensively explored in several association studies of bipolar disorder (BD). However, because of conflicting results of independent studies and low statistical power of individual studies to detect small differences between cases and controls, reliable conclusions are difficult to formulate. A method to obtain more reliable conclusions about the involvement of the TH locus in the etiology of BD is meta-analysis. We undertook a meta-analysis of studies that investigated the association between BD and TH genetic markers. The studies were identified by means of computerized searches of several databases, and the scanning of review articles and the reference lists of the primary articles identified. More than 60 publications were reviewed, and 9 relevant articles were included in this meta-analysis, with an overall sample of 1,069 subjects (547 cases and 522 normal controls). The overall odds ratio (and confidence interval) based on combining the results of the studies was 1.02 (0.68-1.54). Test of the null hypothesis that the mean log odds ratio equals zero (chi2 = 0.11; 5 df; P > 0.05) indicated that there was no overall association between bipolar disorder and tyrosine hydroxylase.

Bipolar Disorder↗
PubMed1997

The return of thalidomide: are birth defects surveillance systems ready?

In the 1960s, thalidomide caused limb deficiencies in thousands of infants worldwide. The limb deficiencies were frequently of the intercalary type. As a result, numerous countries started birth defect surveillance programs. In 1967, the Centers for Disease Control (CDC) started the Metropolitan Atlanta Congenital Defects Program (MACDP), a population-based surveillance system, to provide early warning against new teratogens. Recent studies have shown that thalidomide may be beneficial for a range of conditions, including cancer and AIDS, and it may once again become widely available. Here, we examine the ability of MACDP to detect an increase in the birth prevalence of limb deficiency as an early warning of fetal exposure to thalidomide. We calculated base rates for all limb deficiencies, for bilateral nonsyndromic intercalary or preaxial deficiencies, and for all nonsyndromic intercalary limb deficiencies among Atlanta infants born from 1968 through 1993. We used relative risk estimates from previous studies and a range of pregnancy exposure rates for thalidomide. We tested the statistical power of MACDP to detect subtle changes in the birth prevalence of these defects using Poisson and cumulative sum (CUSUM) techniques. The base rates for all limb deficiencies, for bilateral intercalary or preaxial deficiencies, and for all intercalary limb deficiencies, were 0.53, 0.035, and 0.022/1,000, and the estimated relative risks were 175, 4,570, and 8,180, respectively. We varied the assumed rate of exposure to thalidomide from 1/10,000 to 5/100. With a 1/1,000 exposure rate, both Poisson and CUSUM techniques will detect a rate change in intercalary limb deficiency in about 6 months of monitoring, and a rate change in bilateral intercalary or preaxial deficiencies in about 12 months of monitoring. When monitoring all limb deficiencies, a pregnancy exposure rate of 3.5% or less would go unnoticed by the Poisson method and would take more than 50 years for the CUSUM method to signal an alarm with a 1/1,000 exposure rate. However, for rates of exposure less than 1/1,000, a progressively longer period of time or larger sample are needed to detect a rate change by both methods. Our findings highlight the importance of enlarging the monitored population and correct case classification in birth defects surveillance.

Abnormalities, Drug-Induced↗
PubMed1998

European Multicentre Association Study of Schizophrenia: a study of the DRD2 Ser311Cys and DRD3 Ser9Gly polymorphisms.

As part of the European Multicentre Association Study of Schizophrenia (EMASS), we studied polymorphisms in the dopamine DRD2 and DRD3 receptor genes. The EMASS collaboration was established to create a large, statistically powerful sample of schizophrenic patients and controls from different European centres. Previous studies have suggested associations between schizophrenia and the Ser311Cys polymorphism in exon 7 of the dopamine DRD2 receptor gene [Arinami et al., (1994): Lancet 343:703-704] and a polymorphism Ser9gly in exon 1 of the dopamine DRD3 receptor gene [Crocq et al. (1992): J Med Genet 29:858-860]. We tested for these associations in samples of 373 and 413, and 311 and 306 patients and controls, respectively. We found no evidence for allelic association between schizophrenia and the Cys311 variant of the DRD2 receptor gene and no homozygotes for this variant were observed by any group. However, an excess of homozygotes for both alleles of the DRD3 polymorphism was observed in schizophrenic patients (chi2 = 8.54, P = 0.003, odds ratio = 1.64, 95% CI = 1.18-2.29). We also observed a significant excess of the 1-1 (Ser9Ser) genotype (chi2 = 8.13, P = 0.004, odds ratio = 1.7, 95% CI = 1.18-2.4). No evidence of heterogeneity between samples was detected and there was no evidence of an allelic association. These findings suggest that the rare Cys311 variant in exon 7 of the DRD2 receptor gene does not play a role in the pathogenesis of schizophrenia in European populations. Currently, our results do support the previous findings of an association between increased homozygosity of the Ser/Gly variant of the Dopamine D3 receptor gene and schizophrenia.

Alleles↗
PubMed1999

Effect of developmental and ancestral high-altitude exposure on VO(2)peak of Andean and European/North American natives.

Peak oxygen consumption (VO(2)peak) was measured in 150 adult males (18-35 years old) in Bolivia, using a complete migrant study design to partition developmental from ancestral (genetic) effects of high-altitude (HA) exposure. High-altitude natives (HANs, Aymara/Quechua ancestry, n = 75) and low-altitude natives (LANs, European/North American ancestry, n = 75) were studied at high altitude (3,600-3,850 m) and near sea level (420 m). HAN and LAN migrant groups to a nonnative environment were classified as: multigeneration migrants, born and raised in a nonnative environment; child migrants who migrated to the nonnative environment during the period of growth and development (0-18 years old); and adult migrants who migrated after 18 years of age. Variability in VO(2)peak due to high-altitude adaptation was modeled by covariance analysis, adjusting for fat-free mass and physical activity (training) differences between groups. A trend for increased VO(2)peak with increasing developmental high-altitude exposure in migrant groups did not reach statistical significance, but low statistical power may have limited the ability to detect this effect. HANs and LANs born, raised, and tested at high altitude had similar VO(2)peak values, indicating no genetic effect, or an effect much smaller than that reported previously in the literature. There was no functional correlation between forced vital capacity and VO(2)peak, within or across groups. These results do not support the hypothesis that Andean HANs have been selected to express a greater physical work capacity in hypoxia.

Adaptation, Physiological↗