Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration.

BACKGROUND: Disturbed sleep is associated with cognitive decline in neurodegenerative diseases such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). The progressive sequence of how neurodegeneration affects aspects of sleep architecture in conjunction with behavioural changes is not well understood. METHODS: We investigated changes in sleep architecture, spectral power and circadian rhythmicity in the tet-off rTg4510 mouse overexpressing human P301L tau within the same subjects over time. Doxycycline-induced transgene-suppressed rTg4510 mice, tTa carriers and wild-type mice were used as comparators. Spectral power and sleep stages were measured from within the home cage environment using EEG electrodes. In addition, locomotor activity and performance during a T-maze task were measured. RESULTS: Spectral power in the delta and theta bands showed a time-dependent decrease in rTg4510 mice compared to all other groups. After the initial changes in spectral power, wake during the dark period increased whereas NREM and number of REM sleep bouts decreased in rTg4510 compared to wild-type mice. Home cage locomotor activity in the dark phase significantly increased in rTg4510 compared to wild-type mice by 40 weeks of age. Peak-to-peak circadian rhythm amplitude and performance in the T-maze was impaired throughout the experiment independent of time. At 46 weeks, rTG4510 mice had significant degeneration in the hippocampus and cortex whereas doxycycline-treated rTG4510 mice were protected. Pathology significantly correlated with sleep and EEG outcomes, in addition to locomotor and cognitive measures. CONCLUSIONS: We show that reduced EEG spectral power precedes reductions in sleep and home cage locomotor activity in a mouse model of tauopathy. The data shows increasing mutant tau changes sleep architecture, EEG properties, behaviour and cognition, which suggest tau-related effects on sleep architecture in patients with neurodegenerative diseases.

Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.

The ability of the N-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2 in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.

Association of an interleukin 1 alpha polymorphism with Alzheimer's disease.

BACKGROUND: Retrospective epidemiologic studies suggest that individuals exposed to anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs have a lower probability of developing AD as well as an older age at onset for the illness. Neuroinflammation may play an important role in the pathogenesis of AD. Interleukin 1 (IL-1), a potent proinflammatory cytokine, is colocalized immunohistochemically to neuritic plaques, a requisite neuropathologic feature for AD. A polymorphism in the 5'-flanking regulatory region at -889 of the IL-1 alpha gene (a C-to-T transition designated as IL-1A[-889] allele 2) may cause an overexpression of IL-1 alpha, a finding shown to be associated with inflammatory diseases. The IL-1A(-889) allele 2 polymorphism may be associated with AD pathogenesis. METHODS: A total of 259 patients with AD and 192 nondemented control subjects were included from two different centers (Indianapolis, IN, and Munich, Germany). Genotyping for APOE alleles and IL-1A(-889) allele 2 was performed by PCR-based amplification followed by restrictive endonuclease digestion. Statistical analyses were conducted by center-, gender group-, and age group-stratified Mantel-Haenszel odds ratios, CI, and p values. RESULTS: The allele frequency of IL-1A(-889) allele 2 was 46% in clinically diagnosed patients with probable AD versus 34% in control subjects from the combined centers. CONCLUSION: The authors found an increased risk for AD with an estimated Mantel-Haenszel odds ratio of 1.68 (95% CI 1.1 to 2.6; p = 0.022) for heterozygous carriers and 7.2 (95% CI 2.0 to 24.5; p = 0.003) for individuals homozygous for IL-1A(-889) allele 2. They found no evidence for an interaction between the IL-1A and the apoE epsilon 4 polymorphisms (carriers and homozygotes), age, or gender with regard to conferred risk. The data strongly support an association between the IL-1A(-889) allele 2, especially in homozygotes, and later-onset AD.

Trends in the incidence of acute myocardial infarction between 1984 and 1993 - The Halifax County MONICA Project.

BACKGROUND: According to vital statistics data for Halifax County, between 1984 and 1993 the annual mortality rate decreased for ischemic heart disease and myocardial infarction (MI). OBJECTIVES: To estimate the change in MI mortality, applying standardized diagnostic criteria; to determine whether decreased case fatality or decreased MI event rate, or both, caused decreased mortality; and to determine the contribution of MI incidence rate to altered event rate. PATIENTS AND METHODS: All persons in the study area aged 25 to 74 years and admitted to hospital or dying outside hospital with suspected acute coronary syndromes were registered prospectively. Demographic, health history and clinical data were extracted from medical records or collected from medical examiner reports, next-of-kin interviews or family physicians. Definite or possible MI was diagnosed according to World Health Organization MONItoring of trends and determinants in CArdiovascular disease (MONICA) criteria. Trends in age- and sex-standardized rates were estimated by using log-linear regression analysis. RESULTS: Of 4283 patients admitted to hospital for MI, 23.9% died within 28 days; 1401 patients who had suffered an MI died before admission to hospital. MI mortality decreased annually by 3.9% (95% CI 1.9 to 5.8); two-thirds of the decline was due to MI event rates (2.6%; CI 1.3 to 3.8) and one-third to a decrease in 28-day case fatality (1.3%; CI 0.2 to 2. 3). A decrease in MI incidence rate (3.2%; CI 1.7 to 4.8), rather than a decline in MI recurrence rate (1.4%; CI 0.7 to -3.5), was the major reason for the declining event rate. CONCLUSIONS: A decrease in the incidence of MI, possibly due to primary prevention, had a major impact on the declining MI mortality. Decreased in-hospital MI fatality, possibly due to improved treatment, was responsible for the decline in case fatality.

1,2-Dibenzamidobenzene inhibitors of human factor Xa.

High-throughput screening of a combinatorial library of diamidophenols yielded lead compounds with the ability to inhibit human factor Xa (fXa) at micromolar concentrations (e.g. compound 4, fXa apparent K(ass) = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showed that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phenyl group of one benzoyl group (A-ring) was substituted in the 4-position with relatively small lipophilic or polarizable groups such as methoxy, vinyl, or chloro and the phenyl group of the other benzoyl group (B-ring) was substituted in the 4-position with larger lipophilic groups such as tert-butyl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide variety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxyl substitution produced slightly higher levels of activity than other substituents when present in combination with favorable B-ring substitution. Methylation of the amide nitrogen atoms was found to greatly decrease activity. Compound 12 is the highest affinity fXa inhibitor in this group of compounds, having fXa apparent K(ass) = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can serve to guide future SAR studies.

A randomized, placebo-controlled trial of erythromycin estolate chemoprophylaxis for household contacts of children with culture-positive bordetella pertussis infection.

CONTEXT: Household contacts of patients with pertussis are at increased risk of acquiring infection. Chemoprophylaxis has been recommended to decrease transmission, particularly to young infants who are at increased risk of severe disease. Although epidemiologic investigations of outbreaks have suggested a benefit, there have been no prospective studies evaluating the efficacy of chemoprophylaxis in preventing secondary cases of pertussis. OBJECTIVE: To determine whether erythromycin estolate chemoprophylaxis is effective in household contacts of children with culture-positive pertussis. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Community based. SUBJECTS: All household contacts of 152 children with culture-positive pertussis who provided consent (n = 362). After withdrawals, there were 135 households with 310 contacts. Exclusions included pregnancy, age <6 months, already receiving an erythromycin-containing antibiotic, and erythromycin allergy. INTERVENTUINS: Erythromycin estolate (40 mg/kg/day in 3 divided doses; maximum dose 1 g) or placebo for 10 days. Nasopharyngeal cultures, pertussis antibodies, and clinical symptoms were assessed before and after treatment. PRIMARY OUTCOME: Measure efficacy of erythromycin estolate chemoprophylaxis calculated by the proportion of households in each group with a member who developed a nasopharyngeal culture positive for Bordetella pertussis. RESULTS: There was no difference in the development of respiratory tract symptoms compatible with a case definition of pertussis in the erythromycin- and placebo-treated groups. There were 20 households with secondary culture-positive cases of pertussis; 4 households in the erythromycin-treated group and 15 in the placebo-treated group (efficacy of erythromycin chemoprophylaxis for bacterial eradication 67.5% [95% confidence interval: 7.6-88.7]). However, medication-associated adverse reactions were reported by 34.0% of erythromycin and 15.7% of placebo recipients. CONCLUSIONS: Under the conditions of this study, erythromycin estolate prevented culture-positive pertussis in household contacts of patients with pertussis but did not prevent clinical pertussis.

Comparison of a fifth dose of a five-component acellular or a whole cell pertussis vaccine in children four to six years of age.

BACKGROUND AND OBJECTIVES: Acellular pertussis vaccines are now preferred for all five childhood immunization doses; however, there are few data on the safety and immunogenicity of five consecutive doses. This study compared a fifth dose of an acellular and a whole cell pertussis vaccine in 4- to 6-year-old children previously immunized with four doses of acellular or whole cell pertussis vaccine. STUDY DESIGN: In a double blind, multicenter study, 366 healthy children were randomly allocated to receive a single injection of a 5-component acellular or a whole cell pertussis vaccine, each combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine. RESULTS: Although injection site redness > or =50 mm and swelling > or =50 mm were common in children who had received five doses of acellular (50% and 48.1%, respectively) or whole cell (66.2% and 59.7%) pertussis vaccine, limb soreness and limitation of motion were less frequently reported after acellular (1.9% and 0%) than after whole cell (49.2% and 36.3%; P < 0.0001) pertussis vaccine. Pre-fifth dose antipertussis antibody titers were higher in children who previously had received four doses of acellular pertussis vaccine. Postimmunization antibody titers against pertussis toxin, filamentous hemagglutinin, pertactin and tetanus toxin were higher in recipients of five doses of acellular pertussis vaccine, whereas antibody titers to diphtheria toxin, pertussis fimbriae and poliovirus serotypes were higher in recipients of five doses of the whole cell pertussis vaccine (P < 0.05 for all comparisons). CONCLUSIONS: A regimen consisting of five doses of a five-component acellular pertussis combination vaccine is safe and immunogenic in pre-school children. Local adverse reactions are common but are less painful and activity-limiting than a regimen of five doses of a whole cell pertussis vaccine.

Ten-year trends of heart disease risk factors in the Halifax County MONICA population. MONItoring of trends and determinants in CArdiovascular disease.

OBJECTIVE: To investigate trends in heart disease risk factors (RFs) in the general population of Halifax County, Nova Scotia during a 10-year period. DESIGN: Two independent random samples of the population of Halifax County were surveyed in 1985 and 1995; age ranges were 25-64 years and 25-74 years. Blood pressure, cholesterol and body weight were measured. Smoking and health history were obtained by questionnaire. MAIN RESULTS: Participation rate was 66.3% in 1985 and 1995. All RFs were negatively correlated with education attainment. RF changes from 1985 to 1995 were related to education level. Among survey participants, mean body mass index increased from 26.7 kg/m2 to 27.6 kg/m2 (P + 0.005) for men, and from 25.5 kg/m2 to 27.3 kg/m2 (P < 0.00001) for women. Average smoking rate increased from 32.0% to 34.6% (not significant) in men and from 27.7% to 29.1% (not significant) in women. Age-specific smoking rate increased by 13% (P = 0.14) in younger women and decreased by 10% in older women. (P = 0.00). Mean levels of blood cholesterol decreased by 0.2 mmol/L (P = 0.002) in men and 0.1 mmol/L (P = 0.20) in women. Systolic blood pressure increased by 6.3 mmHg (P < 0.0001) in men and by 7.9 mmHg (P < 0.0001) in women, being steepest in the lower education group. Mortality predicted from RFs declined between the survey years, but less than the observed mortality. This discrepancy may result from the effect of medical care or the delayed effect of RF changes. CONCLUSIONS: Some risk factors show a disturbing trend, indicating that an increased effort or a change in strategy is needed to combat the risk of ischemic heart disease.

Safety and immunogenicity of a new influenza vaccine grown in mammalian cell culture.

In a phase I safety and immunogenicity study, 112 healthy adult volunteers were randomly allocated to receive a new bivalent (A/Texas/36/91[H1N1-like], B/Harbin/7/94) split virion influenza vaccine propagated in Madin-Darby Canine Kidney cell culture or an identical vaccine manufactured using currently licensed egg propagated virus technology. Soreness at the injection site was common but generally mild (75% of the cell culture-derived vaccine group and 62.5% of the egg-derived vaccine group; p = not significant). General reactions were less common; headache was the most frequently reported adverse effect (26.8 and 30.4%, respectively; p = not significant). Geometric mean haemagglutination inhibition titres post-immunization against the A/Texas strain were 1012 reciprocal dilution in the cell culture-derived vaccine group and 790 in the egg-derived vaccine group; against the B/Harbin strain titres were 420 and 447, respectively (all comparisons, p = not significant). It is concluded that the cell culture-derived split virion influenza vaccine is safe and immunogenic in healthy adult volunteers.

Comparison of parental and health care professional preferences for the acellular or whole cell pertussis vaccine.

OBJECTIVE: To compare the preferences of mothers, physicians and nurses for use of a new generic acellular pertussis vaccine which is less reactogenic than and as effective as a conventional whole cell vaccine, but which would require multiple injections rather than a single injection to deliver all other recommended vaccines. METHODS: A convenience sample of 400 mothers of 1-month-old infants, 100 immunizing physicians and 100 immunizing nurses were surveyed over a 2 1/2-month period. Information about pertussis and both whole cell and acellular pertussis vaccines was provided, and a questionnaire was used to assess knowledge and attitudes about pertussis vaccine, vaccine preference and reasons for selection. In addition to their own preferences health care professionals were asked to predict which vaccine mothers would prefer and to predict why mothers would choose a particular vaccine. RESULTS: Mothers preferred the acellular vaccine over the whole cell vaccine by a nearly 2:1 margin (57.3% vs. 29.5%). Health care professionals preferred the whole cell vaccine by the same 2:1 margin (61.1% vs. 29.3%). Only 19.1% of health care professionals predicted that mothers would accept the acellular vaccine if it meant multiple injections. More mothers were concerned by the common reactions caused by the whole cell vaccine (75.8% vs. 52%; P = 0.001); more health care professionals felt that multiple injections were stressful (89% vs. 70%; P = 0.001) and that they could be associated with long term effects (17% vs. 8.8%; P = 0.003). More health care professionals than mothers said that the need for multiple injections would influence their decision to accept the acellular vaccine (76.5% vs. 38.3%; P = 0.001). CONCLUSIONS: Mothers prefer a less reactogenic vaccine product even if it requires multiple injections. Health care professionals are more concerned about multiple injections and are poor predictors of mothers' vaccine preference. Multiple injections may be more a barrier to immunization for health care professionals than for mothers.

Seven days of erythromycin estolate is as effective as fourteen days for the treatment of Bordetella pertussis infections.

OBJECTIVE AND METHODS: Although 14 days of erythromycin is recommended for the treatment of Bordetella pertussis infection, there have been no prospective controlled studies to support the contention that this long course of therapy is required to eradicate the microorganism from the nasopharynx or to prevent bacteriological relapse. We randomly allocated children and adults with culture-positive community-acquired pertussis to either 7 or 14 days of erythromycin estolate treatment (40 mg/kg/d; maximum dose 1 g/d). Nasopharyngeal aspirate cultures were obtained by study nurses during home visits before and at the end of treatment, and 1 week after the completion of treatment. B pertussis-specific antibodies were measured before treatment and 1 month later. Information about clinical symptoms, adverse reactions, and compliance were collected at each scheduled contact. RESULTS AND CONCLUSIONS: A total of 168 participants were eligible for analysis (74 treated for 7 days and 94 treated for 14 days). Bacteriological persistence (positive end of therapy culture) occurred once in each group, and bacteriological relapse (positive culture 1 week after completion of treatment) occurred in one participant treated for 7 days. The overall failure rate (persistence plus relapse) of 2.70% in the 7-day group was not different than the rate of 1.06% in the 14-day group. The study had a power of 99.99% at the 5% level to detect a difference in failure rates of 10% and a power of 80% to detect a difference of 5%. We conclude that 7 days of erythromycin estolate is as effective as 14 days for the eradication of B pertussis.

Decreasing mortality from acute myocardial infarctions: effect of attack rates and case severity.

Mortality from myocardial infarction (MI) has declined in many countries and the reasons for the decline have not been fully quantified. We used the database of the Halifax County MONICA Project to test the hypothesis that the decline of in-hospital mortality from MI can be explained by a trend toward less severe disease as opposed to improved treatment. During the study period 1984-1993, 14,130 people aged 25-74 had been admitted to hospital with suspected MI. Of these, 3774 were diagnosed as definite MI by standardized criteria (480 fatal). For each patient, clinical history, serial cardiac enzymes, and ECG treatment regimen during hospital stay were extracted from patient charts. Survival status 28 days after onset of symptoms was determined. A severity index predicting 28-day case fatality was derived from health status at admission time. During the study period the rate of definite MI in the MONICA target population showed a general downward trend from 221 to 179 per 100,000/year (p = 0.0002). The severity index increased during the observation time (p < 0.0001), predicting 25% higher mortality. Case fatality fluctuated, but showed a marginally significant decline. We conclude that part of the decreased in-hospital mortality from MI is due to lower attack rates. The remainder occurred despite increased case severity and is possibly due to improved in-hospital treatment.

Safety and immunogenicity of two inactivated poliovirus vaccines in combination with an acellular pertussis vaccine and diphtheria and tetanus toxoids in seventeen- to nineteen-month-old infants.

OBJECTIVES: To compare the safety and immunity of an acellular pertussis vaccine containing pertussis toxoid, filamentous hemagglutinin, 69 kd protein, fimbriae 2 and 3 combined with diphtheria and tetanus toxoids given as single or separate injection with inactivated poliovirus vaccine (MRC-5-or Vero cell-derived) or live attenuated polio vaccine. METHODS: A total of 425 healthy children between 17 and 19 months of age who were receiving the fourth dose of their routine immunization series were randomly allocated to receive either the acellular pertussis vaccine and oral poliovirus vaccine or one of two inactivated poliovirus vaccines as a combined injection or separate injections. RESULTS: Although minor adverse events were commonly reported, differences between the groups were few. Fever and decreased feeding were less common in recipients of live attenuated poliovirus vaccine than the combination vaccine containing MRC-5 cell-derived inactivated poliovirus vaccine. A significant antibody response was demonstrated in all groups against all the antigens contained in the vaccines. Antibodies against poliovirus were higher in the groups immunized with the inactivated poliovirus vaccine than the live attenuated vaccine. Anti-69 kd protein antibodies were higher in the group given the MRC-5 cell-derived inactivated poliovirus vaccine as a combined injection than in the group given the separate injection or the group immunized with the live attenuated poliovirus vaccine. CONCLUSION: The five-component acellular pertussis vaccine combined with diphtherid and tetanus toxoids is safe and immunogenic when combined with either MRC-5- or Vero cell-derived inactivated poliovirus vaccine. This will facilitate the implementation of acellular pertussis vaccine and the movement to inactivated poliovirus vaccine programs.

Safety and immunogenicity of an acellular pertussis diphtheria tetanus vaccine given as a single injection with Haemophilus influenzae b conjugate vaccine.

To determine if an acellular pertussis-diphtheria-tetanus vaccine could be combined with a Haemophilus influenzae b conjugate vaccine as a single injection, we randomized 468 children between 17 and 21 months of age previously immunized with three doses of each vaccine to receive a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids, and Haemophilus influenzae b-tetanus toxoid conjugate vaccine either as separate injections on separate days, separate injections on the same day, or as a single combined injection. Rates of adverse reactions were similar amongst the groups except for increased injection site tenderness (29.2% vs 17%, RR 1.76, 95% CI 1.09-2.85) and fussiness (36.4% vs 23.3%, RR 1.59, 95% CI 1.05-2.41) in the group given the combined injection rather than separate injections on separate days. Antibody levels against the capsular polysaccharide of H. influenzae b after the single combined injection (47.1 micrograms ml-1) were lower than after separate injections on the same day (66.0 micrograms ml-1; P < 0.05) but higher than when the injections were administered on separate days (28.4 micrograms ml-1; P < 0.001). We conclude that the five-component acellular pertussis vaccine is safe and immunogenic when combined with diphtheria and tetanus toxoids and H. influenzae b-tetanus toxoid conjugate vaccine in children receiving the fourth dose of the immunization series.

Optimal sample allocation in clinical trials designed to investigate relative risks.

Clinical trials with more than two groups are becoming increasingly common, especially trials with both active and placebo control groups. Equal allocation of subjects to each of the groups is the most common sample allocation, but in clinical trials where the purpose is to test hypotheses of relative risk, such as vaccine trials, equal allocation can be substantially sub-optimal. Optimal allocation for clinical trials has been considered previously, but not for trials with more than two groups. In this paper optimal sample allocation for relative risk trials is investigated in a variety of situations. The main results are as follows: (i) there are many situations where reductions of more than 20 per cent in sample size can be obtained by using optimal allocation instead of equal allocation; (ii) the optimal allocation for two group studies is not optimal in general; (iii) in many situations optimal allocation increases a subject's chances of being enrolled to a test treatment, and (iv) in most cases a grid search using the likelihood score asymptotic power function is the easiest method of finding an approximately optimal allocation. Extensions to situations more general than those covered here are sketched.

Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up.

BACKGROUND AND DESIGN: Methotrexate (MTX) hepatotoxicity in psoriatic patients is well recognized, but there are discrepancies in the reported incidence and associated risk factors. This retrospective study describes 104 Nova Scotian patients with psoriasis seen between 1979 and 1990. Patients received MTX over one to 11 years (mean 3.38), with baseline and annual follow-up liver biopsies. Clinical data were obtained by chart review. Statistical analysis evaluated the risks associated with obesity, diabetes, alcohol consumption and duration of therapy, with the histological grade of liver biopsies. RESULTS: Of the 104 patients, 35 were obese, 10 were diabetic and 37 occasionally consumed alcohol. At the end of the study, 21 patients had developed severe hepatic fibrosis (grade IIIB), and three developed liver cirrhosis (grade IV). Significant risk of severe hepatotoxicity is related to diabetes (P = 0.02) but not to obesity (P = 0.12) or alcohol consumption (P = 0.12). All patients with cirrhosis took MTX for two years in standard doses of 20 to 25 mg/week. CONCLUSIONS: In this first Canadian study evaluating MTX hepatotoxicity in psoriatics, the incidence of severe hepatotoxicity is high: 23.1% (24 of 104 patients). This study shows that diabetic patients are particularly at increased risk of MTX hepatotoxicity. Occasional alcohol consumption is not associated with increased risk. Three patients who developed cirrhosis over two years of standard MTX therapy may represent a subset of psoriatics with increased hepatic susceptibility to MTX. Another three patients whose severe hepatic fibrosis had regressed upon discontinuation of MTX, but who developed accelerated recurrence of the severe hepatic fibrosis upon resumption of MTX therapy, also suggest the possibility of unusual sensitivity to the drug. These cases emphasize the need for continuing surveillance, with regular liver biopsies, of psoriatic patients on MTX.

Effects of recruitment strategy on response rates and risk factor profile in two cardiovascular surveys.

BACKGROUND: The study was set up to assess the effect of recruitment methods on participation rate, response bias and cardiovascular risk factor estimates. METHODS: Two random samples of men and women in Halifax County aged 25-74 were drawn from the same sampling frame. Their respective sizes were 1007 (NSHHS) and 3036 (MONICA) people. Recruitment by Nova Scotia Heart Health Survey (NSHHS) was through face-to-face contact, whereas the MONICA survey relied on invitation by mail. Outcome measures were response rates at various stages of the recruitment process and the differences in cardiovascular risk factor estimates. RESULTS: Face-to-face recruitment located 51% and mail recruitment located 47% of their respective samples; face-to-face recruitment resulted in fewer individuals who refused to participate in the survey, but also produced fewer who were prepared to provide blood samples in addition to answering questionnaires. By-mail recruits were more likely to have post-secondary education, but did not differ in the proportion of smokers, mean diastolic blood pressure or body mass index, if controlled for education level, gender and age. However, the mean systolic blood pressure was 5.7 mmHg higher and the mean cholesterol level 0.44 mmol/l lower in face-to-face recruits. CONCLUSIONS: Controlling for age, gender and education level eliminates the effect of recruitment bias on most cardiovascular risk factors estimates. The exceptions in our study were systolic blood pressure and cholesterol, where methodological factors may have played a role.

Adverse reactions and antibody response to four doses of acellular or whole cell pertussis vaccine combined with diphtheria and tetanus toxoids in the first 19 months of life.

To assess the safety, immunogenicity, and lot consistency of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoid (Connaught Laboratories Limited), we randomly allocated 432 infants to receive one of three lots of an acellular pertussis vaccine or a single lot of whole cell pertussis vaccine. Infants were immunized at 2, 4 and 6 months of age and between 17 and 19 months of age. Local and systemic adverse reactions were reported significantly more frequently by recipients of the whole cell than acellular vaccine after each dose. The antibody response against pertussis toxin, filamentous hemagglutinin, and 69 kDa protein was of greater magnitude in acellular pertussis vaccine recipients than whole cell pertussis vaccine recipients. Small differences were detected amongst the vaccine lots tested. We conclude that the acellular pertussis vaccine is safe and immunogenic for the first four doses in children under 2 years of age.

Effect of inactivated poliovirus vaccine on the antibody response to Bordetella pertussis antigens when combined with diphtheria-pertussis-tetanus vaccine.

To determine if inactivated poliovirus vaccine combined with diphtheria and tetanus toxoids and whole-cell pertussis vaccine interferes with the immunogenicity of pertussis vaccine, we performed a randomized trial of diphtheria and tetanus toxoids and pertussis vaccine combined with inactivated poliovirus vaccine given as a single injection or as two separate injections at the same visit to infants immunized at 2, 4, and 6 months of age. A total of 84 infants were enrolled in the study; 44 received the single injection, and 40 received separate injections. Before immunization, there were no differences in antibody values between the two groups. After two vaccine doses, infants immunized with the single injection had significantly lower values of antibody to filamentous hemagglutinin (8.3 vs. 23.7 ELISA units; P < .001), fimbriae (266.5 vs. 771.8 ELISA units; P < 0.01), and the 69-kD membrane protein (442.2 vs. 1,352 ELISA units; P < .001). After the third dose, these differences persisted, and differences were also detected for antibody to pertussis toxin (10.0 vs. 35.5 ELISA units; P < .001) and a whole-bacteria antigen preparation (2,667 vs. 3,829 ELISA units; P < .05). We conclude that there is a diminished antibody response to the pertussis vaccine when inactivated poliovirus vaccine is combined with the diphtheria and tetanus toxoids and pertussis vaccine.