Cylindrospermopsin toxicity in mice following a 90-d oral exposure.

Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses in Australia through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90 d) of purified CYN from 75 to 300 µg/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 µg/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level.

Safety of fenbendazole in Chinese ring-necked pheasants (Phasianus colchicus).

Ring-necked pheasants raised on propagation farms can be severely parasitized with Syngamus trachea (gapeworm) and other parasitic worms. Fenbendazole is a highly effective benzimidazole-class anthelmintic that is not currently approved for game bird species in the United States. The objective of this work was to provide target animal safety data to support a label claim for fenbendazole in pheasants at 100 parts per million (ppm) in the feed for 7 consecutive days. Demonstration of safety in young pheasants and a separate demonstration of reproductive safety in adult birds were required. In the young bird study, 160 Chinese ring-necked pheasants (Phasianus colchicus, 80 males and 80 females) were fed a commercial game bird starter ration containing no antibiotics, growth promoters, or coccidiostats until day 0 of the study (approximately 21 days of age). On day 0 the birds were placed on their respective study diets containing fenbendazole at 0, 100, 300, and 500 ppm for 21 days (three times the normal treatment duration). Clinical observations were recorded twice daily. Feed consumption, feed conversion rate, and body weights were determined for each pen. Three birds from each pen were randomly selected for necropsy, histopathology, and clinical pathology. Birds were carefully examined for feathering abnormalities immediately following euthanasia. The remaining birds in each pen were submitted for drug concentration analysis so that concentrations (for low vs. high treatment levels) could be correlated with clinical observations, clinical pathology, and histologic findings. There no morbidities or mortalities after study day--1. There were no statistically significant treatment-related differences in feed consumption, feed conversion rates, body weights, serum biochemistry profiles, hematologic profiles, gross necropsy findings, histopathologic examination, and feathering. Allowable liver and muscle concentrations of fenbendazole sulfone in turkeys are 6 and 2 ppm, respectively, with a 6-hr feed withdrawal. Analysis of fenbendazole concentrations in kidney, liver, leg/thigh, and breast muscle and skin with associated fat revealed that, even at the highest dose level used and with no feed withdrawal, fenbendazole concentrations were relatively low in these tissues. These findings indicate that fenbendazole has a relatively wide margin of safety in young pheasants and that the proposed dose of 100 ppm in the feed for 7 consecutive days is well within the margin of safety. In the reproductive safety study, two large game bird farms fed fendbendazole at 100 ppm for 7 days and collected data on hatching percentage of pheasant eggs before and after treatment. Reproductive performance in hen pheasants was not adversely affected.

Impact of mental health problems on case fatality in male cancer patients.

BACKGROUND: Although mortality rates are elevated in psychiatric patients relative to their healthy counterparts, little is known about the impact of mental health on survival in people with cancer. METHODS AND RESULTS: Among 16 498 Swedish men with cancer, survival was worse in those with a history of psychiatric hospital admissions: multiply-adjusted hazard ratio (95% confidence interval) comparing cancer mortality in men with and without psychiatric admissions: 1.59 (1.39, 1.83). CONCLUSION: Survival in cancer patients is worse among those with a history of psychiatric disease. The mechanisms underlying this association should be further explored.

Amyloid deposition in 2 feline thymomas.

Two cases of feline thymoma with amyloid deposition were encountered between 1982 and 2010. Neoplastic cells were separated by abundant, pale eosinophilic, homogeneous material that was congophilic and birefringent. Ultrastructurally, the neoplastic cells were connected by desmosomes, and the extracellular deposits were composed of nonbranching, hollow-cored fibrils, 8-10 nm in diameter. In the case with sufficient archived tissue for additional sections, the amyloid remained congophilic following potassium permanganate incubation, and the neoplastic cells were immunoreactive for pancytokeratin. The histologic, histochemical, ultrastructural, and immunohistochemical features of both neoplasms are consistent with epithelial-predominant thymoma with the unusual feature of intratumoral amyloid deposition. The affinity of the amyloid for Congo red following potassium permanganate incubation is consistent with non-AA amyloid. The ultrastructural findings were consistent with amyloid production by the neoplastic epithelial cells.

Associations between types of dietary fat and fish intake and risk of stroke in the Caerphilly Prospective Study (CaPS).

BACKGROUND: Few population-based longitudinal studies on diet and stroke have been conducted, and associations between dietary fat and fish intake and risk of stroke are unclear. OBJECTIVES: To prospectively examine relationships between intakes of total fat, saturated fat, unsaturated fat, white fish and oily fish and risk of stroke in a well-defined population of 2710 middle-aged men. STUDY DESIGN: Prospective cohort study. METHODS: Detailed information on health and lifestyle factors was collected via interview, and diet was assessed on three occasions using a food frequency questionnaire. Stroke ascertainment was by self-report and inspection of clinical records. Extracted data were assessed by two independent experts. RESULTS: During a median follow-up of 18 years, 225 strokes (209 ischaemic and 19 haemorrhagic) were eligible for inclusion in the analyses. For most recent diet (i.e. food frequency questionnaire data collected immediately prior to the stroke event), there was a slightly lower risk of stroke with higher intakes of unsaturated fat and oily fish. Multiple adjusted hazard ratios (HRs) for the lowest vs highest quintiles of unsaturated fat and oily fish intakes were 0.66 [95% confidence interval (CI) 0.41-1.05, P trend = 0.13] and 0.66 (95% CI 0.41-1.05, P trend = 0.09), respectively. Baseline and cumulative diets showed a slightly higher risk of stroke with higher intake of white fish; HRs for the lowest vs highest quintiles were 1.16 (95% CI 0.76-1.77, P trend = 0.22) and 1.28 (95% CI 0.77-2.13, P trend = 0.48), respectively. CONCLUSIONS: Overall, strong associations were not found between intakes of different types of fat and fish and risk of stroke in middle-aged men. The inverse associations between unsaturated fat and oily fish intakes and risk of stroke were weak, but the direction of association was broadly consistent with other studies; however, these relatively weak associations were not conventionally statistically significant.

Immunoglobulin structure: variation in the sequence of Bence Jones proteins.

Analysis of the amino acid sequence of one Bence Jones protein is almost comtplete. Many points of interchange occur in the amino terminal. portion of the molecule relative to partial-sequence data for other proteins. Most, but not all, are, compartible with one-step mutations. Such structural variation in immunoglobulin light chains may result from many related genes.

Diagnostic accuracy of contrast-enhanced computed tomography for assessment of mandibular and medial retropharyngeal lymph node metastasis in dogs with oral and nasal cancer.

The diagnostic accuracy of contrast-enhanced CT for detection of cervical lymph node metastasis in dogs is unknown. The purpose of this retrospective, observational, diagnostic accuracy study was to assess the efficacy of CT for detection of mandibular and medial retropharyngeal lymph node metastasis in dogs. Histopathology of dogs with cancer of the head, CT and bilateral mandibular and medial retropharyngeal lymphadenectomy was reviewed. A single radiologist measured lymph nodes to derive short axis width and long-short axis ratios. Two blinded radiologists separately assessed lymph node margins, attenuation and contrast enhancement and each provided a final subjective interpretation of each node site as benign or neoplastic. Where radiologists' opinions differed, a consensus was reached. Sensitivity, specificity and accuracy were calculated for mandibular and medial retropharyngeal sites. Agreement between radiologists was assessed. Fisher's exact test and the Kruskal-Wallis H-test were used to assess associations between variables. Forty-one primary tumours were recorded in 40 dogs. Metastasis to mandibular or retropharyngeal lymph nodes occurred in 16 out of 40 dogs (43/160 nodes). Agreement between radiologists was almost perfect for margination, attenuation and enhancement, strong for interpretation of mandibular lymph node metastasis, and weak for interpretation of medial retropharyngeal lymph node metastasis. Sensitivity of CT was 12.5% and 10.5%, specificity was 91.1% and 96.7%, and accuracy was 67.5% and 76.3% for mandibular and medial retropharyngeal lymph nodes respectively. No individual CT findings were predictive of nodal metastasis. Given the low sensitivity of CT, this modality cannot be relied upon alone for assessment of cervical lymph node metastasis in dogs.

Determinants of outcome in critically ill octogenarians after surgery: an observational study.

BACKGROUND: The population in the UK is growing older and the number of elderly patients cared for on intensive care units (ICU) is increasing. This study was designed to identify risk factors for mortality in critically ill patients of >80 yr of age after surgery. METHODS: We identified 275 patients, aged 80 yr or greater, admitted to the ICU after surgery. After exclusions, 255 were selected for further analysis. Multivariate analysis was then performed to determine the covariates associated with hospital mortality. RESULTS: The overall ICU and hospital mortality was 20.4% and 33.3%, respectively. Patients who received i.v. vasoactive drugs on days 1 and 2 had hospital mortality of 54.4% and 60.5%, respectively. Multivariate analysis showed that requirement for i.v. vasoactive drugs within the first 24 h on ICU [odds ratio (OR) 4.29; 95% CI, 2.35-7.84, P<0.001] and requirement for i.v. vasoactive drugs for a further 24 h (OR 3.63; 95% CI, 1.58-8.37, P<0.01) were associated with hospital mortality. The requirement for i.v. vasoactive drugs was also strongly associated with hospital mortality in all the subgroups studied (elective surgery, emergency surgery, and emergency laparotomy). CONCLUSIONS: For patients aged 80 yr and more, admitted to ICU after surgery, the requirement for i.v. vasoactive drugs in the first and second 24 h was the strongest predictor of hospital mortality.

Ten-year life expectancy after primary total hip replacement.

We determined the ten-year life expectancy of 5831 patients who had undergone 6653 elective primary total hip replacements at a regional orthopaedic centre between April 1993 and October 2004. Using hospital, general practitioner and the local health authority records, we recorded the dates of death for those who died following surgery. The mean age at operation was 67 years (13 to 96) with a male:female ratio of 2:3. Of 1154 patients with a ten-year follow-up 340 (29.5%) had died a mean of 5.6 years (0 to 10) after surgery. Using Kaplan-Meier curves, the ten-year survival was 89% in patients under 65 years at surgery, 75% in patients aged between 65 and 74 years, and 51% in patients over 75. The standardised mortality rates were considerably higher for patients under 45 years, 20% higher for those between 45 and 64 years, and steadily reduced in patients aged 65 and over. The survival of cemented hip replacement derived from the Swedish Hip Arthroplasty Register Annual Report 2004 exceeds the life expectancy of patients over the age of 60 in our area, suggesting that cemented hip replacement is the procedure of choice in this population.

The Exeter Universal stem: a minimum ten-year review from an independent centre.

We reviewed 142 consecutive primary total hip replacements implanted into 123 patients between 1988 and 1993 using the Exeter Universal femoral stem. A total of 74 patients (88 hips) had survived for ten years or more and were reviewed at a mean of 12.7 years (10 to 17). There was no loss to follow-up. The rate of revision of the femoral component for aseptic loosening and osteolysis was 1.1% (1 stem), that for revision for any cause was 2.2% (2 stems), and for re-operation for any cause was 21.6% (19 hips). Re-operation was because of failure of the acetabular component in all but two hips. All but one femoral component subsided within the cement mantle to a mean of 1.52 mm (0 to 8.3) at the final follow-up. One further stem had subsided excessively (8 mm) and had lucent lines at the cement-stem and cement-bone interfaces. This was classified as a radiological failure and is awaiting revision. One stem was revised for deep infection and one for excessive peri-articular osteolysis. Defects of the cement mantle (Barrack grade C and D) were found in 28% of stems (25 hips), associated with increased subsidence (p = 0.01), but were not associated with endosteal lysis or failure. Peri-articular osteolysis was significantly related to the degree of polyethylene wear (p < 0.001), which was in turn associated with a younger age (p = 0.01) and male gender (p < 0.001). The use of the Exeter metal-backed acetabular component was a notable failure with 12 of 32 hips (37.5%) revised for loosening. The Harris-Galante components failed with excessive wear, osteolysis and dislocation with 15% revised (5 of 33 hips). Only one of 23 hips with a cemented Elite component (4%) was revised for loosening and osteolysis. Our findings show that the Exeter Universal stem implanted outside the originating centre has excellent medium-term results.

Radon and cancers other than lung cancer in underground miners: a collaborative analysis of 11 studies.

BACKGROUND: Exposure to the radioactive gas radon and its progeny (222Rn and its radioactive decay products) has recently been linked to a variety of cancers other than lung cancer in geographic correlation studies of domestic radon exposure and in individual cohorts of occupationally exposed miners. PURPOSE: This study was designed to characterize further the risks for cancers other than lung cancer (i.e., non-lung cancers) from atmospheric radon. METHODS: Mortality from non-lung cancer was examined in a collaborative analysis of data from 11 cohorts of underground miners in which radon-related excesses of lung cancer had been established. The study included 64,209 men who were employed in the mines for 6.4 years on average, received average cumulative exposures of 155 working-level months (WLM), and were followed for 16.9 years on average. RESULTS: For all non-lung cancers combined, mortality was close to that expected from mortality rates in the areas surrounding the mines (ratio of observed to expected deaths [O/E] = 1.01; 95% confidence interval [CI] = 0.95-1.07, based on 1179 deaths), and mortality did not increase with increasing cumulative exposure. Among 28 individual cancer categories, statistically significant increases in mortality for cancers of the stomach (O/E = 1.33; 95% CI = 1.16-1.52) and liver (O/E = 1.73; 95% CI = 1.29-2.28) and statistically significant decreases for cancers of the tongue and mouth (O/E = 0.52; 95% CI = 0.26-0.93), pharynx (O/E = 0.35; 95% CI = 0.16-0.66), and colon (O/E = 0.77; 95% CI = 0.63-0.95) were observed. For leukemia, mortality was increased in the period less than 10 years since starting work (O/E = 1.93; 95% CI = 1.19-2.95) but not subsequently. For none of these diseases was mortality significantly related to cumulative exposure. Among the remaining individual categories of non-lung cancer, mortality was related to cumulative exposure only for cancer of the pancreas (excess relative risk per WLM = 0.07%; 95% CI = 0.01-0.12) and, in the period less than 10 years since the start of employment, for other and unspecified cancers (excess relative risk per WLM = 0.22%; 95% CI = 0.08-0.37). CONCLUSIONS: The increases in mortality from stomach and liver cancers and leukemia are unlikely to have been caused by radon, since they are unrelated to cumulative exposure. The association between cumulative exposure and pancreatic cancer seems likely to be a chance finding, while the association between cumulative exposure and other and unspecified cancers was caused by deaths certified as due to carcinomatosis (widespread disseminated cancer throughout the body) that were likely to have been due to lung cancers. This study, therefore, provides considerable evidence that high concentrations of radon in air do not cause a material risk of mortality from cancers other than lung cancer. IMPLICATIONS: Protection standards for radon should continue to be based on consideration of the lung cancer risk alone.

Multicenter case-control study of exposure to environmental tobacco smoke and lung cancer in Europe.

BACKGROUND: An association between exposure to environmental tobacco smoke (ETS) and lung cancer risk has been suggested. To evaluate this possible association better, researchers need more precise estimates of risk, the relative contribution of different sources of ETS, and the effect of ETS exposure on different histologic types of lung cancer. To address these issues, we have conducted a case-control study of lung cancer and exposure to ETS in 12 centers from seven European countries. METHODS: A total of 650 patients with lung cancer and 1542 control subjects up to 74 years of age were interviewed about exposure to ETS. Neither case subjects nor control subjects had smoked more than 400 cigarettes in their lifetime. RESULTS: ETS exposure during childhood was not associated with an increased risk of lung cancer (odds ratio [OR] for ever exposure = 0.78; 95% confidence interval [CI] = 0.64-0.96). The OR for ever exposure to spousal ETS was 1.16 (95% CI = 0.93-1.44). No clear dose-response relationship could be demonstrated for cumulative spousal ETS exposure. The OR for ever exposure to workplace ETS was 1.17 (95% CI = 0.94-1.45), with possible evidence of increasing risk for increasing duration of exposure. No increase in risk was detected in subjects whose exposure to spousal or workplace ETS ended more than 15 years earlier. Ever exposure to ETS from other sources was not associated with lung cancer risk. Risks from combined exposure to spousal and workplace ETS were higher for squamous cell carcinoma and small-cell carcinoma than for adenocarcinoma, but the differences were not statistically significant. CONCLUSIONS: Our results indicate no association between childhood exposure to ETS and lung cancer risk. We did find weak evidence of a dose-response relationship between risk of lung cancer and exposure to spousal and workplace ETS. There was no detectable risk after cessation of exposure.

The association of fetal and childhood growth with risk of schizophrenia. Cohort study of 720,000 Swedish men and women.

Previous investigations of the association of schizophrenia with patterns of pre- and post-natal growth have been based on small numbers of cases or have not taken account of the effects of prematurity on birthweight. We investigated the association of fetal growth with schizophrenia in a large cohort of Swedish males and females. We linked data from the Swedish Medical Birth Register (1973-1980), Inpatient and Discharge Register (1988-2002), Military Service Conscription Register (1990-1997), and the Population and Housing Censuses (1970 and 1990). Altogether 719,476 males and females were followed up from the age of 16 for a mean of 9.9 years. There were 736 incident cases of schizophrenia. Even in models that did not control for gestational age there was little evidence of an association between birthweight and schizophrenia (hazard ratio per kg increase in birthweight: 0.90 (95% CI 0.78 to 1.03); the hazard ratio in babies weighing <2.5 kg compared to 3.5-4.0 kg was 1.29 (95% CI 0.85 to 1.96). There was an inverse association of birth length with schizophrenia across the range of birth lengths. Short babies were at an increased risk (hazard ratio per 10 cm increase in birth length: 0.53, 95% CI 0.31 to 0.89 (fully adjusted model)). All associations were little changed when analyses were restricted to term (>36 week gestation) babies. In males, low body mass index and short height at age 18 were associated with increased risk. There is some evidence that patterns of risk in relation to fetal growth differ depending on post-natal growth patterns: the increased risk associated with low body mass index was restricted to long babies who became light adults. The exposures underlying these associations and the biological mechanisms mediating them require clarification.

Radon exposure and cancers other than lung cancer in Swedish iron miners.

Data are presented on the risks of cancers other than lung cancer in a cohort of iron miners from northern Sweden occupationally exposed to elevated levels of the radioactive gas radon. Compared with rates for the four northernmost counties of Sweden, mortality was increased for all cancers other than lung cancer (ratio of observed to expected deaths 1.21, 95% confidence interval 1.03-1.41), stomach cancer (ratio of observed to expected deaths 1.45, 95% confidence interval 1.04-1.98), and rectal cancer (ratio of observed to expected deaths 1.94, 95% confidence interval 1.03-3.31). Despite these overall increases, mortality was not significantly associated with cumulative exposure to radon, either for all cancers other than lung cancer or for any site of cancer other than lung cancer individually. However, the data from this cohort on its own have limited power; and for several sites of cancer the data in this study would be consistent with a radon-related increase. Further study of cancers other than lung cancer in populations exposed to radon is required.

Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

BACKGROUND: Subgroup analyses are common in randomised controlled trials (RCTs). There are many easily accessible guidelines on the selection and analysis of subgroups but the key messages do not seem to be universally accepted and inappropriate analyses continue to appear in the literature. This has potentially serious implications because erroneous identification of differential subgroup effects may lead to inappropriate provision or withholding of treatment. OBJECTIVES: (1) To quantify the extent to which subgroup analyses may be misleading. (2) To compare the relative merits and weaknesses of the two most common approaches to subgroup analysis: separate (subgroup-specific) analyses of treatment effect and formal statistical tests of interaction. (3) To establish what factors affect the performance of the two approaches. (4) To provide estimates of the increase in sample size required to detect differential subgroup effects. (5) To provide recommendations on the analysis and interpretation of subgroup analyses. METHODS: The performances of subgroup-specific and formal interaction tests were assessed by simulating data with no differential subgroup effects and determining the extent to which the two approaches (incorrectly) identified such an effect, and simulating data with a differential subgroup effect and determining the extent to which the two approaches were able to (correctly) identify it. Initially, data were simulated to represent the 'simplest case' of two equal-sized treatment groups and two equal-sized subgroups. Data were first simulated with no differential subgroup effect and then with a range of types and magnitudes of subgroup effect with the sample size determined by the nominal power (50-95%) for the overall treatment effect. Additional simulations were conducted to explore the individual impact of the sample size, the magnitude of the overall treatment effect, the size and number of treatment groups and subgroups and, in the case of continuous data, the variability of the data. The simulated data covered the types of outcomes most commonly used in RCTs, namely continuous (Gaussian) variables, binary outcomes and survival times. All analyses were carried out using appropriate regression models, and subgroup effects were identified on the basis of statistical significance at the 5% level. RESULTS: While there was some variation for smaller sample sizes, the results for the three types of outcome were very similar for simulations with a total sample size of greater than or equal to 200. With simulated simplest case data with no differential subgroup effects, the formal tests of interaction were significant in 5% of cases as expected, while subgroup-specific tests were less reliable and identified effects in 7-66% of cases depending on whether there was an overall treatment effect. The most common type of subgroup effect identified in this way was where the treatment effect was seen to be significant in one subgroup only. When a simulated differential subgroup effect was included, the results were dependent on the nominal power of the simulated data and the type and magnitude of the subgroup effect. However, the performance of the formal interaction test was generally superior to that of the subgroup-specific analyses, with more differential effects correctly identified. In addition, the subgroup-specific analyses often suggested the wrong type of differential effect. The ability of formal interaction tests to (correctly) identify subgroup effects improved as the size of the interaction increased relative to the overall treatment effect. When the size of the interaction was twice the overall effect or greater, the interaction tests had at least the same power as the overall treatment effect. However, power was considerably reduced for smaller interactions, which are much more likely in practice. The inflation factor required to increase the sample size to enable detection of the interaction with the same power as the overall effect varied with the size of the interaction. For an interaction of the same magnitude as the overall effect, the inflation factor was 4, and this increased dramatically to of greater than or equal to 100 for more subtle interactions of < 20% of the overall effect. Formal interaction tests were generally robust to alterations in the number and size of the treatment and subgroups and, for continuous data, the variance in the treatment groups, with the only exception being a change in the variance in one of the subgroups. In contrast, the performance of the subgroup-specific tests was affected by almost all of these factors with only a change in the number of treatment groups having no impact at all. CONCLUSIONS: While it is generally recognised that subgroup analyses can produce spurious results, the extent of the problem is almost certainly under-estimated. This is particularly true when subgroup-specific analyses are used. In addition, the increase in sample size required to identify differential subgroup effects may be substantial and the commonly used 'rule of four' may not always be sufficient, especially when interactions are relatively subtle, as is often the case. CONCLUSIONS--RECOMMENDATIONS FOR SUBGROUP ANALYSES AND THEIR INTERPRETATION: (1) Subgroup analyses should, as far as possible, be restricted to those proposed before data collection. Any subgroups chosen after this time should be clearly identified. (2) Trials should ideally be powered with subgroup analyses in mind. However, for modest interactions, this may not be feasible. (3) Subgroup-specific analyses are particularly unreliable and are affected by many factors. Subgroup analyses should always be based on formal tests of interaction although even these should be interpreted with caution. (4) The results from any subgroup analyses should not be over-interpreted. Unless there is strong supporting evidence, they are best viewed as a hypothesis-generation exercise. In particular, one should be wary of evidence suggesting that treatment is effective in one subgroup only. (5) Any apparent lack of differential effect should be regarded with caution unless the study was specifically powered with interactions in mind. CONCLUSIONS--RECOMMENDATIONS FOR RESEARCH: (1) The implications of considering confidence intervals rather than p-values could be considered. (2) The same approach as in this study could be applied to contexts other than RCTs, such as observational studies and meta-analyses. (3) The scenarios used in this study could be examined more comprehensively using other statistical methods, incorporating clustering effects, considering other types of outcome variable and using other approaches, such as Bootstrapping or Bayesian methods.

Associations of height, leg length, and lung function with cardiovascular risk factors in the Midspan Family Study.

BACKGROUND: Taller people and those with better lung function are at reduced risk of coronary heart disease (CHD). Biological mechanisms for these associations are not well understood, but both measures may be markers for early life exposures. Some studies have shown that leg length, an indicator of pre-pubertal nutritional status, is the component of height most strongly associated with CHD risk. Other studies show that height-CHD associations are greatly attenuated when lung function is controlled for. This study examines (1) the association of height and the components of height (leg length and trunk length) with CHD risk factors and (2) the relative strength of the association of height and forced expiratory volume in one second (FEV(1)) with risk factors for CHD. SUBJECTS AND METHODS: Cross sectional analysis of data collected at detailed cardiovascular screening examinations of 1040 men and 1298 women aged 30-59 whose parents were screened in 1972-76. Subjects come from 1477 families and are members of the Midspan Family Study. SETTING: The towns of Renfrew and Paisley in the West of Scotland. RESULTS: Taller subjects and those with better lung function had more favourable cardiovascular risk factor profiles, associations were strongest in relation to FEV(1). Higher FEV(1) was associated with lower blood pressure, cholesterol, glucose, fibrinogen, white blood cell count, and body mass index. Similar, but generally weaker, associations were seen with height. These associations were not attenuated in models controlling for parental height. Longer leg length, but not trunk length, was associated with lower systolic and diastolic blood pressure. Longer leg length was also associated with more favourable levels of cholesterol and body mass index than trunk length. CONCLUSIONS: These findings provide indirect evidence that measures of lung development and pre-pubertal growth act as biomarkers for childhood exposures that may modify an individual's risk of developing CHD. Genetic influences do not seem to underlie height-CHD associations.

The long-term effect of advice to eat more fish on blood pressure in men with coronary disease: results from the diet and reinfarction trial.

BACKGROUND: Systematic reviews of fish and fish oil supplements have reported modest reductions in blood pressure (BP). Many of the trials included in these reviews used high doses of fish oil and most were of short duration. METHOD: Between 1983 and 1987 2033 men under the age of 70, who had recently suffered a myocardial infarction, were enrolled in a 2-year trial of dietary advice-the Diet and Reinfarction Trial (DART). Participants were randomised in a factorial design to receive intensive advice to eat more fish, less fat or more fibre. Those men randomised to receive fish advice were encouraged to eat two portions of fatty fish each week. Intake of eicosapentaenoic acid was 0.33 g per day in the fish advice arm and 0.10 g per day in men not given fish advice. RESULTS: The difference in systolic BP in the fish advice arm, adjusted for age and BP at baseline, was -0.61 mm Hg (95% CI -2.15, 0.92) at 6 months and 0.40 mm Hg (95% CI -1.33, 2.13) at 2 years. The difference in diastolic BP in the fish advice arm, adjusted for age and BP at baseline, was -0.50 mm Hg (95% CI -1.47, 0.46) at 6 months and 0.19 mm Hg (95% CI -0.88, 1.26) at 2 years. CONCLUSIONS: Advice to eat modest amounts of fish has little effect on BP in men with coronary disease.

Modulation by canine interferon-gamma of major histocompatibility complex and tumor-associated antigen expression in canine mammary tumor and melanoma cell lines.

In an effort to enhance the antigenicity of canine tumor cells, canine interferon-gamma (CnIFN-gamma) was applied in vitro to seven canine mammary tumor (CMT) and two canine melanoma (CML) cell lines. Surface expression of major histocompatibility complex (MHC) antigens and tumor-associated antigens (TAA) was measured by a flow cytometric fluorescence assay using commercially available anti-MHC antibodies, and anti-canine TAA monoclonal antibodies generated against CMT and CML cell lines. Compared to constitutive antigen levels in untreated cells, treatment with CnIFN-gamma resulted in increased expression of MHC class I and II antigens (up to 19- and 167-fold, respectively) and a TAA (up to 5-fold) by CMT cell lines, and increased expression of class I antigen (131-fold) by one CML and of class II antigen (18-fold) by the other CML cell line. Expression of MHC antigens and a TAA by tumor cells was increased by Cn-IFN-gamma treatment, and such an increase may be of potential benefit in tumor cell recognition and rejection by the immune system.

The long-term effect of dietary advice in men with coronary disease: follow-up of the Diet and Reinfarction trial (DART).

OBJECTIVE: To assess the long-term effect of dietary advice on diet and mortality after a randomised trial of men with a recent history of myocardial infarction. DESIGN: Questionnaire survey and mortality follow-up after a trial of dietary advice. SETTING: Twenty-one hospitals in south Wales and south-west England. SUBJECTS: Former participants in the Diet and Reinfarction Trial. MAIN OUTCOME MEASURES: Current fish intake and cereal fibre intake. All-cause mortality, stroke mortality and coronary mortality. RESULTS: By February 2000, after 21147 person years of follow-up, 1083 (53%) of the men had died. Completed questionnaires were obtained from 879 (85%) of the 1030 men alive at the beginning of 1999. Relative increases in fish and fibre intake were still present at 10 y but were much smaller. The early reduction in all-cause mortality observed in those given fish advice (unadjusted hazard 0.70 (95% CI 0.54, 0.92)) was followed by an increased risk over the next 3 y (unadjusted hazard 1.31 (95% CI 1.01, 1.70). Fat and fibre advice had no clear effect on coronary or all-cause mortality. The risk of stroke death was increased in the fat advice group-the overall unadjusted hazard was 2.03 (95% CI 1.14, 3.63). CONCLUSIONS: In this follow-up of a trial of intensive dietary advice following myocardial infarction we did not observe any substantial long-term survival benefit. Further trials of fish and fibre advice are feasible and necessary to clarify the role of these foods in coronary disease.