Environmental Mediation and The Twin Design

Behavior genetic twin designs are increasingly used to study the effects of a measured environment whilst controlling for genetic variation. In this research note, we show that, in the context of the classical twin design, (1) when the environmental variable is necessarily shared between twins, the notion of controlling for genetic influence is logically flawed and (2) when the environmental variable varies between twins in the same family, partial control for genetic influence is possible, but only if appropriate analytic models are used, which is commonly not the case. Based on a simple simulation study, recommendations are given as to which methods should be applied and which should be avoided.     

Tiagabine reduces ethanol reward in C57BL/6 mice under acute and chronic administration regimens

Three experiments conducted on male C57BL/6 (B6) mice examined the effects of subcutaneous injections of the GABA uptake inhibitor, tiagabine, on appetitive (lever responding) and consummatory behavior (fountain contacts) of food restricted B6 mice for 12% ethanol and water rewards (Exp-1), and for food reward (Exp-2) delivered on a fixed ratio 4 schedule of reinforcement. Effects of acute injections (1,3,6,9 mgkg) and chronic administration (6,9 mg/kg) was examined. Exp-3 examined tiagabine effects on the voluntary consumption of continuously available 12% ethanol, and on the interactive effects of tiagabine and ethanol on motor activity of non-food restricted B6 mice. Results of Exp-1 and Exp-2 indicated that tiagabine can reduce appetitive behavior for ethanol reward with no evidence of tolerance upon chronic exposure. Tiagabine doses that reduced ethanol reward had less effect on behavior maintained by either water or food, and had no effect on motor activity. In contrast to the absence of tolerance to its effect on appetitive behavior for ethanol, mice rapidly developed tolerance to tiagabine's initial reduction of the consummatory response for ethanol (Exp-1), and the intake of freely available ethanol exceeded pre-tiagabine levels after several daily injections (Exp-3). Importantly, mice developed tolerance to tiagabine's sedative effect after three daily injections and its sedation was not enhanced when combined with ethanol, an effect consistent with the lack of a tiagabine + ethanol interaction previously reported for humans. The results of the experiments suggest that in addition to reducing alcohol withdrawal symptoms, tiagabine might also reduce the potency of ethanol-conditioned cues that drive appetitive behavior for ethanol.     

PHARMAC and tobacco control in New Zealand: government policy 'up in smoke'

There is increasing concerning amongst the medical profession in New Zealand about the adverse effect that PHARMAC has on the health of New Zealanders through restricting the availability of medications. In this article, the circumstances surrounding the restrictions limiting the availability of the smoking cessation treatment bupropion are presented. The authors conclude that the decision by PHARMAC not to fund bupropion is directly contrary to Government policy and is inconsistent with evidence-based medicine and international recommendations. It is suggested that the PHARMAC decision seriously questions the Ministry of Health's commitment to smoking cessation and the health of disadvantaged groups in New Zealand, particularly Maori.     

Structural polymorphism of the fourth component of human complement

The fourth component of human complement (C4) in 102 individual plasma samples has been examined by the technique of antigen-antibody crossed electrophoresis (AACE). Electrophoretic heterogeneity of C4 was manifested by the repeated occurrence of seven different precipitin patterns. These patterns were formed by varying combinations of three subtypes of C4, differing in electrophoretic mobility. The subtypes were designated C, A, and A(1), in order of increasing electrophoretic mobility toward the anode. The evidence that the observed electrophoretic heterogeneity of the C4 molecule represents structural polymorphism rests on five points: the pattern obtained from the plasma of a given individual was reproducible in different runs and with different bleedings; all seven patterns could be demonstrated on the same electrophoretic run; C4 of a given subtype retained its characteristic mobility after purification, when run alone or mixed with plasma containing C4 of other subtypes; the subtypes A(1) and C comprising pattern 6 could be separated chromatographically as well as electrophoretically; and the characteristic relative mobilities of different C4 subtypes, in plasma or after purification, were retained even after the rather large shift in mobility associated with conversion to C4i. The ratio of C4 hemolytic activity to protein concentration varied according to the subtype composition of individual samples, with highest ratios occurring with patterns composed of subtype C alone, intermediate values with patterns consisting of A and C, and lower values occurring with patterns containing subtype A alone. Although the mechanism of inheritance of this polymorphism is not yet clear, the data suggest that subtypes A and A(1) are inherited as autosomal codominant characteristics, independent of the inheritance of subtype C.     

A 30-year analysis of cardiac neoplasms at autopsy

INTRODUCTION: Cardiac neoplasms are rare and the vast majority are metastatic in origin. Symptoms of cardiac neoplasms (primary or metastatic) usually appear late in the course of the disease and are often ignored because of the more severe effects of the primary malignant disorder or its therapy. Consequently, cardiac neoplasms, especially metastatic ones, are often not discovered until autopsy. OBJECTIVES: To assess the incidence of cardiac neoplasms at autopsy and to determine the sites of origins of metastatic cardiac neoplasms. METHODS: The pathology records from consecutive autopsies performed at the University Health Network, Toronto, Ontario, from January 1973 to May 2004 were reviewed. They showed 266 cases of neoplasms involving the heart among 11,432 consecutive autopsies. These cases were then categorized based on their system of origin and further subclassified into specific primary site categories. As well, the type of cardiac tissue affected was noted in 193 cases (72.6%). RESULTS: The 266 autopsy cases involving cardiac neoplasms represented 2.33% of the total number of autopsies. Among the 266 cases, two neoplasms were primaries, while 264 were metastatic in origin. Metastatic cardiac neoplasms most frequently metastasized from the respiratory system, followed (in order of decreasing frequency) by the hematopoietic, gastrointestinal, breast and genitourinary systems. A minority of metastatic cardiac neoplasms were found to have spread from other systems. Cardiac neoplasms most frequently involved the pericardium, followed (in order of decreasing frequency) by the myocardium, epicardium and endocardium. CONCLUSIONS: There were 132 times more metastatic cardiac neoplasms than primary cardiac neoplasms found in the present study. The most common sites of metastatic origin were the lungs, bone marrow (leukemia/multiple myeloma), breasts and lymph nodes (lymphoma). Leukemias were more prevalent in the present study than in previous studies. The pericardium was the tissue that was most frequently affected by metastatic cardiac neoplasms.     

High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin: outcomes at 6 months and 1 year in the SYNERGY trial

Context  The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days. Objective  To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up. Design, Setting, and Patients  Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year. Main Outcome Measures  Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator–reported need for rehospitalization; 1-year outcome was all-cause death. Results  Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55). Conclusions  In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies. ClinicalTrials.gov Identifier:  NCT00043784.      

Simple lightweight disposable continuous positive airways pressure mask to effectively treat acute pulmonary oedema: randomized controlled trial

Objective: To compare the novel Boussignac valve continuous positive airways pressure (CPAP) delivery mask and a standard closed‐circuit Drager CF800 CPAP system in the management of acute pulmonary oedema (APO) patients. Methods: This was a randomized controlled trial whereby patients presenting to the ED with APO and who met the study criteria received either CPAP via the Boussignac valve system or from a standard Drager CF800. Baseline physiological and arterial gas data were recorded and repeated at 30 and 60 min after CPAP commenced. The primary outcome was mean change in pCO₂ at 60 min between the two systems. Results: There were 39 evaluable patients (19 Boussignac, 20 Drager). The mean change in pCO₂ at 60 min compared to baseline was similar in the two groups (Boussignac 0.9 kPa vs. Drager 1.2 kPa, mean difference ?0.3; 95% CI ?1.0–0.5, P = 0.45). In addition, there were no significant differences at 60 min in regards to respiratory rate decrease, Boussignac 17.3/min versus Drager 19.6/min (mean difference 1.3; 95% CI ?3.3–5.8, P = 0.58) or peripheral SaO₂ increase, Boussignac 10.7% versus Drager 14.6% (mean difference ?3.9; 95% CI ?9.9–2.1, P = 0.19). There was no significant difference in disposition from the ED or the complication rate. Conclusions: The Boussignac valve system may be an effective lightweight disposable method of delivering CPAP to patients with APO. It appears to perform as effectively as much larger, more expensive and less transportable equipment.     

The relationship of fatigue to mental and physical health in a community sample

BACKGROUND: Previous studies have shown fatigue and depression/anxiety to be highly associated with each other. The present study seeks to differentiate between fatigue and depression/anxiety and to investigate the familiality/heritability of fatigue using sib-pairs. METHOD: The GENESiS study is a questionnaire study based in the United Kingdom that includes a five-item fatigue scale and four mental health measures (GHQ-12, EPQ-N, MASQ-AA, MASQ-HPA). Fatigue data from 10,444 sibling pairs were analysed using multivariate methods and model fitting techniques to investigate the familiality/heritability of fatigue and its relationship with the other mental health measures and physical health items. RESULTS: Fatigue correlated highly with GHQ-12 (r=0.62, p<0.001). A principal components analysis of the fatigue scale and the GHQ-12 revealed one main component which correlated highly with mental health items, and a smaller second component which correlated modestly with physical health items. Fatigue showed a modest sibling correlation (0.09, p<0.001), and multivariate modelling revealed evidence for familial effects on fatigue that were independent of the mental health measures. CONCLUSIONS: Fatigue showed a strong relationship with both physical illness and mental health measures. Fatigue is modestly familial and at least part of this familial factor is not shared with mental health measures.