Exhaled breath condensate hydrogen peroxide, pH and leukotriene B4 are associated with lower airway inflammation and airway cytology in the horse.

BACKGROUND: Exhaled breath condensate (EBC) analysis is a noninvasive method to assess the lower respiratory tract. In human subjects, EBC hydrogen peroxide (H2 O2 ), pH and leukotriene B4 (LTB4 ) are useful for detection and monitoring of inflammatory lung diseases, including asthma. OBJECTIVES: To determine associations between EBC biomarkers and cytological and endoscopic definitions of lower airway inflammation (LAI) while controlling for sampling and environmental variables. STUDY DESIGN: Prospective, cross-sectional study. METHODS: Clinical, endoscopic and airway cytological findings from 47 horses were compared with EBC pH and concentrations of H2 O2 and LTB4 by univariate and multivariable analyses. Dichotomous (presence/absence of airway inflammation) and continuous outcome variables (differential cell counts in tracheal aspirate and bronchoalveolar lavage fluid, BALF) were evaluated and potential effects of collection and methodological factors were included. RESULTS: EBC pH and H2 O2 concentrations were higher in horses with LAI and both were positively associated with the percentage of neutrophils in BALF (P<0.05). Mast cell percentage in BALF was negatively associated with EBC pH, and BALF eosinophil percentage was positively associated with EBC LTB4 (P<0.05). Ambient temperature, relative humidity and assay methodology significantly impacted some analytes. MAIN LIMITATIONS: LAI is challenging to categorise due to a variety of clinical and cytological phenotypes. Although the study was designed to overcome this limitation, numbers of horses were small in some categories. CONCLUSIONS: EBC pH and H2 O2 concentrations are altered by airway inflammation, suggesting a role for these biomarkers in the diagnosis and monitoring of airway disease. Environmental and methodological factors can influence these biomarkers and should be considered in the interpretation of results.

Evaluation of Pharmacokinetic and Pharmacodynamic Drug-Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild-to-Moderate Hypertension.

Sacubitril/valsartan (LCZ696) is indicated for the treatment of patients with heart failure and reduced ejection fraction (HFrEF). Since patients with HFrEF may receive sacubitril/valsartan and sildenafil, both increasing cyclic guanosine monophosphate, the present study evaluated the pharmacokinetic and pharmacodynamic drug interaction potential between sacubitril/valsartan and sildenafil. In this open-label, three-period, single sequence study, patients with mild-to-moderate hypertension (153.8 ± 8.2 mmHg mean systolic blood pressure (SBP)) received a single dose of sildenafil 50 mg, sacubitril/valsartan 400 mg once daily for 5 days, and sacubitril/valsartan and sildenafil coadministration. When coadministered with sildenafil, the AUC and Cmax of valsartan decreased by 29% and 39%, respectively. Coadministration of sacubitril/valsartan and sildenafil resulted in a greater decrease in BP (-5/-4/-4 mmHg mean ambulatory SBP/DBP/MAP (mean arterial pressure)) than with sacubitril/valsartan alone. Both treatments were generally safe and well tolerated in this study; however, the additional BP reduction suggests that sildenafil should be administered cautiously in patients receiving sacubitril/valsartan. Unique identifier: NCT01601470.

International survey on the use and welfare of zebrafish Danio rerio in research.

A survey was conducted regarding zebrafish Danio rerio use for scientific research with a focus on: anaesthesia and euthanasia; housing and husbandry; breeding and production; refinement opportunities. A total of 98 survey responses were received from laboratories in 22 countries in Europe, North America, South America, Asia and Australia. There appears a clear and urgent need to identify the most humane methods of anaesthesia and euthanasia. Aversive responses to MS-222 were widely observed raising concerns about the use of this anaesthetic for D. rerio. The use of anaesthesia in fin clipping for genetic identification is widely practised and there appears to be an opportunity to further develop less invasive methods and refine this process. Optimization (and potentially standardization) of feeding is an area for further investigation. Given that diet and body condition can have such profound effects on results of experiments, differences in practice could have significant scientific implications. Further research into transition between dark and light phases in the laboratory appears to represent an opportunity to establish best practice. Plants and gravel were not considered practical by many laboratories. The true value and benefits need to be established and communicated. Overproduction is a concern both from ethical and financial viewpoints. There is an opportunity to further reduce wastage of D. rerio. There are clear concerns and opportunities for the scientific community to work together to further improve the welfare of these important laboratory models.

Roles for primary cilia in gonadotrophin-releasing hormone neurones in the mouse.

During embryonic development, gonadotrophin-releasing hormone (GnRH) neurones make an extraordinary migration out of the nose and into the brain where, in adulthood, they drive the pituitary regulation of gonadal function and fertility. Primary cilia are antennae-like, immotile organelles that project from the surface of nearly all cells, including GnRH neurones. Links between defects in primary cilia and a variety of human pathologies have been discovered that suggest a role for primary cilia in embryogenesis and reproductive function. The present study aimed to investigate whether GnRH neurone primary cilia are critical for their embryonic migration and the adult control of fertility. To achieve this, we used a Cre-loxP strategy to selectively disrupt primary cilia by deleting Kif3a, an intraflagellar transport protein family member essential for primary cilia assembly and function, specifically in GnRH neurones. Confocal analysis revealed that, in Kif3a(fl/fl) (WT-Kif3a) controls, all GnRH neurones possessed primary cilia, whereas, in GnRH-Cre(+/-) ;Kif3a(fl/fl) (GnRH-Kif3aKO) mice, 60% of GnRH neurones lacked any evidence of primary cilia and the remaining 40% possessed only stunted primary cilia (< 2 µm). Despite abolishing normal primary cilia assembly in GnRH neurones from embryogenesis, adult GnRH neurone distribution and reproductive function was remarkably normal. The total number of GnRH neurones was the same in GnRH-Kif3aKO and WT-Kif3a controls; however, a significant increase (25%) was identified in the number of GnRH neurones sampled through the midpoint of the rostral pre-optic area in GnRH-Kif3aKO mice (P < 0.05). The time to vaginal opening was not different in GnRH-Kif3aKO mice, although they displayed significantly advanced first oestrus (P < 0.05), and oestrous cycle length was increased (P < 0.05). However, females displayed normal basal levels of luteinising hormone, responded normally to oestrogen-induced negative- and positive-feedback, and displayed normal fecundity. Taken together, these data suggest that primary cilia and associated signal transduction pathways play a role in the topographical distribution and specific functions of GnRH neurones; however, they are not essential for fertility.

Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome.

Metabolic syndrome, a cluster of risk factors that increase the risk of cardiovascular morbidity and mortality, is common in patients with hypertension. Chronic renin-angiotensin-aldosterone system (RAAS) activation, shown by elevated plasma renin activity (PRA), is implicated in many of the features of metabolic syndrome. The direct renin inhibitor aliskiren may be of benefit in this patient group as aliskiren targets the RAAS at the rate-limiting step. In this double-blind study, 141 patients with hypertension (mean baseline BP 155/93 mm Hg) and metabolic syndrome (modified National Cholesterol Education Program ATP III criteria) were randomized to aliskiren 300 mg or irbesartan 300 mg once daily. Patients treated with aliskiren 300 mg had their mean sitting blood pressure (BP) lowered by 13.8/7.1 mm Hg after 12 weeks, significantly greater (P≤0.001) than the 5.8/2.8 mm Hg reduction observed in patients treated with irbesartan 300 mg. A significantly greater proportion of patients treated with aliskiren achieved BP control to <135/85 mm Hg (29.2 vs 16.7% with irbesartan; P=0.019). Aliskiren treatment led to a 60% decrease in PRA from baseline, whereas irbesartan increased PRA by 99% (both P<0.001). Aliskiren and irbesartan had similar effects on glucose and lipid profiles and on a panel of biomarkers of inflammation and cardiovascular risk. Both aliskiren and irbesartan were well tolerated. Collectively, these results suggest that aliskiren 300 mg may offer treatment benefits compared with irbesartan 300 mg for BP reduction in patients with hypertension and metabolic syndrome.

Ethics of primate use.

This article provides an overview of the ethical issues raised by the use of non-human primates (NHPs) in research involving scientific procedures which may cause pain, suffering, distress or lasting harm. It is not an exhaustive review of the literature and views on this subject, and it does not present any conclusions about the moral acceptability or otherwise of NHP research. Rather the aim has been to identify the ethical issues involved and to provide guidance on how these might be addressed, in particular by carefully examining the scientific rationale for NHP use, implementing fully the 3Rs principle of Russell and Burch (1959) and applying a robust "harm-benefit assessment" to research proposals involving NHPs.

Refinements in husbandry, care and common procedures for non-human primates: Ninth report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement.

Preface Whenever animals are used in research, minimizing pain and distress and promoting good welfare should be as important an objective as achieving the experimental results. This is important for humanitarian reasons, for good science, for economic reasons and in order to satisfy the broad legal principles in international legislation. It is possible to refine both husbandry and procedures to minimize suffering and improve welfare in a number of ways, and this can be greatly facilitated by ensuring that up-to-date information is readily available. The need to provide such information led the British Veterinary Association Animal Welfare Foundation (BVAAWF), the Fund for the Replacement of Animals in Medical Experiments (FRAME), the Royal Society for the Prevention of Cruelty to Animals (RSPCA) and the Universities Federation for Animal Welfare (UFAW) to establish a Joint Working Group on Refinement (JWGR) in the UK. The chair is Professor David Morton and the secretariat is provided by the RSPCA. This report is the ninth in the JWGR series. The RSPCA is opposed to the use of animals in experiments that cause pain, suffering, distress or lasting harm and together with FRAME has particular concerns about the continued use of non-human primates. The replacement of primate experiments is a primary goal for the RSPCA and FRAME. However, both organizations share with others in the Working Group, the common aim of replacing primate experiments wherever possible, reducing suffering and improving welfare while primate use continues. The reports of the refinement workshops are intended to help achieve these aims. This report produced by the British Veterinary Association Animal Welfare Foundation (BVAAWF)/Fund for the Replacement of Animals in Medical Experiments (FRAME)/Royal Society for the Prevention of Cruelty to Animals (RSPCA)/Universities Federation for Animal Welfare (UFAW) Joint Working Group on Refinement (JWGR) sets out practical guidance on refining the husbandry and care of non-human primates (hereinafter primates) and on minimizing the adverse effects of some common procedures. It provides a valuable resource to help understand the physical, social and behavioural characteristics and needs of individual primates, and is intended to develop and complement the existing literature and legislative guidelines. Topics covered include refinements in housing, husbandry and common procedures such as restraint, identification and sampling, with comprehensive advice on issues such as primate communication, assessing and facilitating primate wellbeing, establishing and maintaining social groups, environmental and nutritional enrichment and animal passports. The most commonly used species are the key focus of this resource, but its information and recommendations are generally applicable to other species, provided that relevant individual species characteristics are taken into account.

Charcot neuroarthropathy triggered by osteomyelitis and/or surgery.

INTRODUCTION: Charcot neuroarthropathy (CN) is a rare but devastating complication of diabetic neuropathy. Osteomyelitis is also a complication of the diabetic foot and it may be difficult to differentiate from CN. PATIENTS AND METHODS: A patient with Type 1 diabetes and peripheral neuropathy developed a foot ulcer complicated by osteomyelitis of the first proximal phalanx. He was successfully treated with antibiotics and surgical excision of the infected bone. Six months later, he developed a hot, swollen, red foot and X-ray showed destruction of the second and third metatarsal heads. At the second presentation, it was difficult to determine whether this was a recurrence of osteomyelitis or a new onset of CN. Thus, to obtain a definitive diagnosis, recourse was made to more sophisticated imaging techniques. RESULTS: 99mTc methylenediphosphonate (MDP) bone scans and magnetic resonance imaging proved inconclusive to differentiate between osteomyelitis and CN. Subsequently, an indium-labelled white cell scan confirmed the absence of osteomyelitis and the patient was successfully treated for CN. DISCUSSION: Infection and/or surgery may be predisposing factors in the development of diabetic CN but the combination of the two could accelerate the onset of the Charcot process in people with diabetes and neuropathy.

Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension.

BACKGROUND: Aliskiren is the first in a new class of orally effective renin inhibitors for the treatment of hypertension. METHODS: In 569 patients with mild-to-moderate hypertension, blood pressure (BP), plasma renin activity (PRA) and plasma renin concentration (PRC) were measured before and after 8 weeks of double-blind treatment with once-daily oral doses of aliskiren (150, 300 or 600 mg), irbesartan 150 mg or placebo. RESULTS: Aliskiren 150, 300 and 600 mg and irbesartan 150 mg significantly reduced mean cuff sitting systolic BP (SBP) from baseline (p < 0.001 vs. placebo). Aliskiren 150, 300 and 600 mg significantly reduced geometric mean PRA by 69%, 71% and 75% from baseline respectively (p < 0.05 vs. placebo). Irbesartan 150 mg significantly increased PRA by 109% (p < 0.05 vs. placebo). Aliskiren dose-dependently increased PRC from baseline by 157%, 246% and 497%, at 150, 300 and 600 mg respectively, compared with a 9% decrease with placebo (p < 0.05). PRC increased significantly more with aliskiren 300 and 600 mg compared with irbesartan 150 mg (105%; p < 0.05). Regression analysis showed no significant correlations between baseline PRA and changes in SBP in any of the treatment groups, but interestingly, the slopes of the regression lines between changes in SBP and log-transformed baseline PRA were +2.0 for placebo and -1.5, -1.8 and -2.3 for aliskiren 150, 300 and 600 mg respectively. The slope for irbesartan 150 mg (-1.4) was similar to that for aliskiren 150 mg. CONCLUSIONS: Aliskiren reduces SBP and PRA and increases PRC dose-dependently. In contrast, irbesartan reduces SBP but increases both PRC and PRA. As PRA is a measurement of angiotensin I-generating capacity, PRA can be used for measuring the ability of an antihypertensive agent to prevent the generation or action of Ang II, either directly (renin inhibitors, beta-blockers, central alpha(2)-agonists) or indirectly (AT(1)-receptor blockers, ACE inhibitors).

Nibbling within the nucleus: turnover of nuclear contents.

As the site of gene expression and regulation, the nucleus is the control center of the cell. It might be thought that degradation of nuclear contents is strictly 'off-limits,' given the importance of the genetic information contained within the nucleus, but it has recently been reported that partial degradation of the nucleus may occur in yeast. Here we summarize the evidence for the degradation and quality control of proteins found with the nucleus and its compartments, and of nucleic acids that may occur under certain specific conditions. Only under certain special conditions such as differentiation of the lens are the entire nuclear contents degraded.

Training of staff for the delivery of PET/CT services in the UK.

Evidence for the cost effectiveness of PET/CT imaging is now driving the widespread introduction of PET/CT services throughout the UK. The provision of PET/CT facilities will require a workforce of medical, scientific, technical and engineering staff who are adequately trained and fit for purpose. Suitably trained staff in this speciality are scarce. The development and accreditation of training courses and other educational resources for training programmes in all disciplines will therefore be required at a national and regional level. The implementation of PET/CT training can be achieved more cost-effectively by developing multi-professional learning resources whenever possible. It is intended that the recommendations would be implemented by close co-operation of both public and private healthcare providers together with educational establishments.

Social interaction with non-averse group-mates modifies a learned food aversion in single- and mixed-species groups of tamarins (Saguinus fuscicollis and S. labiatus).

For social species, being a member of a cohesive group and performing activities as a coordinated unit appear to provide a mechanism for the efficient transmission of information about food. Social learning about food palatability was investigated in two captive primates, Saguinus fuscicollis and S. labiatus, which form stable and cohesive mixed-species groups in the wild. We explored whether an induced food aversion toward a preferred food is modified during and after social interaction with non-averse conspecifics or congeners. Sets of intra- and interspecific pairs were presented with two foods, one of which was considered distasteful by one of the pairs (the other was palatable), and their behavior was compared pre-interaction, during interaction, and post-interaction. For the aversely-conditioned individuals of both species, the change in social context corresponded to a change in their preference for the food that they considered unpalatable, regardless of whether they had interacted with a conspecific or congeneric pair, and the change in food preference was maintained post-interaction. In a control condition, in which averse individuals did not have the opportunity to interact with non-averse animals, S. fuscicollis sampled the preferred food, but not as quickly as when given the opportunity to interact. We conclude that the social learning demonstrated here may allow individual tamarins to track environmental change, such as fruit ripening, more efficiently than asocial learning alone, because social learners can more quickly and safely focus on appropriate behavior by sharing up-to-date foraging information. Furthermore, since the behavior of congeners, as well as conspecifics, acts to influence food choice in a more adaptive direction, social learning about food palatability may be an advantage of mixed-species group formation to tamarins of both species.

Differential cell cycle progression patterns of infiltrating leukocytes and resident cells after balloon injury of the rat carotid artery.

The heterogeneous nature of the cell populations involved in vascular repair remains a major hurdle for the assessment of the cellular events that take place in injured arteries. The present experiments were designed to estimate the proportions and cell cycle progression of infiltrating leukocytes versus resident vascular cells after balloon injury of the rat common carotid artery. After tissue disaggregation, cell suspension samples from each artery were analyzed by flow cytometry. Cells were stained with anti-CD45 or anti-alpha-smooth muscle actin antibodies to identify leukocytes and smooth muscle cells, respectively. A day after injury, a 12-fold increase in CD45+ leukocytes was found. Double labeling with CD45 and CD-3, ED-1, or granulocyte markers revealed that most infiltrating cells were monocytes and granulocytes. Approximately 14% of infiltrating leukocytes were found to enter apoptosis at day 1, and 17% entered S phase at day 3. In contrast, the highest proliferation rate of resident alpha-smooth muscle actin-positive cells was observed at day 7 (19%). The present results demonstrate that infiltrating leukocytes and resident vascular smooth muscle cells have dissimilar cell cycle profiles. Furthermore, our study demonstrates the feasibility of using flow cytometry to quantitatively determine the cell types and their relative activation state in injured arteries.

Pulmonary (99m)Tc-DTPA aerosol clearance and survival in usual interstitial pneumonia (UIP).

BACKGROUND: Clearance of inhaled technetium 99m-labelled diethylenetriamine penta-acetic acid ((99m)Tc-DTPA) from the lungs is a potential indicator of disease progression in patients with idiopathic pulmonary fibrosis (IPF). METHODS: We prospectively analysed the usefulness of this technique for predicting survival in 106 non-smoking patients with usual interstitial pneumonia (UIP) pattern IPF diagnosed by high resolution CT (HRCT) scanning or histological examination (M/F 65/41, mean (SD) age 61 (11) years). DTPA clearance was analysed according to both mono-exponential and bi-exponential models. Half times for the fast (t(0.5)F) and slow (t(0.5)S) components of clearance, the percentage contribution of the fast component (fF), and half time for mono-exponential approximation to the early part of the clearance curve (t(0.5)) were calculated. RESULTS: The patients had substantially faster t(0.5) (mean 23.9 (9.6) minutes) than normal values (>45 minutes). Thirty seven patients (35%) died during follow up (median 15 months). Univariate Cox regression analysis identified significant predictors of survival as age, forced expiratory volume in 1 second (FEV(1)), forced vital capacity (FVC), total lung capacity (TLC), % predicted TLC, carbon monoxide transfer factor (TLCO), % predicted TLCO, arterial oxygen tension (PaO(2)), oxygen saturation, t(0.5)F, and HRCT fibrosis score. Multiple stepwise Cox regression analysis identified t(0.5)F (p=0.03, hazard ratio 0.747, 95% CI 0.578 to 0.964), % predicted TLC (p=0.02, hazard ratio 0.976, 95% CI 0.956 to 0.995), % predicted TLCO (p=0.003, hazard ratio 0.960, 95% CI 0.935 to 0.986), and age (p=0.003, hazard ratio 1.062, 95% CI 1.021 to 1.104) as independent predictors of survival. CONCLUSION: These data suggest that (99m)Tc-DTPA clearance t(0.5)F measurement may predict survival in patients with UIP pattern IPF.

Expression of protein tyrosine phosphatase-like molecule ICA512/IA-2 induces growth arrest in yeast cells and transfected mammalian cell lines.

The ICA512/IA-2 molecule, a protein with similarity to receptor-type protein tyrosine phosphatases, was discovered during studies to identify autoantigens in Type 1 diabetes. The biological function of ICA512/IA-2 is unknown. We describe striking effects of ICA512/IA-2 on viability and growth of both yeast cells and cultured mammalian cells. In transformed yeast Saccharomyces cerevisiae cells, expression of ICA512/IA-2 induced growth retardation as judged by measurements of optical density and counts of colony-forming units. In contrast, expression of the intracellular domain (amino acids 600-979) of ICA512/IA-2 in yeast or mammalian cells had no such effects. In investigations on apoptosis, expression of ICA512/IA-2 in yeast cells caused loss of plasma membrane asymmetry, but not release of cytochrome c from mitochondria which did occur in a control system after expression of the pro-apoptotic molecule Bax. Possible interactions between ICA512/IA-2 and components of the cytoskeleton were not supported by studies on staining of fixed yeast cells with phalloidin-Texas Red. With transfected mammalian cell lines COS-7 and NIH3T3, expression of ICA512/IA-2 likewise induced growth arrest, with some of the morphological features of apoptosis. Thus obligatory expression of ICA512/IA-2 in eukaryotic cells causes disruption of cellular activities, with growth arrest in yeast and nuclear pycnosis/fragmentation in mammalian cells. A possible explanation is that growth inhibition reflects a part of the presently unknown function of ICA512/IA-2.

Lesion-targeted injectable vectors for vascular restenosis.

Pathologic lesions caused by catheter-based revascularization procedures for occlusive artery disease include disruption of the endothelium, exposure of extracellular matrix (ECM) proteins, and proliferation of vascular smooth muscle cells, which lead to neointima formation and restenosis. We have developed matrix-collagen-targeted retroviral vectors that are able to accumulate at sites of vascular injury (Hall et al., Hum. Gene Ther. 1997;8:2183-2192; Hall et al., Hum. Gene Ther. 2000;11:983-993). The primary tissue-targeting motif, adapted from the physiological surveillance sequence found in von Willebrand factor, served to localize and concentrate the vector within vascular lesions. In the present study, we evaluated the efficiency of this vector-targeting system in rats with nonligated balloon-injured carotid arteries. Both intraarterial (by retrograde femoral artery catheterization) and intravenous (via femoral vein) injection of a matrix-targeted vector enhanced transduction of neointimal cells ( approximately 20%) at severely denuded areas when compared with the nontargeted vector (<1%). Further, intraarterial instillation of a matrix-targeted, but not a nontargeted, vector bearing an antisense cyclin G1 construct inhibited neointima lesion formation in the injured carotid arteries. Taken together, these data indicate that strategic targeting of retroviral vectors to vascular lesions would have therapeutic potential in the management of vascular restenosis and many other disorders of uncontrolled proliferation where endothelial disruption, ECM remodeling, and collagen deposition form the nexus for preferential vector localization and concentration in vivo.

Long term inhibition of neointima formation in balloon-injured rat arteries by intraluminal instillation of a matrix-targeted retroviral vector bearing a cytocidal mutant cyclin G1 construct.

Restenosis from neointimal proliferation is a frequent complication of intracoronary stenting and catheter-based revascularization procedures. Currently, there is no known therapeutic strategy that has been sufficiently effective to warrant its widespread use. In the present study, the anti-proliferative properties of a matrix (collagen)-targeted retroviral vector bearing a mutant cyclin G1 (DNT 41-249) construct was evaluated in vitro and in vivo. In controlled one-month efficacy studies, the intraluminal instillation of the mutant cyclin G1 vector significantly inhibited neointima lesion formation in balloon-injured rat arteries without neointimal growth, associated necrosis or intense inflammatory reaction. Taken together, these data extend the potential utility of the matrix-targeted mutant cyclin G1 retroviral vector for management of vascular restenosis.

CGP 43371 paradoxically inhibits development of rabbit atherosclerotic lesions while inducing extra-arterial foam cell formation.

Ansamycins are hypolipidemic compounds which, when administered to various animal species, dramatically lower high density lipoprotein (HDL) cholesterol levels, in addition to reducing the levels of other lipoprotein classes. The current study tested one of these ansamycins (CGP 43371) for its hypolipidemic and anti-atherosclerotic activity in cholesterol-fed rabbits. Rabbits were fed a 0.25% cholesterol-enriched diet with or without admixed CGP 43371, equivalent to 30 mg/kg per day for 16 weeks. Compared with control rabbits, CGP 43371 treatment lowered total cholesterol levels (46%, P<0.05) and lipoprotein cholesterol levels (HDL, 58%; VLDL, 49% [both P<0.05]; LDL, 28% [not significant]). Despite the dramatic lowering of HDL cholesterol levels, aortic atherosclerosis, assessed by grossly visible sudanophilia, was significantly inhibited versus controls (total aorta=38%; aortic arch=32%; thoracic aorta=60%). Of particular note in CGP 43371-treated rabbits was a striking splenomegaly, which correlated with the presence of massive accumulations of macrophage foam cells in the splenic red pulp. We speculate that CGP 43371 inhibits the development of atheroselerotic lesions in rabbits by both a hypolipidemic mechanism, and by a mechanism(s) in which macrophage foam cells accumulate in the spleen.

Cohort differences in genetic and environmental influences on retrospective reports of conduct disorder among adult male twins.

BACKGROUND: Rates of child and adolescent conduct disorder (CD) have increased steadily over the past several decades. What is not known is whether the underlying genetic and environmental influences on individual differences in CD have also changed. METHODS: Retrospective reports of antisocial behaviour prior to age 18 were obtained from a population-based sample of 2769 adult males from male-male twin pairs born between 1940 and 1974. Using a summary score of number of CD symptoms, structural equation modelling was used to investigate whether mean level and variation in CD increased with more recent cohorts, and whether any increase in variance could be explained by familial or non-familial factors. RESULTS: Both mean level CD symptoms and variation were increased in more recent cohorts. Model fitting indicated that the primary increase in variance was due to familial factors, most notably, an increase in the shared environmental influences on CD, from 0.01 (95 % CI = 0.00; 0.27) to 0.30 (95 % Cl = 0.01; 0-44). Heritability estimates remained largely unchanged, although an increase in genetic factors could not be ruled out. CONCLUSIONS: Secular changes in sociodemographic factors responsible for increasing rates of CD may also account for the greater magnitude of shared environmental influences on variation in CD found among more recent cohorts.