Evaluation of the carcinogenic potential of clofibrate in the FVB/Tg.AC mouse after oral administration--part I

This study was conducted as part of the International Life Sciences Institute (ILSI) program to evaluate the carcinogenic potential of clofibrate, a nongenotoxic, peroxisome proliferator-activated receptor (PPAR) alpha agonist following oral administration to Tg.AC (transgenic) and wild-type FVB (nontransgenic) mice for a minimum for 6 months. Clofibrate was well tolerated at doses up to 500 (males) and 650 (females) mg/kg/day. Oral administration of clofibrate to Tg.AC or FVB (wild-type) male and female mice for 6 months did not result in the increased formation of neoplastic lesions. Epithelial hyperplasia in the urinary bladder (Tg.AC and FVB) and prostate gland (Tg.AC only), and interstitial-cell hyperplasia in the testes (Tg.AC) were noted at 500 mg/kg/day. Non-neoplastic nonproliferative findings included hepatic hypertrophy and hematopoietic changes (myeloid hyperplasia, myelodysplasia, lymphoid depletion, and erythropoiesis) in Tg.AC and FVB mice of both sexes; reproductive (cystic degeneration and dilatation, hypospermia, spermatocele, dilated inspissated protein) and urogenital (tubular-cell hypertrophy, degenerative/regenerative nephropathy, necrosis/fibrosis) changes in Tg.AC and FVB male mice; congestion in the lung in male Tg.AC mice; gall bladder dilatation in female Tg.AC mice; and adrenal (intracellular lipofuscinosis and atrophy) and heart (eosinophillic myofibers) findings in Tg.AC mice of both sexes and in female FVB mice. The results of this study indicate that the clofibrate is not carcinogenic when administered to Tg.AC mice by oral gavage for 6 months at doses up to 500 (males) and 650 (females) mg/kg/day, which did produce liver hypertrophy.     

Simon Campbell on the ups and downs of drug discovery and development. Interview by Jayne Carey and Samantha Barton

Simon Campbell discusses his role in the development of sildenafil and doxazosin, as well as his current role as President of the RSC. Campbell goes on to give his opinions on how technological advances are influencing the changing roles of synthetic and medicinal chemists.     

A noninvasive isotopic approach to estimate the bone lead contribution to blood in children: implications for assessing the efficacy of lead abatement

Lead hazard control measures to reduce children's exposure to household lead sources often result in only limited reductions in blood lead levels. This may be due to incomplete remediation of lead sources and/or to the remobilization of lead stores from bone, which may act as an endogenous lead source that buffers reductions in blood lead levels. Here we present a noninvasive isotopic approach to estimate the magnitude of the bone lead contribution to blood in children following household lead remediation. In this approach, lead isotopic ratios of a child's blood and 5-day fecal samples are determined before and after a household intervention aimed at reducing the child's lead intake. The bone lead contribution to blood is estimated from a system of mass balance equations of lead concentrations and isotopic compositions in blood at the different times of sample collection. The utility of this method is illustrated with three cases of children with blood lead levels in the range of 18-29 microg/dL. In all three cases, the release of lead from bone supported a substantial fraction of the measured blood lead level postintervention, up to 96% in one case. In general, the lead isotopic compositions of feces matched or were within the range of the lead isotopic compositions of the household dusts with lead loadings exceeding U.S. Environmental Protection Agency action levels. This isotopic agreement underscores the utility of lead isotopic measurements of feces to identify household sources of lead exposure. Results from this limited number of cases support the hypothesis that the release of bone lead into blood may substantially buffer the decrease in blood lead levels expected from the reduction in lead intake.     

Risk Factors for Intimate Partner Violence and Associated Injury Among Urban Women

The objective of this study was to identify risk factors for abuse and IPV related injury among an urban population. This study reports an additional analysis of a case-control study conducted from 1994 to 2000 in 11 USA metropolitan cities where of 4746 women, 3637 (76.6%) agreed to participate. Control group women (N = 845) were identified through random digit dialing. Significant risk factors for abuse included women’s young age (adjusted odds ratio (AOR) 2.05 p = .011), being in fair or poor mental health (AOR 2.65 p < .001), and former partner (AOR 3.33 p < .001). Risk factors for partners perpetrating IPV included not being a high school graduate (AOR 2.06 p = .014), being in fair or poor mental health (AOR 6.61 p < .001), having a problem with drug (AOR 1.94 p = .020) or alcohol use (AOR 2.77 p = .001), or pet abuse (AOR 7.59 p = .011). College completion was observed to be protective (AOR 0.60, p < .001). Significant risk factors for injury included partner’s fair or poor mental health (AOR 2.13, p = .008), suicidality (AOR 2.11, p = .020), controlling behavior (AOR 4.31, p < .001), prior domestic violence arrest (AOR 2.66, p = .004), and relationship with victim of more than 1 year (AOR 2.30, p = .026). Through integration of partner related risk factors into routine and/or targeted screening protocols, we may identify more abused women and those at greater risk of abuse and injury.     

Free fatty acids are associated with obesity, insulin resistance, and atherosclerosis in renal transplant recipients

BACKGROUND: Insulin resistance (IR) may be implicated in the pathogenesis of atherosclerosis in renal transplant recipients (RTRs) and be contributed to, in part, by free fatty acids (FFAs), produced in excess in centrally obese individuals. The aim of this study was to determine the prevalence of IR and the relationships between FFAs, central obesity, and atherosclerosis in a cohort of prevalent RTRs. METHODS: Observational data were collected on 85 RTRs (mean age 54 years; 49% male, 87% Caucasian). Fasting serum was analyzed for FFAs, glucose, and insulin; IR was calculated using the homeostasis model assessment (HOMA-IR) score. Vascular structure was assessed by carotid intima-media thickness (IMT) measurement. Linear regression analyses were performed to determine the factors associated with IR and atherosclerosis. RESULTS: IR occurred in 75% of RTRs, and FFA levels were independently associated with its occurrence (beta: -0.55, 95% CI: -1.02 to -0.07, P = 0.02). Other variables independently associated with IR were male sex, body mass index, central obesity, diabetes, systolic blood pressure and corticosteroid use. There was a significant correlation between FFA levels and IMT (r = 0.3, P=0.01). On multivariate analysis, IMT correlated with elevated FFA (beta: 0.07, 95% CI: 0.02-0.12, P = 0.007), diabetes mellitus (P = 0.05), older age (P < 0.002), and a body mass index >25 kg/m (P = 0.002). CONCLUSIONS: FFAs are associated with the development of IR and may be involved in the pathogenesis of atherosclerosis in RTRs. Additional studies are required to explore these associations further before considering whether an interventional trial aimed at lowering FFA would be a worthwhile undertaking.     

Repair of injuries to the thoracic aorta and great vessels: Auckland, New Zealand 1995-2004

BACKGROUND: Traumatic injury to the aorta and great vessels is a surgical emergency with survivors who reach hospital typically having suffered multiple injuries. There are several diagnostic and treatment options available, with new modalities emerging to challenge the gold standards. A review of recent trends in management of these injuries in Auckland, New Zealand was carried out and patient outcomes assessed. METHODS: The charts of patients admitted to Auckland and Green Lane Hospital's cardiothoracic intensive care unit, with a diagnosis of injury to the thoracic aorta or great vessels since 1995 were retrospectively reviewed. Imaging techniques, injury types and treatment methods were analysed along with survival and neurological morbidity. RESULTS: In the study period our unit operated on 29 cases of traumatic rupture of the thoracic aorta or great vessels. Digital subtraction angiography and more recently, multidetector computed tomography scanning have been used to diagnose the injury. Twenty-seven injuries were to the aorta and two to the innominate artery. The 30-day survival rate of those reaching the operating theatre was 90%. There was one case of postoperative hemiparesis and five cases of recurrent laryngeal nerve injury, but none of spinal cord ischaemic injury. Endoluminal stent grafting was carried out for one patient, without complication. CONCLUSIONS: Good survival rates exist for those who reach surgery for traumatic rupture of the aorta or great vessels. Multidetector computed tomography scanning is an alternative to digital subtraction angiography, potentially reducing treatment delay. In addition endoluminal grafting as opposed to open repair has been reported as a safe technique. The injury remains a surgical emergency requiring urgent diagnosis and transfer to an equipped cardiothoracic unit for definitive treatment.     

Risk factors and prevalence of perioperative cognitive dysfunction in abdominal aneurysm patients

BACKGROUND: Perioperative delirium is common in high-risk surgery and is associated with age, education, preoperative cognitive functioning, pre-existing medical conditions, and postoperative complications. We investigated these factors as well as lifestyle and demographic variables by using cognitive measures that were more sensitive than those used in previous studies. METHODS: Extensive medical and demographic data were collected on 102 patients between 41 and 88 years of age to identify comorbidities and lifestyle considerations preoperatively. Elective abdominal aortic aneurysm surgery was performed under combined general/epidural anesthesia with postoperative epidural analgesia. A battery of sensitive, cognitive measures was administered preoperatively, at the time of discharge from hospital, and 3 months postoperatively. Symptoms of delirium were assessed during the first 6 postoperative days using Diagnostic and Statistical Manual of Mental Disorders-4th Edition criteria. Intraoperative and postoperative data, including medications, vital signs, conduct of the surgery and anesthesia, complications, and details of pain control, were collected. RESULTS: Delirium occurred in 33% of the patients during the first 6 days after surgery. Longer duration of delirium was related to lower education, preoperative depression, and greater preoperative psychoactive medication use. Characteristics of the surgery and hospital stay were unrelated to the development of delirium. Patients who were diagnosed with delirium had lower cognitive scores during each of the three assessment periods, even when controlling for age and education. Logistic regression analysis indicated that the most powerful preoperative predictors of delirium were number of pack years smoked (P = .001), mental status scores (P = .003), and number of psychoactive medications (P = .005). CONCLUSION: A significant proportion of patients undergoing elective abdominal aortic aneurysm repair are susceptible to the development of delirium and are at risk for cognitive dysfunction after surgery. Our findings have implications for promoting long-term lifestyle changes, including smoking cessation and improved management of mental health as risk-reduction strategies.     

Otoplasty

Multiple techniques have been advocated over the years for the appropriate and natural-appearing correction of the prominent ear. There is no single technique that can re-create the complex three-dimensional nature of the otherwise normal human ear. We have to evaluate each individual ear and patient and correct the abnormalities with a technique that each surgeon feels comfortable with and that can repeatedly provide gratifying results. Ultimately, the simplest technique that can obtain the maximum effect should be employed. A concentration on the male patient and specific concerns with these patients are discussed. Multiple techniques are presented to adequately treat a variety of anatomic variations. Surgical complications and their treatment are also discussed.