Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.     

The curvilinear relationship of early-life adversity and successful aging: the mediating role of mental health

Objectives: The steeling effect suggests that early-life adversity can have a beneficial impact later in life. However, little is known about its underlying mechanisms and long-term outcomes . The study aimed to examine the role of early-life adversity (ELA) on successful aging, and whether this relationship can be explained by mental and physical health.

Method: Socio-demographics, early-life adversity (ELA), individual quality of life (iQoL), and mental and physical health of 270 individuals (M_age = 66.82 years, 71.5% female) were assessed. Polynomial regressions and mediation analyses were conducted.

Results: Significant inverse U-shaped associations were found between ELA and iQoL (β = ?.59, p = .005) and between ELA and mental health (β = ?.64, p = .002), but not between ELA and physical health. Furthermore, mental health significantly mediated the relationship between ELA and iQoL (b = ?.84, BCa CI [?1.66, ?.27]).

Conclusion: Highest level of individual quality of life (i.e. successful aging) was related to a moderate amount of ELA. Additionally, mental health significantly mediated this relationship. These findings suggest that some amount of ELA could be beneficial for successful aging. Resource-focused interventions are needed to improve health and promote successful aging for an underdetected, at-risk subgroup with low early-life adversity.     

“Harry Wynne” Child & Youth Care Practices and Values: A Reflection on a Study of Heroin Misusers in Ireland

This discussion paper sets out to explore ‘doing’ research with a hard-to-reach population from a relational child and youth care perspective. It sets out some of the delimitations in undertaking such research and discusses some of our findings in realtion to the individual and the family contexts.     

Report of a National Conference on Donation after Cardiac Death

A national conference on organ donation after cardiac death (DCD) was convened to expand the practice of DCD in the continuum of quality end-of-life care. This national conference affirmed the ethical propriety of DCD as not violating the dead donor rule. Further, by new developments not previously reported, the conference resolved controversy regarding the period of circulatory cessation that determines death and allows administration of pre-recovery pharmacologic agents, it established conditions of DCD eligibility, it presented current data regarding the successful transplantation of organs from DCD, it proposed a new framework of data reporting regarding ischemic events, it made specific recommendations to agencies and organizations to remove barriers to DCD, it brought guidance regarding organ allocation and the process of informed consent and it set an action plan to address media issues. When a consensual decision is made to withdraw life support by the attending physician and patient or by the attending physician and a family member or surrogate (particularly in an intensive care unit), a routine opportunity for DCD should be available to honor the deceased donor's wishes in every donor service area (DSA) of the United States.     

Concomitant mitral valve surgery with aortic valve replacement: a 21-year experience with a single mechanical prosthesis

Background  

Long-term survival for combined aortic and mitral valve replacement appears to be determined by the mitral valve prosthesis from our previous studies. This 21-year retrospective study assess long-term outcome and durability of aortic valve replacement (AVR) with either concomitant mitral valve replacement (MVR) or mitral valve repair (MVrep). We consider only a single mechanical prosthesis.     

Puncture wound related pseudomonas infections of the foot in children

Eleven children with Pseudomonas aeruginosa infection complicating foot puncture wounds were reviewed. Delay in presentation (mean 2 days) and diagnosis (mean 9 days) due to a paucity of clinical signs of deep infection was characteristic of this condition. Septic arthritis (5 patients) and osteomyelitis (3 patients) were frequent complications. Treatment involved multiple surgical debridements and prolonged intravenous antibiotic therapy. The clinical outcome was good although long-term radiographic changes were common.     

The effect of gastroesophageal reflux on the pediatric airway.

The child with airway signs and symptoms that may be associated with GER presents diagnostic challenges. A high index of suspicion may be needed to make the diagnosis of GER, because no one test gives consistently definitive results. Specialists from multiple disciplines, including otolaryngology, gastroenterology, pulmonology, pediatrics, critical care, anesthesiology, and pediatric surgery may ultimately need to work together to arrive at the correct diagnosis and implement appropriate therapy.     

Hormone receptors in vestibular schwannomas

Summary The possibility that steroid hormones play a role in vestibular schwannoma proliferation has been suggested by a number of investigators. There is conflicting information about the presence of steroid hormone receptors in these tumors. The aim of this study was to examine the expression of androgen, progesterone, glucocorticoid and estrogen receptor messenger ribonucleic acid levels (mRNA) in twenty-one vestibular schwannomas by either Northern blot analysis or the polymerase chain reaction (PCR).Glucocorticoid receptor mRNA was expressed in all twentyone tumors examined. Only two male specimens were positive for androgen receptor mRNA expression by PCR-Southern blot analysis. Thirty-three percent of the schwannomas (7/21) showed a strong band for progesterone receptor mRNA by PCR-Southern blot analysis; there were an equal number of males and females in this group. Estrogen receptor mRNA levels were undetectable in all tumors examined by PCR-Southern blot analysis. These studies suggest that the pattern of steroid receptor expression is different in schwannomas than in meningiomas. Individual vestibular schwannomas need to be examined for their steroid receptor mRNA expression mRNA expression to know whether they will be responsive.     

Choreic syndrome and coeliac disease: a hitherto unrecognised association.

Coeliac disease has been associated with a variety of neurological conditions, most frequently cerebellar ataxia and peripheral neuropathy. To date, chorea has not been associated with coeliac disease. We present the case histories of 4 individuals with coeliac disease and chorea (4 women, average age of onset of chorea 61 years). Unexpectedly, most of these patients showed a notable improvement in their motor symptoms after the introduction of a gluten-free diet.