Pro-survival function of MEF2 in cardiomyocytes is enhanced by ß-blockers.

ß1-Adrenergic receptor (ß1-AR) stimulation increases apoptosis in cardiomyocytes through activation of cAMP/protein kinase A (PKA) signaling. The myocyte enhancer factor 2 (MEF2) proteins function as important regulators of myocardial gene expression. Previously, we reported that PKA signaling directly represses MEF2 activity. We determined whether (a) MEF2 has a pro-survival function in cardiomyocytes, and (b) whether ß-adrenergic/PKA signaling modulates MEF2 function in cardiomyocytes. Initially, we observed that siRNA-mediated gene silencing of MEF2 induces cardiomyocyte apoptosis as indicated by flow cytometry. ß1-AR activation by isoproterenol represses MEF2 activity and promotes apoptosis in cultured neonatal cardiomyocytes. Importantly, ß1-AR mediated apoptosis was abrogated in cardiomyocytes expressing a PKA-resistant form of MEF2D (S121/190A). We also observed that a ß1-blocker, Atenolol, antagonizes isoproterenol-induced apoptosis while concomitantly enhancing MEF2 transcriptional activity. ß-AR stimulation modulated MEF2 cellular localization in cardiomyocytes and this effect was reversed by ß-blocker treatment. Furthermore, Kruppel-like factor 6, a MEF2 target gene in the heart, functions as a downstream pro-survival factor in cardiomyocytes. Collectively, these data indicate that (a) MEF2 has an important pro-survival role in cardiomyocytes, and (b) ß-adrenergic signaling antagonizes the pro-survival function of MEF2 in cardiomyocytes and ß-blockers promote it. These observations have important clinical implications that may contribute to novel strategies for preventing cardiomyocyte apoptosis associated with heart pathology.

ICP10PK inhibits calpain-dependent release of apoptosis-inducing factor and programmed cell death in response to the toxin MPP+.

Apoptosis is a widely accepted component of the pathogenesis of Parkinson's disease (PD), a debilitating neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. However, additional death programs were implicated, and current understanding of the cycle of intracellular events that leads to the demise of these neuron Jis limited. Gene therapy strategies were proposed to inhibit apoptosis, but they have met with relatively limited success. Here we report that the antiapoptotic herpes simplex virus type 2 gene ICP10PK protects neuronally differentiated PC12 cells from death caused by 1-methyl-4-phenylpyridinium (in vitro PD model) through inhibition of calpain I activation and the resulting inhibition of Bax translocation to the mitochondria, apoptosis-inducing factor release and caspase-3 activation. Neuroprotection is through ICP10PK-mediated activation of the PI3-K/Akt survival pathway and upregulation/stabilization of the antiapoptotic protein Bcl-2 and the cytoprotective chaperone heat-shock protein 70.

Performance and use of a ribonucleotide reductase herpes simplex virus type-specific serological assay.

In response to the increasingly evident need for herpes simplex virus (HSV) serotype-specific serologic assays that rely on proteins other than glycoprotein-G (gG), we developed a rapid serologic assay that is based on type-specific epitopes within the large subunit of HSV ribonucleotide reductase (R1). The assay (Au-2 enzyme-linked immunosorbent assay [ELISA]) uses an HSV type 2 (HSV-2) R1 peptide antigen. It provides a reliable method for detecting serotype-specific antibody to a protein other than gG-2. The Au-2 ELISA has high sensitivity and specificity as determined by direct comparison to Western blotting, a widely accepted "gold standard," and to ELISA with an HSV-1 R1 peptide (Au-1). The use of the Au-2 ELISA in conjunction with the gG-2-based assays will improve the sensitivity and specificity of serologic diagnosis and patient management.

Adherence issues in children and adolescents receiving highly active antiretroviral therapy.

The introduction of highly active antiretroviral therapies (HAART) for the treatment of paediatric HIV infection poses additional adherence challenges for children and families living with HIV A preliminary survey of 18 parents of children receiving HAART in Australia showed that although parents report high level of child adherence to HAART, specific features of the medication regimen, such as taste and number of medications made administration of HAART extremely difficult.Moreover, interaction between the treatment regimen and the day-to-day lives of families increases the adherence challenge. While some agreement exists in relation to the concerns families have about negative aspects of HAART; the diversity of issues suggests the need for ongoing and individualized support and information to families.

Child and parent satisfaction with the use of spacer devices in acute asthma.

OBJECTIVE: To evaluate child and parent satisfaction with the use of spacers in acute asthma. METHODS: All parents of children presenting to the emergency department of Sydney Children's Hospital over a 3-month period with mild to moderately severe acute asthma who were treated with bronchodilators by spacer device were asked to complete an anonymous questionnaire. Children aged 8 years and older completed a separate questionnaire independently. RESULTS: One hundred and eleven of 158 parents (70%) responded. The majority (84%) found it 'easy' or 'very easy' to use the spacer and 85% reported that they intended to use the spacer at home. Of those parents who had previously used a nebulizer (n = 73), 84% said that the spacer was easier to use, 77% said that the spacer was better tolerated by their child and 84% said that overall they preferred the spacer. Seventeen of 31 children aged 8-14 years treated with a spacer (55%) responded to the satisfaction survey. All respondents found it 'easy' or 'OK' to use the spacer and the majority (82%) 'liked it' or thought 'it was OK'. The majority of children (82%) said that they preferred using spacers because it was quicker (29%) or easier to use (53%). CONCLUSION: The use of spacer devices in mild to moderately severe acute asthma is highly acceptable for children and parents; the majority prefer this mode of drug delivery to nebulization.

Evaluating the effectiveness of evidence-based guidelines for the use of spacer devices in children with acute asthma.

OBJECTIVE: To change standard practice from using nebulisers to metered dose inhalers and holding chambers (spacers) in children presenting with mild to moderate acute asthma. DESIGN: A before-after comparison of children with acute asthma presenting to the emergency department (ED) between August and October 1999 with those presenting between June and August 1997. SETTING: A tertiary care metropolitan children's hospital. INTERVENTIONS: Evidence-based clinical practice guidelines for using spacers were developed by a local multidisciplinary consensus process. A multifaceted guideline implementation program was used in 1999. MAIN OUTCOME MEASURES: Physician prescribing practices (spacer use); clinical outcomes (need for hospitalisation, admission to intensive care unit, and length of stay [LOS]). RESULTS: 75 of 247 children (30%; 95% CI, 25%-36%) required hospital admission in 1999. This was similar to the 1997 study period, when 95 of 326 (29%; 95% CI, 24%-34%) children were admitted. Of those with mild to moderate asthma, 160 (68%) received bronchodilators in the ED; 151 (94%) were initially treated with a spacer device in 1999. In 1997, no children were initially treated with spacers in the ED. The median (range) LOS in hospital for children with asthma of all severities was 1.7 (0.5-19.8) days in 1999 and 1.7 (0.2-7.6) days in 1997 (P=0.85). CONCLUSIONS: We successfully changed standard practice from using nebulisers to spacers for bronchodilator delivery in children with mild to moderate acute asthma, with no difference in the need for or duration of hospitalisation.

A quality assurance review of outpatient care of children with life-threatening asthma exacerbations.

OBJECTIVES: A hospital admission for asthma represents an opportunity to address and improve asthma control. The aims of this study were to compare the ambulatory care of children admitted to the intensive care unit (ICU) following a life-threatening asthma exacerbation with published guidelines of asthma management and to identify areas that could be targeted for change. METHODS: A retrospective review of case notes of children admitted to the ICU with asthma over a 6-month period. Variables recorded were: demographic; asthma history (including prior pattern of asthma, hospital admissions, interval treatment and managing doctor); admission details (consultation of respiratory team and asthma educator); and discharge management. RESULTS: There were 40 admissions of 38 children (24 males) with mean age 5.7 years (range 1.1-14 years). The majority (58%) had previous admissions for asthma (55 admissions in 22 children), with 23% of these to ICU. Sixty three per cent of those with previous admissions had persistent asthma, but only 29% were on inhaled corticosteroid (ICS). Most (60%) were managed by their local medical officer (LMO). Use of ICS was more likely if managed by a paediatrician. A respiratory subspecialist was consulted in 42% and the asthma educator in 70% of ICU admissions. Discharge medication included ICS in 74%, with no interval treatment in 18% of admissions. Follow up was by a respiratory subspecialist in 25% of cases. CONCLUSION: Asthma management before and after admission with life-threatening asthma did not conform to available guidelines. Persistent asthma was under-treated. Paediatricians were more likely to use interval treatment than LMO. We identified areas in which quality of care and outcome could be improved in this vulnerable group of asthmatics.

Service providers' perceptions of substance use self-help groups.

Using a two-stage Delphi procedure, an investigation was carried out into health and welfare professionals' knowledge of and relationship with self-help groups (SHGs). Professionals indicated that they perceived SHGs to be generally helpful for persons with substance use problems. Provision of social support was the most commonly perceived helpful aspect of SHGs, and unsuitability for some clients was the most commonly perceived unhelpful-aspect. Persons motivated to address their problems were those perceived to be most likely to find a SHG useful, with those not so motivated, or who deny their problem, being perceived to be least likely to find a SHG useful. Drug and alcohol user treatment specialists reported greater perceived failure of SHGs to address underlying psychopathology and greater perceived benefit for clients lacking social support. This may be of particular relevance for future attempts to investigate the process of recovery in SHGs.

Long-term glucose homeostasis in patients on home parenteral nutrition.

Glycated haemoglobin (Hb A1c) was used as a marker of long-term hyperglycaemia in patients receiving high glucose loads for home parenteral nutrition (HPN). Thirty-six patients received a median weekly glucose delivery of 2000 g (800-4200) at a median infusion rate of 11.8 mg/kg/min (5.0-19.2). There was no correlation between Hb A1c (median- 3.1%, range 2.0-6.3%) and glucose infusion rate or weekly glucose load. It is concluded that significant prolonged hyperglycaemia does not appear to be a problem in patients on HPN managed by this unit.

Prolonged peripheral parenteral nutrition with an ultrafine cannula and low-osmolality feed.

Peripheral parenteral nutrition is an attractive alternative to centrally delivered parenteral nutrition because it obviates the need for central venous cannulation and its attendant complications. Some 45 consecutive patients were fed peripherally using a 22-G polyurethane catheter and a fat-based, low-osmolality feed. Of these patients, 36 were fed for a median of 8.5 (range 3-31) days without peripheral vein thrombophlebitis (PVT). Seven patients developed PVT after a median of 6 (range 5-7) days. The cumulative daily risk of PVT was 0.016 episodes per day. These results suggest that prolonged (more than 7 days) problem-free peripheral parenteral nutrition is possible.

Essential fatty acid status in patients on long-term home parenteral nutrition.

BACKGROUND: Patients on total parenteral nutrition are known to be at risk of the development of essential fatty acid deficiency, presenting as a syndrome with scaly skin lesions and characterized by low plasma and erythrocyte linoleic acid concentrations. The essential fatty acid status of patients on long-term home parenteral nutrition who do have access to oral feeds has not been studied. METHODS: With the use of an isocratic high-performance liquid chromatography method, fatty acids were measured in the erythrocytes and plasma of 25 nonfasting patients on long-term home parenteral nutrition and the findings compared with those of 46 hospital outpatients not on nutrition support and five laboratory staff. RESULTS: Statistically significant differences in the two groups were limited to the erythrocytes. Linoleic acid was significantly lower (25.2 vs 40.7 mumol/10(6) red blood cells, p < .0001) and showed a significant correlation with triceps skinfold thickness (r = .52, p = .013). Palmitoleic and oleic acids were higher in patients than controls (10.8 vs 8.4 mumol/10(6) red blood cells, p = .009; 61.2 vs 51.7 mumol/10(6) red blood cells, p = .003). CONCLUSIONS: Despite IV linoleic acid administration, patients on long-term home parenteral nutrition have low erythrocyte stores of this essential fatty acid. This appears to be related to their low body fat stores. We suggest that they may be using much of the infused linoleic acid as an energy source and therefore are at risk of subclinical essential fatty acid deficiency.

Reported management of patients with sore throat in Australian general practice.

BACKGROUND: Sore throat is one of the commonest presenting symptoms in general practice in Australia, and results in the prescription of an antibiotic in 50-90% of cases, despite the finding of bacterial throat infection in around 30% of cases or fewer. AIM: This study set out to examine whether inaccurate knowledge about the pathophysiological features and management of sore throat helps to explain the high level of inappropriate antibiotic prescribing for sore throat by general practitioners. METHOD: A questionnaire with four case vignettes of sore throat presentations was sent to 400 randomly selected general practitioners, practising in Victoria, Australia. Of 367 eligible respondents, 284 responded (77%). RESULTS: Of the respondents 97% reported that they would prescribe an antibiotic for the case of tonsillitis, 70% for the case of possible glandular fever, 29% for the child with probable viral sore throat and 9% for the adult with probable viral infection. There were no differences in prescribing rates between general practitioners of different sex, practice location, practice type or qualification. Overall, 25% of the antibiotics which formed the respondents' first choice were inappropriate broad-spectrum antibiotics. CONCLUSION: General practitioners are generally accurate in their assessment of the features of sore throats, but less accurate in their knowledge of appropriate antibiotics.

The incidence and management of catheter occlusion in patients on home parenteral nutrition.

For patients on Home parenteral nutrition (HPN), catheter-related problems are the major source of morbidity and occlusion of the central venous catheter is one of these. We have managed 17 episodes of catheter occlusion in 10 patients on HPN. The median time from insertion to occlusive episode was 23 months. 10 catheters (59%) were saved by the used of thrombolytics (one by thrombolytics and ethanol) and 7 were replaced. The recent incidence of catheter occlusion in this cohort was one episode per 150 patient-months of HPN (0.08 episodes per year). Patients with Crohns disease appear to be at greater risk of developing catheter occlusion (p = <0.05).

Pseudomonas infection of the catheter exit site successfully managed with topical acetic acid.

A case of recurrent catheter exit site infection with Pseudomonas aeruginosa is presented in a patient receiving home parenteral nutrition. The past episodes were managed by elective catheter replacement following extrusion of the catheter cuff. We describe the successful use of acetic acid to the exit site which resulted in the eradication of the organism and complete resolution of all signs.