Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spray-dried and electron-beam sterilised vaccines in non-human primates

Currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. To overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza A vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. We evaluated the efficacy of novel antigen stabilizing and protecting solutions (SPS) to protect influenza A(H1N1)pdm09 split virus antigen under experimental conditions in vitro and in vivo.     

Evaluating a cognitive analytic therapy service; practice‐based outcomes and comparisons with person‐centred and cognitive‐behavioural therapies

Objectives. Evaluations of the clinical effectiveness of cognitive analytic therapy (CAT) are scarce and therefore represent an urgent service and research need. This paper sought to evaluate a CAT service by profiling CAT clients, examining the outcomes achieved by the CAT service and also comparing such outcomes with those achieved by other services, namely the person‐centred service and the cognitive‐behavioural service. Design. Patients in routine practice were matched according to the amount of therapy time received (either brief or medium‐term contracts) and the degree of initial presenting psychological distress. Methods. Patients completed a variety of validated scales of psychological functioning (Beck Depression Inventory‐II (BDI‐II), Brief Symptom Inventory (BSI), and Inventory of Interpersonal Problems (IIP‐32)) at assessment and termination of psychological intervention. Results. The results indicate broad similarities between the outcomes achieved by the services, with rates of clinically significant improvement comparable, in the main, across the three services. Conclusions. The results are discussed in terms of (a) the service delivery implications and (b) future indicated pragmatic research and evaluation efforts.     

A Review of the Clinical Presentation of Dientamoebiasis

Among 750 symptomatic and asymptomatic patients, Dientamoeba fragilis was detected at a prevalence of 5.2% and more common than Giardia intestinalis. Most infected patients presented with diarrhea and abdominal pain with symptoms greater than 2 weeks duration being common. Bacterial and viral causes of infection were excluded by routine microbiological techniques. Treatment of D. fragilis infection with either iodoquinol, paromomycin, or combination therapy resulted in the eradication of the parasite and complete resolution of symptoms. Treatment failure/relapses were associated only with the use of metronidazole. Nineteen patients were examined for pin worm, no Enterobius vermicularis, a proposed vector of transmission, were detected. Intermittent shedding of D. fragilis was found to be highly variable. These studies confirm the pathogenic nature of D. fragilis and we recommend laboratories routinely test for the organism.     

Implementation of a community liaison pharmacy service: a randomised controlled trial

Objective The aim of this study was to provide a pharmacy service to improve continuity of patient care across the primary‐secondary care interface. Setting The study involved patients discharged from two acute‐care tertiary teaching hospitals in Melbourne, Australia, returning to independent living. Methods Consecutive patients admitted to both hospitals who met the study criteria and provided consent were recruited. Recruited patients were randomised to receive either standard care (discharge counselling, provision of compliance aids and communication with primary healthcare providers when necessary) or the intervention (standard care and a home visit from a community liaison pharmacist (CLP) within 5 days of discharge). Participant medication was reviewed during the visit according to set protocols and compliance and medication understanding was measured. All participants were telephoned 8–12weeks after discharge to assess the impact of the intervention on adherence and medication knowledge. Key findings The CLP visited 142 patients with a mean time of 4.2 days following hospital discharge (range = 1–14 days). Consultations lasted 15–105 min (mean, 49 min; SD, ± 21 min). The CLPs retrospectively coded 766 activities and interventions that occurred during home visits, subsequently categorised into three groups: counselling and education, therapeutic interventions and other interventions. No statistical difference was detected in the number of medications patients reported taking at follow‐up: the mean value was 7.72 (SD, ± 3.27) for intervention patients and 7.55 (SD, ± 3.27) for standard‐care patients (P = 0.662). At follow‐up self‐perceived medication understanding was found to have improved in intervention patients (P < 0.001) and significant improvements from baseline in medication adherence were found in both standard‐care (P < 0.022) and intervention (P < 0.005) groups; however, adherence had improved more in intervention patients. Conclusion The community liaison pharmacy service provided critical and useful interventions and support to patients, minimising the risk of medication misadventure when patients were discharged from hospital to home.     

A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. RESULTS: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. CONCLUSIONS: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.     

Biomolecular mimicry in the actin cytoskeleton: mechanisms underlying the cytotoxicity of kabiramide C and related macrolides

This study characterizes the interactions between kabiramide C (KabC) and related macrolides and actin and establishes the mechanisms that underlie their inhibition of actin filament dynamics and cytotoxicity. The G-actin-KabC complex is formed through a two-step binding reaction and is extremely stable and long-lived. Competition-binding studies show that KabC binds to the same site on G-actin as Gelsolin domain 1 and CapG. KabC also binds to protomers within F-actin and results in the severing and capping of the (+) end; these studies suggest that free KabC and related macrolides act as biomimetics of Gelsolin. The G-actin-KabC complex binds to the (+) end of a growing filament, where it functions as a novel, unregulated, (+)-end capper and is largely responsible for the inhibition of motility and cytokinesis in approximately 10 -100 nM KabC-treated cells. KabC and related macrolides are useful probes to study the regulation of the actin filament (+) end and may lead to new therapies to treat diseases of the actin cytoskeleton.