Parent initiated prednisolone for acute asthma in children of school age : randomised controlled crossover trial

Objective To evaluate the efficacy of a short course of parent initiated oral prednisolone for acute asthma in children of school age.

Design Double blind, randomised, placebo controlled, crossover trial in which episodes of asthma, rather than participants, were randomised to treatment.

Setting The Barwon region of Victoria, Australia.

Participants Children aged 5-12 years with a history of recurrent episodes of acute asthma.

Intervention A short course of parent initiated treatment with prednisolone (1 mg/kg a day) or placebo.

Main outcome measures The primary outcome measure was the mean daytime symptom score over seven days. Secondary outcome measures were mean night time symptom score over seven days, use of health resources, and school absenteeism.

Results 230 children were enrolled in the study. Over a three year period, 131 (57%) of the participants contributed a total of 308 episodes of asthma that required parent initiated treatment: 155 episodes were treated with parent initiated prednisolone and 153 with placebo. The mean daytime symptom score was 15% lower in episodes treated with prednisolone than in those treated with placebo (geometric mean ratio 0.85, 95% CI 0.74 to 0.98; P=0.023). Treatment with prednisolone was also associated with a 16% reduction in the night time symptom score (geometric mean ratio 0.84, 95% CI 0.70 to 1.00; P=0.050), a reduced risk of health resource use (odds ratio 0.54, 95% CI 0.34 to 0.86; P=0.010), and reduced school absenteeism (mean difference −0.4 days, 95% CI −0.8 to 0.0 days; P=0.045).

Conclusion A short course of oral prednisolone initiated by parents when their child experiences an episode of acute asthma may reduce asthma symptoms, health resource use, and school absenteeism. However, the modest benefits of this strategy must be balanced against potential side effects of repeated short courses of an oral corticosteroid.

Two-year combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for Crohn's disease

Background & Aims: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn’s disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn’s disease, with a further year of follow-up. Methods: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Those in remission (Crohn’s Disease Activity Index ≤150) at week 16 continued their study medications in the maintenance phase of the trial. Primary end points were the proportion of patients experiencing at least 1 relapse at 12, 24, and 36 months. Results: At week 16, there were significantly more subjects in remission in the antibiotic arm (66%) than the placebo arm (50%; P = .02). Of 122 subjects entering the maintenance phase, 39% taking antibiotics experienced at least 1 relapse between weeks 16 and 52, compared with 56% taking placebo (P = .054). At week 104, the figures were 26% and 43%, respectively (P = .14). During the following year, 59% of the antibiotic group and 50% of the placebo group relapsed (P = .54). Conclusions: Using combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for up to 2 years, we did not find evidence of a sustained benefit. This finding does not support a significant role for Mycobacterium avium subspecies paratuberculosis in the pathogenesis of Crohn’s disease in the majority of patients. Short-term improvement was seen when this combination was added to corticosteroids, most likely because of nonspecific antibacterial effects.

Histological assessment of intermediate - and long-term creatine monohydrate supplementation in mice and rats

Creatine monohydrate (CrM) supplementation appears to be relatively safe based on data from short-term and intermediate-term human studies and results from several therapeutic trials. The purpose of the current study was to characterize pathological changes after intermediate-term and long-term CrM supplementation in mice [healthy control and SOD1 (G93A) transgenic] and rats (prednisolone and nonprednisolone treated). Histological assessment (18-20 organs/tissues) was performed on G93A mice after 159 days, and in Sprague-Dawley rats after 365 days, of CrM supplementation (2% wt/wt) compared with control feed. Liver histology was also evaluated in CD-1 mice after 300 days of low-dose CrM supplementation (0.025 and 0.05 g · kg^-1 · day^-1) and in Sprague-Dawley rats after 52 days of CrM supplementation (2% wt/wt) with and without prednisolone. Areas of hepatitis were observed in the livers of the CrM-supplemented G93A mice (P < 0.05), with no significant inflammatory lesions in any of the other 18-20 tissues/organs that were evaluated. The CD-1 mice also showed significant hepatic inflammatory lesions (P < 0.05), yet there was no negative effect of CrM on liver histology in the Sprague-Dawley rats after intermediate-term or long-term supplementation nor was inflammation seen in any other tissues/organs (P = not significant). Dietary CrM supplementation can induce inflammatory changes in the liver of mice, but not rats. The observed inflammatory changes in the murine liver must be considered in the evaluation of hepatic metabolism in CrM-supplemented mice. Species differences must be considered in the evaluation of toxicological and physiological studies.

Incidence, clinical spectrum, diagnostic features, treatment and predictors of paradoxical reactions during antibiotic treatment of Mycobacterium ulcerans infections

Background: Paradoxical reactions from antibiotic treatment of Mycobacterium ulcerans have recently been recognized. Data is lacking regarding their incidence, clinical and diagnostic features, treatment, outcomes and risk factors in an Australian population.

Methods: Data was collected prospectively on all confirmed cases of M. ulcerans infection managed at Barwon Health Services, Australia, from 1/1/1998-31/12/2011. Paradoxical reactions were defined on clinical and histological criteria and cases were determined by retrospectively reviewing the clinical history and histology of excised lesions. A Poisson regression model was used to examine associations with paradoxical reactions.

Results: Thirty-two of 156 (21%) patients developed paradoxical reactions a median 39 days (IQR 20-73 days) from antibiotic initiation. Forty-two paradoxical episodes occurred with 26 (81%) patients experiencing one and 6 (19%) multiple episodes. Thirty-two (76%) episodes occurred during antibiotic treatment and 10 (24%) episodes occurred a median 37 days after antibiotic treatment. The reaction site involved the original lesion (wound) in 23 (55%), was separate to but within 3 cm of the original lesion (local) in 11 (26%) and was more than 3 cm from the original lesion (distant) in 8 (19%) episodes. Mycobacterial cultures were negative in 33/33 (100%) paradoxical episodes. Post-February 2009 treatment involved more cases with no antibiotic modifications (12/15 compared with 11/27, OR 5.82, 95% CI 1.12-34.07, p = 0.02) and no further surgery (9/15 compared with 2/27, OR 18.75, 95% CI 2.62-172.73, p < 0.001). Six severe cases received prednisone with marked clinical improvement. On multivariable analysis, age ≥ 60 years (RR 2.84, 95% CI 1.12-7.17, p = 0.03), an oedematous lesion (RR 3.44, 95% CI 1.11-10.70, p=0.03) and use of amikacin in the initial antibiotic regimen (RR 6.33, 95% CI 2.09-19.18, p < 0.01) were associated with an increased incidence of paradoxical reactions.

Conclusions: Paradoxical reactions occur frequently during or after antibiotic treatment of M. ulcerans infections in an Australian population and may be increased in older adults, oedematous disease forms, and in those treated with amikacin. Recognition of paradoxical reactions led to changes in management with less surgery, fewer antibiotic modifications and use of prednisolone for severe reactions.

Forgotten but not gone - Scrofuloderma in a migrant student from India

A 34-year-old Indian student who immigrated to Australia five years ago presented with a four-week history of neck pain. Physical examination revealed two firm fixed cervical lymph nodes in the anterior triangle and midline region which were tender on palpation and erythematous on inspection. Cording phenomenon was found on ZN staining of FNA sample and mycobacterium tuberculosis (M.tb) PCR confirmed the diagnosis with incomplete resistance to isoniazid. Patient was treated with other three first line antituberculosis medications for nine months with an excellent outcome. Prednisolone was also used as adjunctive therapy and tapered during the course of treatment.

Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program

Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming.