Background: More than 4 million children are exposed annually to sedatives and general anaesthetics (GAs) in the USA alone. Recent data suggest that common GAs can be detrimental to brain development causing neurodegeneration and long-term cognitive impairments. Challenged by a recent US Food and Drug Administration (FDA) warning about potentially neurotoxic effects of GAs in children, there is an urgent need to develop safer GAs. Methods: Postnatal Day 7 (P7) rat pups of both sexes were exposed to six (repeated every 2 h) injections of equipotent hypnotic doses of ketamine or the neuroactive steroid (3b,5b,17b)-3-hydroxyandrostane-17-carbonitrile (3b-OH) for 12 h. Loss of righting reflex was used to assess hypnotic properties and therapeutic index; quantitative caspase-3 immunohistochemistry was used to assess developmental neuroapoptosis; patch-clamp recordings in acute brain slices were used to assess the effects of 3b-OH on neuronal excitability and synaptic transmission. Cognitive abilities of rats exposed to ketamine, 3b-OH, or vehicle at P7 were assessed in young adulthood using the radial arm maze. Results: The neuroactive steroid 3b-OH has a therapeutic index similar to ketamine, a commonly used clinical GA. We report that 3b-OH is safe and, unlike ketamine, does not cause neuroapoptosis or impair cognitive development when administered to P7 rat pups. Interestingly, 3b-OH blocks T-type calcium channels and presynaptically dampens synaptic transmission at hypnotically-relevant brain concentrations, but it lacks a direct effect on g-aminobutyric acid A or glutamate-gated ion channels.

Objective To further test the application of topical steroids in boys referred to a paediatric surgical practice with pathological, non‐retractable foreskins diagnosed as phimosis. Patients and methods This prospective study comprised two groups of 20 boys each (mean age 4.1 years, range 3–6) diagnosed as having phimosis; twice daily, a topical steroid (0.05% betamethasone cream) was applied on the narrowed preputial skin in the first group and a neutral cream (Vaseline) in the second (control) group. Patients were treated for 4 weeks and the retractability of the foreskin and any side‐effects assessed. Results Good retraction of the foreskin was achieved in 19 patients treated with betamethasone cream and the response was unsatisfactory in 16 patients from the control group; these 16 boys and one 6‐year‐old boy treated with betamethasone were circumsized. There were no side‐effects or problems after the application of either cream. Conclusion Treatment with 0.05% betamethasone cream is a simple and safe method for the treatment of phimosis in boys older than 3 years. An early operation is necessary in cases of genuine phimosis when 1 month of treatment with topical steroids has failed. We strongly support the saying, ‘The fortunate foreskin of an infant boy will usually be left well alone by everyone but its owner’.

Commonly used general anesthetics can have adverse effects on the developing brain by triggering apoptotic neurodegeneration, as has been documented in the rat. The rational of our study was to examine the molecular mechanisms that contribute to the apoptotic action of propofol anesthesia in the brain of 7-day-old (P7) rats. The down-regulation of nerve growth factor (NGF) mRNA and protein expression in the cortex and thalamus at defined time points between 1 and 24 h after the propofol treatment, as well as a decrease of phosphorylated Akt were observed. The extrinsic apoptotic pathway was induced by over-expression of tumor necrosis factor (TNF) which led to the activation of caspase-3 in both examined structures. Neurodegeneration was confirmed by Fluoro-Jade B staining. Our findings provide direct experimental evidence that the anesthetic dose (25 mg/kg) of propofol induces complex changes that are accompanied by cell death in the cortex and thalamus of the developing rat brain.

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Previously we observed that prolonged exposure to propofol anesthesia causes caspase-3- and calpain-mediated neuronal death in the developing brain. The present study examines the effects of propofol anesthesia on the expression of tumor necrosis factor-α (TNFα), pro-nerve growth factor (NGF), and their receptors in the cortex and the thalamus. We also investigated how propofol influences the expression of Akt and X-linked inhibitor of apoptosis (XIAP) expression, proteins that promote prosurvival pathways. Seven-day-old rats (P7) were exposed to propofol anesthesia lasting 2, 4, or 6 hr and killed 0, 4, 16, or 24 hr after anesthesia termination. The relative levels of mRNA and protein expression were estimated by RT-PCR and Western blot analysis, respectively. The treatments caused marked activation of TNFα and its receptor TNFR-1 and pro-NGF and p75NTR receptor expression. In parallel with the induction of these prodeath signals, we established that propofol anesthesia promotes increased expression of the prosurvival molecules pAkt and XIAP during the 24-hr postanesthesia period. These results show that different brain structures respond to propofol anesthesia with a time- and duration of exposure-dependent increase in proapoptotic signaling and with concomitant increases in activities of prosurvival proteins. We hypothesized that the fine balance between these opposing processes sustains homeostasis in the immature rat brain and prevents unnecessary damage after exposure to an injurious stimulus. The existence of this highly regulated process provides a time frame for potential therapeutic intervention directed toward suppressing the deleterious component of propofol anesthesia.