Determinants of Initial Antibiotic Duration in Very Low Birth Weight Neonates.

INTRODUCTION: Very low birth weight (VLBW) neonates (< 1500 g) are commonly exposed to prolonged antibiotic courses related to concerns for presumed early onset sepsis often with unclear indications. While antibiotics can be life-saving medications, prolonged antibiotic exposure (> 5 days) increases an infant's risk for necrotizing enterocolitis, late onset sepsis, colonization or infection with resistant organisms, and death. The aim of this study is to describe clinical and laboratory factors that influence the length of initial antibiotic courses in VLBW neonates. METHODS: Demographics, perinatal factors, and neonatal clinical and laboratory data were compared in a single-center retrospective cohort of VLBW neonates who received ≤ 3 days versus > 5 days of initial antibiotics. RESULTS: A total of 121 patients were analyzed of which 117 (97%) were started on antibiotics empirically on admission, and 71 (59%) received ≤ 3 days and 50 (41%) received > 5 days of antibiotics. One (0.8%) infant had a positive blood culture (S. oralis). Demographics [gestational age (p < 0.001) and birth weight (p < 0.001)] and neonatal clinical status [Apgar score at 5 min (p = 0.001), CRIB II (p < 0.001), need for inotropes (p = 0.001), and maximum ventilator support (p < 0.001)] were significantly different between the short and prolonged course of antibiotics groups on bivariate analysis. There were no significant differences in perinatal factors or common laboratory markers of sepsis. Maximum ventilator support remained significant on multivariate analysis (p = 0.007). CONCLUSION: In the VLBW population, the clinical status of the neonate, as represented by maximum ventilator support in this study, was the most important factor in determining the duration of initial antibiotic treatment. Laboratory values and perinatal risk factors did not significantly influence prescribing patterns.

5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity.

Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025-0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.

Multiple phenotypes resulting from a mutagenesis screen for pharynx muscle mutations in Caenorhabditis elegans.

We describe a novel screen to isolate pharyngeal cell morphology mutants in Caenorhabditis elegans using myo-2::GFP to rapidly identify abnormally shaped pharynxes in EMS (Ethyl Methanesulfonate) mutagenized worms. We observed over 83 C. elegans lines with distinctive pharyngeal phenotypes in worms surviving to the L1 larval stage, with phenotypes ranging from short pharynx, unattached pharynx, missing cells, asymmetric morphology, and non-adherent pharynx cells. Thirteen of these mutations have been chromosomally mapped using Single Nucleotide Polymorphisms (SNPs) and deficiency strain complementation. Our studies have focused on genetically mapping and functionally testing two phenotypes, the short pharynx and the loss of muscle cohesion phenotypes. We have also identified new alleles of sma-1, and our screen suggests many genes directing pharynx assembly and structure may be either pharynx specific or less critical in other tissues.