Sleep disturbance and rage attacks in opsoclonus-myoclonus syndrome: response to trazodone

OBJECTIVES: Parents of children with opsoclonus-myoclonus syndrome (OMS) frequently describe poor sleep and rage attacks. We hypothesized that these manifestations are related and could result from underlying monoaminergic dysfunction. STUDY DESIGN: We clinically characterized the sleep and behavioral characteristics of 51 young children with OMS; 19 of those with the most disruptive sleep patterns were treated with trazodone, a soporific serotonergic agent. RESULTS: Sleep disturbances, including prolonged sleep latency, fragmented sleep, reduced quantity of sleep, snoring, and non-restorative sleep, were reported in 32 children, and frequent rage attacks were reported in 25. In 59% of the poor sleepers, parents felt that the problem was severe enough to warrant treatment. Children sleeping <10 hours/night had a higher rage frequency than those who slept more. Of the children who required trazodone, 84% were receiving corticosteroids or adrenocorticotropic hormone (corticotrophin), compared with 37% in the subgroup with normal sleep. Trazodone (3.0 +/- 0.4 mg/kg/day) improved sleep and behavior in 95% of the children, significantly increasing total sleep time by 72%, decreasing the number of awakenings by 76%, and reducing rage attacks by 33%. CONCLUSIONS: Children with OMS exhibited multiple types of sleep disturbances, which contributed to rage attacks. Trazodone was effective in improving sleep and decreasing rage attacks and was well tolerated, even in toddlers.     

Long-chain fatty acid oxidation during early human development

Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)/mitochondrial trifunctional protein (MTP) deficiency, disorders of the mitochondrial long-chain fatty acid oxidation, can present with hypoketotic hypoglycemia, rhabdomyolysis, and cardiomyopathy. In addition, patients with LCHAD/MTP deficiency may suffer from retinopathy and peripheral neuropathy. Until recently, there was no indication of intrauterine morbidity in these disorders. This observation was in line with the widely accepted view that fatty acid oxidation (FAO) does not play a significant role during fetal life. However, the high incidence of the gestational complications acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets syndrome observed in mothers carrying a LCHAD/MTP-deficient child and the recent reports of fetal hydrops due to cardiomyopathy in MTP deficiency, as well as the high incidence of intrauterine growth retardation in children with LCHAD/MTP deficiency, suggest that FAO may play an important role during fetal development. In this study, using in situ hybridization of the VLCAD and the LCHAD mRNA, we report on the expression of genes involved in the mitochondrial oxidation of long-chain fatty acids during early human development. Furthermore, we measured the enzymatic activity of the VLCAD, LCHAD, and carnitine palmitoyl-CoA transferase 2 (CPT2) enzymes in different human fetal tissues. Human embryos (at d 35 and 49 of development) and separate tissues (5-20 wk of development) were used. The results show a strong expression of VLCAD and LCHAD mRNA and a high enzymatic activity of VLCAD, LCHAD, and CPT2 in a number of tissues, such as liver and heart. In addition, high expression of LCHAD mRNA was observed in the neural retina and CNS. The observed pattern of expression during early human development is well in line with the spectrum of clinical signs and symptoms reported in patients with VLCAD or LCHAD/MTP deficiency.     

Age-related differences in vasoconstrictor responses to isoprostanes in piglet pulmonary and mesenteric vascular smooth muscle

Isoprostanes are prostaglandin (PG)-like compounds produced nonenzymatically by free radical-catalyzed peroxidation of arachidonic acid. Isoprostanes evoke potent vascular effects but their actions in the neonatal vasculature are poorly known. We aimed to study the effects of 8-iso-PGE(1), 8-iso-PGE(2), 8-iso-PGF(1alpha), 8-iso-PGF(1beta), 8-iso-PGF(2alpha), and 8-iso-PGF(2beta) in pulmonary arteries (PA), pulmonary veins (PV), and mesenteric arteries (MA) from newborn and 2-wk-old piglets. Isoprostanes produced concentration-dependent contractions of PA, PV, and MA (magnitudes up to 1.5- to 2-fold greater than the responses to 62.5 mM KCl) but they were markedly less potent vasoconstrictors than the thromboxane A(2) (TXA(2)) mimetic U46619. Neonatal PA were more sensitive to 8-iso-PGF(1alpha), 8-iso-PGF(1beta), and 8-iso-PGF(2beta) than 2-wk-old PA. Neonatal PV were more sensitive to 8-iso-PGE(2) and 8-iso-PGF(1alpha), and neonatal MA were more sensitive to 8-iso-PGE(2), 8-iso-PGF(1alpha), 8-iso-PGF(1beta), 8-iso-PGF(2alpha), and 8-iso-PGF(2beta) than the corresponding 2-wk-old vessels. The sensitivity to U46619 decreased with postnatal age in MA but did not change in PA and PV. The contractile responses to all the isoprostanes and to U46619 were reverted by the TXA(2) receptor (TP) antagonist SQ 29,548. Moreover, isoprostane-evoked contractions in 2-wk-old PA were reduced by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and hydroxyfasudil) but not by inhibitors of protein kinase C (chelerythrine), mitogen-activated protein kinase kinase (PD 98059) or p38-kinase (SB 203580). In conclusion, isoprostanes produced compound-, tissue-, and age-dependent constriction of neonatal porcine pulmonary and mesenteric vascular smooth muscle. Isoprostane-evoked PA vasoconstriction involved TP receptors and activation of tyrosine kinases and Rho kinases.     

Persistence of group C anticapsular antibodies two to three years after immunization with an investigational quadrivalent Neisseria meningitidis-diphtheria toxoid conjugate vaccine

BACKGROUND: An investigational quadrivalent (A, C, Y and W-135) meningococcal conjugate (MC-4) vaccine was reported to be more immunogenic in 2-year-olds than the currently licensed meningococcal polysaccharide vaccine, but persistence of serum antibody beyond 6 months after conjugate vaccination is unknown. OBJECTIVE: Determine persistence and the immunologic basis of protective activity of group C anticapsular antibodies in sera obtained 2-3 years after MC-4 vaccination. DESIGN: Group C antibody concentrations, bactericidal activity and passive protective activity were measured in sera from 48 children, ages 4-5 years, who had been immunized 2-3 years earlier with an MC-4 vaccine and from 47 children who had not been previously vaccinated. RESULTS: Serum antibody concentrations were higher in the vaccinated than the unvaccinated children (geometric means, 0.30 and 0.09 mug/mL, respectively, P < 0.0001). Bactericidal titers > or =1/4 (considered protective) were infrequent in both vaccinated and unvaccinated children (14.6 and 6.4%, respectively, P = 0.3). Passive protective activity against bacteremia in the infant rat model was more frequent in sera from vaccinated (37.5%) than sera from unvaccinated children (12.5%, P < 0.02). The proportion of sera with passive protective activity increased with increasing anticapsular antibody concentrations (P < 0.0001). INTERPRETATION: Serum group C antibody concentrations remained elevated for 2-3 years after MC-4 vaccination, and passive protective activity was more frequent in vaccinated than unvaccinated children. However, serum antibody concentrations in many vaccinated children were no longer sufficient to activate complement-mediated bacteriolysis in vitro or to confer passive protection against experimental group C disease.     

Sex differences in brain activation elicited by humor

With recent investigation beginning to reveal the cortical and subcortical neuroanatomical correlates of humor appreciation, the present event-related functional MRI (fMRI) study was designed to elucidate sex-specific recruitment of these humor related networks. Twenty healthy subjects (10 females) underwent fMRI scanning while subjectively rating 70 verbal and nonverbal achromatic cartoons as funny or unfunny. Data were analyzed by comparing blood oxygenation-level-dependent signal activation during funny and unfunny stimuli. Males and females share an extensive humor-response strategy as indicated by recruitment of similar brain regions: both activate the temporal-occipital junction and temporal pole, structures implicated in semantic knowledge and juxtaposition, and the inferior frontal gyrus, likely to be involved in language processing. Females, however, activate the left prefrontal cortex more than males, suggesting a greater degree of executive processing and language-based decoding. Females also exhibit greater activation of mesolimbic regions, including the nucleus accumbens, implying greater reward network response and possibly less reward expectation. These results indicate sex-specific differences in neural response to humor with implications for sex-based disparities in the integration of cognition and emotion.     

Human infection patterns and heterogeneous exposure in river blindness

Here we analyze patterns of human infection with Onchocerca volvulus (the cause of river blindness) in different continents and ecologies. In contrast with some geohelminths and schistosome parasites whose worm burdens typically exhibit a humped pattern with host age, patterns of O. volvulus infection vary markedly with locality. To test the hypothesis that such differences are partly due to heterogeneity in exposure to vector bites, we develop an age- and sex-structured model for intensity of infection, with parasite regulation within humans and vectors. The model is fitted to microfilarial data from savannah villages of northern Cameroon, coffee fincas of central Guatemala, and forest-dwelling communities of southern Venezuela that were recorded before introducing ivermectin treatment. Estimates of transmission and infection loads are compared with entomological and epidemiological field data. Host age- and sex-heterogeneous exposure largely explains locale-specific infection patterns in onchocerciasis (whereas acquired protective immunity has been invoked for other helminth infections). The basic reproductive number, R0, ranges from 5 to 8, which is slightly above estimates for other helminth parasites but well below previously presented values.     

Visual-spatial attention in alcoholics and illicit stimulant abusers: effects of nicotine replacement

Reports of alcohol or illicit drug-related cognitive impairments have frequently disregarded the potentially confounding effects of smoking status and nicotine withdrawal on these measures. This study addressed this issue by measuring visual-spatial attention via an adaptation of the Posner paradigm in three groups of tobacco smokers: controls without a history of alcoholism or illicit drug use (n=27; 20 male), chronic alcoholics (n=22; 18 male), and illicit stimulant abusers (n=36; 21 male). Throughout testing, nicotine levels were stabilized by the double-blind administration of a high (14 or 21 mg) or low (7 mg) dose transdermal nicotine patch. A significant effect of group was observed for number of correct responses to restriction trials (F=5.48, 2/79 df; p=.006). Performance was normalized in the illicit stimulant group, and alcoholic participants exhibited superior performance relative to both illicit stimulant abusers (p=.002) and controls (p=.01). These findings support the hypothesis that nicotine may have a compensatory or normalizing effect on attentional functions in substance abusers. Whether these results reflect the central nervous system-activating effects of nicotine or merely alleviation of nicotine withdrawal is a topic of ongoing research.