No phenotype associated with established lipopolysaccharide model for cerebral palsy

OBJECTIVE: Cerebral palsy (CP) is associated with childhood spasticity, seizures, and paralysis. Oligodendrocyte damage resulting in periventicular leukomalacia (PVL) in the developing brain has been implicated. Animal models of CP have used prenatal hypoxia and infection with histopathology of PVL as the end point. To evaluate whether this histologic end point is associated with a CP phenotype, we reproduced a lipopolysaccharide (LPS) model for PVL, 1 and evaluated developmental, behavioral, and motor outcomes. STUDY DESIGN: On gestational day 15, Fischer 344 rats were intracervically injected with .1 mg/kg LPS (n = 5) or saline (n = 4). After delivery, evaluation for developmental milestones was performed on days 1 to 21 (LPS = 45; control = 30 pups). Males were also tested at 2.5 months using open-field, rotarod, and anxiety tests. On day 21, 2 pups/litter were perfused for immunohistochemistry, and stained with 2 oligodendrocyte antibodies: 2', d'-cyclic nucleotide phosphodiesterase (CNP), and myelin proteolipid protein (PLP) with relative densities of staining assessed using NIH Image software. Statistical analysis included Mann-Whitney U and analysis of variance (ANOVA). RESULTS: LPS pups demonstrated decreased CNP (P = .04) and PLP (P = .06) staining, replicating the model. There was no difference seen in neonatal weight, righting, negative geotaxis, cliff aversion, rooting, forelimb grasp, audio startle, air righting, eye opening, and activity. Surprisingly, LPS-exposed neonatal rats mastered forelimb placement (P < .01) and surface righting (P = .02) earlier than control rats. There were no differences between adult groups in open field distance traveled (P = .8), open-field locomotion time (P = .6), rotarod (P = .6), or anxiety (P = .7). CONCLUSION: Histologic evidence of white matter damage can be replicated using an LPS model for intrauterine inflammation. Significant phenotypic differences consistent with the motor and cognitive damage sequelae of such lesions (ie, CP) were not demonstrated. When evaluating animal models, it is important to assess not only biochemical markers for human disease, but also clinically relevant phenotypes.     

Prevalence of alpha-globin gene deletions among patients with unexplained microcytosis in a North-American population

Increasing multi-ethnicity is likely to make alpha-thalassemia (alpha-thal) more prevalent in Western metropolitan areas. Multiplex polymerase chain reaction (m-PCR) allows rapid and precise identification of most of alpha-thal carriers. With this method, we sought to determine the prevalence of alpha-thal and the corresponding genotype, among all non repetitive consecutive blood samples that had an unexplained microcytosis. These specimens had been sent to the hematology laboratory for a blood count analysis, found to be microcytic, and secondarily tested for ferritin level and hemoglobin (Hb) high performance liquid chromatography (HPLC) profile. Five hundred and sixteen microcytic blood samples were evaluated and 197 samples with normal ferritin and Hb HPLC were studied by m-PCR. Among 196 interpretable PCRs, 48 alpha-thal cases (24.5%) were identified: 28 with a single alpha-globin gene deletion and 20 with two alpha-globin gene deletions. Of these 20 cases, six showed two deletions in cis. None of the erythrocytic parameters studied predicted the presence of alpha-thal deletions. We conclude that a significant proportion (24.5%) of blood counts with microcytosis not explained by an iron deficiency, an inflammatory state or an abnormal Hb on HPLC, are caused by an alpha-globin gene deletion. The pertinence of genetic counseling for alpha-thal based on molecular diagnosis should be evaluated more formally in urban centers where this genetic condition is likely to have an increasing prevalence and clinical relevance.     

Hepatic pseudocapillarization in aged mice

Age-related changes in the hepatic sinusoid of the rat, human and baboons called pseudocapillarization have been discovered and are important because they are considered to be implicated in the pathogenesis of some age-related diseases. In this study, we investigated whether similar changes occur in the livers of old mice. Livers of young (3-4 months) and old (20-24 months) mice were perfusion-fixed and studied using electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old mice (154+/-4 versus 244+/-8 nm, P<0.001). There was a reduction in fenestrations within the endothelium (porosity decreased from 4.1+/-0.3 to 2.2+/-0.2%, P<0.001). There was perisinusoidal staining with Sirius red in old mice, however, expression of laminin and von Willebrands factor was similar in young and old mice. Novel perisinusoidal fat-engorged stellate cells were found extensively in the old mice. This study confirmed that pseudocapillarization is a widespread aging change in the liver, now documented in several species including the mouse. Mice are an appropriate animal model for studying aging and the hepatic sinusoid.     

Cortical, thalamic, and hypothalamic responses to cooling and warming the skin in awake humans: a positron-emission tomography study

Thermoregulatory mechanisms are remarkably efficient, ensuring minimal temperature variation within the core of the human body under physiological conditions. Diverse afferent and efferent neural pathways contribute to the monitoring of core and skin temperature, generation of heat, and control of thermal exchange with the external environment. We have investigated the cortical, thalamic, and hypothalamic responses to cooling and warming by using positron-emission tomography activation imaging of subjects clad in a water-perfused suit, which enabled rapid change of their skin-surface temperature. Human brain regions that respond to changes in skin temperature have been identified in the somatosensory cortex, insula, anterior cingulate, thalamus, and hypothalamus, with evidence that the hypothalamic response codes for the direction of temperature change. We conclude that signals from thermosensors in the skin providing crucial afferent information to the brain are integrated with signals from central thermosensors, resulting in thermoregulatory responses that maintain core temperature within a remarkably narrow range.     

Predictive value of the early clinical signs in Rett disorder

The British Isles Survey for Rett has registered 1,159 cases over up to 20 years. Indicators of health and severity, recorded at intervals throughout life, are drawn from clinical examinations, reports and postal questionnaires. This study aimed to establish the stability and predictive value of an early severity score based on muscle tone, locomotor ability, feeding difficulty, scoliosis and epilepsy. Data from people with clinically documented classic or non-classic Rett and health records over 20-30 years indicate that severity scores tend to increase throughout the first 15 years and then to stabilise in mild and severe, classic and non-classic Rett. Severity scores before regression reflect later severity scores within relatively wide inter-quartile ranges. In general, the adult severity level is around 40 points above the pre-regression level for classic Rett and around 20 points for non-classic Rett. High early severity scores are associated with reduced cumulative survival. Used with caution, early signs are helpful in diagnosis and prognosis. The mutations T158M, R255X and R168X are generally associated with more severe and R306C and R133C with less severe disease but exceptions make these unreliable predictors of outcome.     

Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using a multimedia training video and CD-ROM we developed after a two-step validation process. We hypothesized that use of CD-ROM interactive training will lead to reliable and valid performance of the neurologic examination by both pediatric neurologists and nonpediatric neurologists. All examiners were asked to take one of six interobserver variability tests found on the CD-ROM on two occasions. In the first interobserver variability evaluation, 89% (531 of 594) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the two items that had a 60% correct rate, the correct response rate rose to 93% (114 of 123). In the second interobserver variability evaluation, 88% (493 of 560) of the responses agreed with the gold standard responses. Following annotated feedback to the examiners about the four items that had a 70% correct rate, the correct response rate rose to 96% (104 of 108). Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children. It provides an effective means to evaluate interobserver variability, offers a route for feedback, and creates an opportunity to reevaluate variability, both immediately and at periodic intervals.     

Estimation of endogenous noradrenaline release in rat brain in vivo using [3H]RX 821002

Noradrenaline plays an important role in many normal brain functions, e.g., attention, memory, and emotion. Dysfunction in the noradrenergic system is thought to lead to a number of abnormal brain conditions. The lack of suitable in vivo tracers to monitor noradrenaline release, levels, and regulation has hampered our fully understanding the roles that it plays in the brain. Presented here are data showing that the in vivo binding of the alpha2-adrenoceptor antagonist [3H]RX 821002 is sensitive to endogenous noradrenaline. Elevation of extracellular noradrenaline, using three different pharmacological challenges in rat, led to a reduction in the binding potential (BP) of [3H]RX 821002 when compared with vehicle controls. The challenges used were i.p. administration of D-amphetamine, the imidazoline2 binding site-selective ligand BU224, and L-deprenyl. Of the cortical regions measured, the reduction in BP reached significance in the anterior cingulate cortex for all of these pharmacological challenges. These initial observations in rat indicate that labelling of the alpha2-adrenoceptors with RX 821002 can be used to estimate changes in extracellular noradrenaline concentration in the cortex. This has the potential to enable the investigation of the role that noradrenaline plays both in the normal and abnormal brain and, if the ligand can be radiolabelled with a suitable positron-emitting isotope at high specific radioactivity, it could be an invaluable PET tracer.     

Risperidone and haloperidol in first-episode psychosis: a long-term randomized trial

OBJECTIVE: The first episode of psychotic illness is a key intervention point. The initial experience with medication can affect willingness to accept treatment. Further, relapse prevention is a treatment cornerstone during the first years of illness because active psychotic illness may affect lifetime outcomes. Thus, initial treatment of active symptoms and subsequent relapse prevention are central goals of pharmacotherapy. This study compared long-term effectiveness of risperidone versus haloperidol in first-episode psychosis patients. METHOD: First-episode psychosis patients (N=555, mean age=25.4 years) participated in a double-blind, randomized, controlled flexible-dose trial that compared risperidone (mean modal dose=3.3 mg) and haloperidol (mean modal dose=2.9 mg). The median treatment length was 206 days (maximum=1,514). RESULTS: Positive and Negative Syndrome Scale scores and Clinical Global Impression ratings improved significantly relative to baseline, with no significant differences between groups. Three-quarters of the patients achieved initial clinical improvement, defined as >20% reduction in total Positive and Negative Syndrome Scale score. However, among those who achieved clinical improvement, 42% of the risperidone group experienced a relapse compared with 55% of the haloperidol group. The median time to relapse was 466 days for risperidone-treated subjects and 205 days for those given haloperidol. These differences were statistically significant based on Kaplan-Meier survival analysis. Adverse effects distinguished the treatments: there were significantly more extrapyramidal signs and symptoms and adjunctive medication use in the haloperidol group and greater prolactin elevation in the risperidone group. There was less weight gain with haloperidol initially but no significant differences between groups at endpoint. CONCLUSIONS: Relatively low doses of antipsychotic drugs lead to significant symptom amelioration in the majority of first-episode psychosis patients. In the long term, risperidone prevents relapse in more patients and for a longer time and also induces less abnormal movements than haloperidol.