Spasmus nutans-like nystagmus is often associated with underlying ocular, intracranial, or systemic abnormalities.

BACKGROUND: There is uncertainty as to whether spasmus nutans (SN) is an isolated idiopathic entity or whether there are underlying conditions that could cause or be associated with the nystagmus. We undertook this study to determine the frequency of ocular, intracranial, and systemic conditions in patients with nystagmus having characteristics of SN. METHODS: We performed a chart review of 22 consecutive patients examined from 2000 through 2005 at the Dean McGee Eye Institute and Children' Hospital of Oklahoma with nystagmus consistent with SN. We collected information related to gender, age at presentation and age at final visit, visual acuity, refractive error, laterality of nystagmus, presence of head nodding and torticollis, pattern of strabismus, neuroimaging and electroretinography results, and other associated clinical findings. RESULTS: Visual acuity was reduced in 75% of eyes at presentation and 58% of eyes at last visit. Eight patients had significant refractive error. Seven patients had strabismus. Two patients had chiasmal gliomas. Four patients had cone or rod/cone dystrophy. Only three patients had no associated ocular, intracranial, or systemic conditions. CONCLUSIONS: A substantial proportion of patients presenting with SN-like nystagmus have important underlying ocular, intracranial, or systemic abnormalities that may require evaluation and management.     

Differences in KRAS mutation spectrum in lung cancer cases between African Americans and Caucasians after occupational or environmental exposure to known carcinogens.

Elevated mortality rates of lung cancer in the Mississippi River corridor in Louisiana have been clearly documented for the past half-century and rank among the highest in the nation. A population-based case-control study of lung cancer termed Lower Mississippi River Interagency Cancer Study was conducted in southern Louisiana. Lung tumor specimens were collected, isolated by laser capture microdissection, subjected to PCR to amplify KRAS, and sequenced to confirm mutation status and specificity. Of the 116 lung tumors analyzed to date, 32 (27.6%) contained mutations in either codon 12 or 13 of KRAS. This frequency is comparable to that reported in the literature; however, the mutation spectrum was strikingly different. Of the 32 mutations observed, 21 (65.6%) resulted in the inappropriate insertion of cysteine, 6 (18.8%) resulted in the insertion of serine, 3 (9.4%) resulted in the insertion of valine, and 1 (3.1%) each resulted in the insertion of aspartate and alanine. These data indicate that an abnormally high proportion of cysteine (P = 0.010) and serine (P = 0.002) mutations was observed in our sample group versus lung cancers reported in the literature. KRAS mutations were more common in African Americans with an odds ratio of 2.4 (P = 0.048), as were serine mutations, although the latter did not reach statistical significance (odds ratio, 2.6; P = 0.373). No association was found between the observed mutation spectrum and known lung cancer risk factors.     

Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies.

Amphotericin B (AmB) has been the most effective systemic antifungal agent, but its use is limited by the dose-limiting toxicity of the conventional micellar dispersion formulation (Fungizone). New formulations with better and improved safety profiles are being developed and include ABELCET (formerly ABLC), but their dispositions have not been well characterized; hence, the reason for their improved profiles remains unclear. This report details the pharmacokinetics of ABELCET examined in various pharmacokinetic and efficacy studies by using whole-blood measurements of AmB concentration performed by high-pressure liquid chromatography. The data indicated that the disposition of AmB after administration of ABELCET is different from that after administration of Fungizone, with a faster clearance and a larger volume of distribution. It exhibits complex and nonlinear pharmacokinetics with wide interindividual variability, extensive distribution, and low clearance. The pharmacokinetics were unusual. Clearance and volume of distribution were increased with dose, peak and trough concentrations after multiple dosings increased less than proportionately with dose, steady state appeared to have been attained in 2 to 3 days, despite an estimated half-life of up to 5 days, and there was no evidence of significant accumulation in the blood. The data are internally consistent, even though they were gathered under different conditions and circumstances. The pharmacokinetics of ABELCET suggest that lower concentrations in blood due to higher clearance and greater distribution may be responsible for its improved toxicity profile compared to those of conventional formulations.     

Axonal trajectories between mouse somatosensory thalamus and cortex

An in vitro brain slice preparation has been used to label fibers connecting the somatosensory thalamus and cortex of the mouse. In 400-800-micron brain slices, the pathway between the ventrobasal complex and somatosensory cortex was labeled under direct vision with horseradish peroxidase crystals (HRP), HRP-Nonidet P-40 (NP40) detergent chips, or a solution of HRP/dimethylsulfoxide. Thalamocortical and corticofugal fibers are organized into a plexiform system of bundles that appears to be fairly constant from animal to animal. Bundles of fibers projecting from the ventrobasal complex course between regularly spaced groups of thalamic neurons. Thalamocortical axons do not invariably leave the thalamus via the fiber bundle closest to the perikarya. Thus, nearest-neighbor relationships are abolished before these axons have even left the thalamus. The axon bundles traverse the thalamic reticular nucleus lateral to the complex. The axons then rotate about one another, analogous to the coiling of strands in rope about a central axis. This accounts for the well known 180 degrees rotation in the mediolateral direction between thalamic and cortical maps. Laterally, fiber bundles converge and diverge within the internal capsule so that nearest-neighbor relationships are lost. Individual thalamocortical axons do not bifurcate proximal to the subcortical white matter. After single bundles of fibers reach a point just below the subcortical white matter, their individual fibers diverge widely. Within the subcortical white matter most afferent fibers make a small dorsally concave loop prior to taking one of two possible courses: some of the fibers ascend directly into the overlying cortex usually angled towards the dorsal surface of the brain; other fibers run in the subcortical white matter for variable distances prior to ascending into cortex. Within somatosensory cortex, smooth axons branch near their terminals in layers IV and VI. Axonal terminal and branching patterns of these axons within somatosensory cortex are similar to those found in in vivo preparations. Most axons are smooth, but other axons are beaded. Some beaded axons project to layer I. Corticofugal fibers are labeled. Fibers leaving somatosensory cortex have an angle of descent opposite to the angle of ascent for afferent fibers, and are often fasciculated in the cortex and subcortical white matter. Within the subcortical white matter efferent fibers often loop in a direction opposite to that of afferent fibers. Corticofugal fibers occasionally give off a collateral corticostriatal branch within the internal capsule.(ABSTRACT TRUNCATED AT 400 WORDS)     

Efficacy and Tolerability of Vigabatrin in Children with Refractory Partial Seizures: A Single-Blind Dose-Increasing Study

Summary: The efficacy and tolerability of vigabatrin (VGB) in children with refractory partial epilepsy were assessed in a single-blind, add-on, fixed-sequence, placebo-controlled trial. After 1-month observation, the patients entered a 7-month treatment period that involved administration of placebo for 1 month followed by VGB at the initial dosage of 40 mg/kg/day, to be increased to 60 and 80 mg/kg/day at 2-month intervals if seizures persisted. Of the 46 children enrolled in the study, 7 dropped out prematurely due to lack of efficacy of the drug (n = 6) or increased seizure frequency (n = 1). In 11 patients who either became seizure-free (n = 3) or improved markedly (n = 8), treatment was completed at a dose <80 mg/kg/day. The average number of seizures per month in the 39 patients who completed the study decreased from 97 during placebo to 21,12, and 9 after 2, 4, and 6 months of VGB treatments respectively (p < 0.0001 at each time). Response to VGB remained statistically significant when dropouts were included in the evaluation. The number of patients who had <50% reduction in seizure frequency after 2, 4, and 6 months was 28, 33, and 35, respectively. Eight patients became seizure-free during the last 2 months of VGB treatment (3 at 40, 3 at 60, and 2 at 80 mg/kg/day, as compared with none during placebo treatment). Serum levels of associated antiepileptic drugs (AEDs) showed no signscant changes, except for serum phenytoin (PHT) concentration, which significantly (p < 0.01) decreased after VGB treatment. Increased appetite and sedation were observed in 17 and 11% of cases, respectively. VGB is effective in the management of refractory partial epilepsy in children, and in some patients a positive dose-response relationship appears to occur over the assessed dosing range.     

The 5-HT(2A) -1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres.

Several case-control association studies have raised the possibility that the A allele of a -1438 G/A polymorphism in the type 2A serotonin receptor (HTR2A) gene may be a risk factor for anorexia nervosa. However the absence of linkage and the existence of negative association studies raise the possibility of false positive findings, resulting from population stratification or lack of statistical power. To address this controversy we recruited a sample of 316 patients with anorexia nervosa from six European centres, and utilised a family-based transmission disequilibrium (TDT) approach to analyse the HTR2A-1438 G/A polymorphism. Age at onset and minimal BMI were also taken into consideration in order to detect clinical heterogeneity or a quantitative trait effect. The TDT approach showed that the A allele was transmitted 133 times and not transmitted 148 times (McNemar chi(2) = 0.29, df = 1, P = 0.59). Also, the haplotype-based haplotype relative risk method showed no evidence for association of the A allele, in samples from each centre (chi(2) < 2.15, df = 1, P > 0.14) and in the total sample (chi(2) = 0.55, df = 1; P = 0.46). Furthermore, we found no evidence for heterogeneity of the A allele frequency between samples (chi(2) = 2.54, df = 4, P = 0.64), either according to minimal-BMI (F1/242 = 2.14, P = 0.45) or age at onset (F1/224 = 2.39; P = 0.12). QTL-TDT analyses also showed no direct role of the A allele on these traits. We thus found no evidence for a significant role of the 5-HT(2A) gene in anorexia nervosa. Previous results may have been exposed to stratification bias (which we controlled by the TDT method) and/or the risk of type 1 error (from which we were less exposed because of the sample size).