Evaluation of new instruments for screening and diagnosis of tics and tic disorders in a well-characterized sample of youth with tics and recruited controls.

Tics and tic disorders can significantly impact children, but limited screening tools and diagnostic challenges may delay access to care. The current study attempted to address these gaps by evaluating sensitivity and specificity of the Motor or Vocal Inventory of Tics (MOVeIT), a tic symptom screener, and the Description of Tic Symptoms (DoTS), a brief diagnostic assessment for tic disorders. Children (n=100, age 6-17 years old) with tic disorders attending a Tourette specialty clinic and a community-recruited sample without tics completed a gold-standard assessment by a tic expert; these evaluations were compared to child self-report and parent and teacher report versions of the MOVeIT, and child and parent versions of the DoTS. The parent and child MOVeIT met or exceeded pre-specified 85% sensitivity and specificity criteria for detecting the presence of tics when compared to a gold-standard tic expert diagnosis. The Teacher MOVeIT had lower sensitivity (71.4%) but good specificity (95.7%) for identifying any tic symptoms compared to gold standard. For determination of the presence or absence of any tic disorder, sensitivity of both parent and child DoTS was 100%; specificity of the parent DoTS was 92.7% and child DoTS specificity was 75.9%. More work may be needed to refine the teacher MOVeIT, but it is also recognized that tic expression may vary by setting. While the MOVeIT and DoTS parent and child questionnaires demonstrated adequate sensitivity and specificity for determining the presence of tics and tic disorders in this well-defined sample, additional testing in a general population is warranted.

Multiple risk factors in neonatal sinovenous thrombosis.

The etiology of neonatal sinovenous thrombosis is poorly understood. The authors report the risk factors and radiologic features of neonatal sinovenous thrombosis seen over an 11-year period. Of 30 patients, 29% received extracorporeal membrane oxygenation treatment, and 23% had congenital heart disease. Genetic thrombophilias were present in four of the seven infants tested. Eighteen neonates had multiple maternal, neonatal, perinatal, or prothrombotic complications. Sinovenous thrombosis was often accompanied by infarction (50%) or intraventricular hemorrhage (33%).

Rat and human aortic smooth muscle cells display differing migration and matrix metalloproteinase activities in response to dexamethasone.

OBJECTIVE: The steroid dexamethasone inhibits neointimal hyperplasia development in rats but not in humans. This study investigates the differential effects of dexamethasone on rat and human smooth muscle cell migration and matrix metalloproteinase (MMP) activity. METHODS: Rat aortic smooth muscle cells were harvested from Sprague-Dawley rats. Human aortic smooth muscle cells were obtained from Clonetics. Boyden chamber migration assays were performed with chemoattractant (platelet-derived growth factor) and varying concentrations of dexamethasone (10(-9) to 10(-5) mol/L). Zymography of culture media was used to assess MMP activity, and Western blot analysis was used for quantification of MMP-2 and tissue inhibitor of MMP-2 (TIMP-2) secretion. RESULTS: Dexamethasone inhibits rat aortic smooth muscle cell migration in a dose-dependent fashion. An increase in concentrations of dexamethasone does not effect human aortic smooth muscle cell migration. Rat aortic smooth muscle cell MMP-2 activity is inhibited with dexamethasone in a dose-dependent fashion, and human aortic smooth muscle cell MMP-2 activity is unchanged with dexamethasone. MMP-2 secretion is inhibited with dexamethasone in rat aortic smooth muscle cells but remains unaltered in human aortic smooth muscle cells. Dexamethasone increases rat aortic smooth muscle cell TIMP-2 secretion, and human aortic smooth muscle cell TIMP-2 secretion remains constant. CONCLUSION: Dexamethasone inhibits rat aortic smooth muscle cell migration, MMP-2 activity, and MMP-2 secretion and increases TIMP-2 secretion. These effects are not observed in human aortic smooth muscle cells. These findings may explain why dexamethasone inhibits neointimal hyperplasia in animal models but is ineffective in humans. Inhibition of human smooth muscle cell migration in vitro may be useful in predicting the effectiveness of future therapeutic agents for treatment of neointimal hyperplasia in humans.

Unique expression patterns of cell fate molecules delineate sequential stages of dentate gyrus development.

The dentate gyrus of the hippocampus is uniquely organized with a displaced proliferative zone that continues to generate dentate granule cells throughout life. We have analyzed the expression of Notch receptors, Notch ligands, and basic helix-loop-helix (bHLH) genes during dentate gyrus development to determine whether the need to maintain a pool of undifferentiated precursors is reflected in the patterns of expression of these genes. Many of these genes are expressed diffusely throughout the cortical neuroepithelium at embryonic days 16 and 17 in the rat, just preceding the migration of newly born granule cells and dentate precursor cells into the dentate anlage. However, at this time, Mash1, Math3, and Id3 expression are all concentrated in the area that specifically gives rise to granule cells and dentate precursor cells. Two days later, at the time of migration of the first granule cells and dentate precursor cells, cells expressing Mash1 are seen in the migratory route from the subventricular zone to the developing dentate gyrus. Newly born granule cells expressing NeuroD are also present in this migratory pathway. In the first postnatal week, precursor cells expressing Mash1 reside in the dentate hilus, and by the third postnatal week they have largely taken up their final position in the subgranular zone along the hilar side of the dentate granule cell layer. After terminal differentiation, granule cells born in the hilus or the subgranular zone begin to express NeuroD followed by NeuroD2. This study establishes that the expression patterns of bHLH mRNAs evolve during the formation of the dentate gyrus, and the precursor cells resident in the mature dentate gyrus share features with precursor cells found in development. Thus, many of the same mechanisms that are known to regulate cell fate and precursor pool size in other brain regions are likely to be operative in the dentate gyrus at all stages of development.

Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy.

BETA2/NeuroD is a homologue of the Drosophila atonal gene that is widely expressed during development in the mammalian brain and pancreas. Although studies in Xenopus suggest that BETA2/NeuroD is involved in cellular differentiation, its function in the mammalian nervous system is unclear. Here we show that mutant mice homozygous for a deletion at the BETA2/NeuroD locus fail to develop a granule cell layer within the dentate gyrus, one of the principal structures of the hippocampal formation. To understand the basis of this abnormality, we analyzed dentate gyrus development by using immunocytochemical markers in BETA2/NeuroD-deficient mice. The early cell populations in the dentate gyrus, including Cajal-Retzius cells and radial glia, are present and appear normally organized. The migration of dentate precursor cells and newly born granule cells from the neuroepithelium to the dentate gyrus remains intact. However, there is a dramatic defect in the proliferation of precursor cells once they reach the dentate and a significant delay in the differentiation of granule cells. This leads to malformation of the dentate granule cell layer and excess cell death. BETA2/NeuroD null mice also exhibit spontaneous limbic seizures associated with electrophysiological evidence of seizure activity in the hippocampus and cortex. These findings thus establish a critical role of BETA2/NeuroD in the development of a specific class of neurons. Furthermore, failure to express BETA2/NeuroD leads to a stereotyped pattern of pathological excitability of the adult central nervous system.

Statistical and genetic aspects of quality control for DNA identification.

Quality control for likelihood ratio (LR) tests on restriction fragment length polymorphisms (RFLPs) and polymerase chain reaction (PCR) markers is provided by the 4N6 program. Examples are given for test of exclusion, coincidence, and kinship that should be used routinely in validation of DNA profiling. They confirm that "in a knowledgeable court DNA profiling is no longer exposed to risk of illogical presentation, blind acceptance or arbitrary rejection" (N. E. Morton, Eur. J. Hum. Genet. 1993, 1, 172-179). However, they remain to be implemented in national systems of quality control. There can be no effective quality control until attempts to fudge gene frequencies in order to retain the Hardy-Weinberg assumption (recommended by the National Research Council) ar abandoned in favour of the population genetic approach that takes gene frequencies from a real population and uses kinship to express genotype probabilities. Since an expert witness cannot know the identity of the culprit, he is obliged to consider multiple hypothesis without usurping the prerogative of the court to favour one of them on the basis of other evidence. It remains to be seen whether the new NRC Committee (and more importantly the international community of forensic scientists) will adopt this fundamental principle, which is especially important in populations like India with preferential endogamy and consanguineous marriage. Alternative procedures and the causes, effects, and remedies of four types of error are also considered.

Bioadhesive lozenge for the improved delivery of cetylpyridinium chloride.

Conventional lozenges produce a high initial release of drug in the oral cavity, which rapidly declines to subtherapeutic levels, and requires multiple daily administration with associated problems of systemic toxicity and compliance. Various multilayer compacts containing cetylpyridinium chloride were evaluated in vitro using release into simulated saliva (buffer pH 6.6). The drug loading, the wax content of the active layer, and the composition of the bioadhesive layer were important variables affecting product performance. Following preliminary in vivo studies, the release of a three-layered device containing drug in a nonadhesive and flavored waxy exposed layer was studied in six humans using HPLC and was shown not to be affected by location within the mouth. In comparison with a proprietary lozenge formulation, the device produced more uniform and effective levels of drug (approximately 20 micrograms.mL-1), with adequate comfort, taste, and irritancy over a period of 3 h.

Use of strips containing tetracycline hydrochloride or metronidazole for the treatment of advanced periodontal disease.

Strips containing tetracycline hydrochloride or metronidazole 25% in polyhydroxybutyric acid as a biodegradable polymer matrix, showed sustained release in simulated gingival fluid pH 6.6 at 37 degrees C. When evaluated in patients suffering from advanced periodontal disease, the greatest response to therapy was observed with tetracycline hydrochloride strips inserted into periodontal pockets at four-day intervals for 16 days, compared with an untreated control group. A reduction in plaque index, gingival index and pocket depth was observed. A favourable alteration occurred in the microbial flora of treated pockets with an increase in the proportion of cocci and decrease in gram-negative rods, fusiforms and spirochetes. Metronidazole strips or root-planning tended not to be as effective. The clinical improvement produced by each treatment was not maintained when treatment was terminated.

In vitro and in vivo evaluation of a bondable compact for the prolonged delivery of triamcinolone acetonide to the oral cavity in patients with lichen planus.

Compacts weighing 40 mg and containing triamcinolone acetonide 70-90% and polyhydroxybutyric acid (PHB) 30-10% or poly (DL-lactic acid) 20% with a diameter of 5 mm were bonded onto the side-wall of molar teeth. In vitro dissolution studies showed the compacts to release 12% of drug in 30 days with an initial burst effect. Drug loading or polymer matrix type had little effect. In vivo studies in dogs showed that compacts containing 80% drug in PHB produced salivary levels of triamcinolone acetonide for 30 days. When evaluated in five patients with lichen planus resistant to conventional therapy, these compacts produce a slight clinical improvement in three subjects. Differential scanning calorimetry studies confirmed that the drug and polymer were present as a physical mix in these compacts.