Generalized lucky-drift model for impact ionization in semiconductors with disorder.

An extension of an original lucky-drift model to the case of disordered semiconductors is proposed, motivated by experimental observations of an avalanche phenomenon in amorphous semiconductors. The generalization encompasses two scattering mechanisms: an inelastic one due to optical phonons and an elastic one due to a disorder potential. An obtained analytical solution is verified by a kinetic Monte Carlo simulation. Eventually, experimental data on a field dependence of the impact ionization coefficient in amorphous selenium are interpreted using reasonable material parameters.

Shared and specific susceptibility loci for schizophrenia and bipolar disorder: a dense genome scan in Eastern Quebec families.

The goal of this study was to identify susceptibility loci shared by schizophrenia (SZ) and bipolar disorder (BP), or specific to each. To this end, we performed a dense genome scan in a first sample of 21 multigenerational families of Eastern Quebec affected by SZ, BP or both (N=480 family members). This probably constitutes the first genome scan of SZ and BP that used the same ascertainment, statistical and molecular methods for the concurrent study of the two disorders. We genotyped 607 microsatellite markers of which 350 were spaced by 10 cM and 257 others were follow-up markers in positive regions at the 10 cM scan. Lander and Kruglyak thresholds were conservatively adjusted for multiple testings. We maximized the lod scores (mod score) over eight combinations (2 phenotype severity levels x 2 models of transmission x 2 analyses, affected/unaffected vs affected-only). We observed five genomewide significant linkages with mod score >4.0: three for BP (15q11.1, 16p12.3, 18q12-q21) and two for the shared phenotype, that is, the common locus (CL) phenotype (15q26,18q12-q21). Nine mod scores exceeded the suggestive threshold of 2.6: three for BP (3q21, 10p13, 12q23), three for SZ (6p22, 13q13, 18q21) and three for the CL phenotype (2q12.3, 13q14, 16p13). Mod scores >1.9 might represent confirmatory linkages of formerly reported genomewide significant findings such as our finding in 6p22.3 for SZ. Several regions appeared to be shared by SZ and BP. One linkage signal (15q26) appeared novel, whereas others overlapped formerly reported susceptibility regions. Despite the methodological limitations we raised, our data support the following trends: (i) results from several genome scans of SZ and BP in different populations tend to converge in specific genomic regions and (ii) some of these susceptibility regions may be shared by SZ and BP, whereas others may be specific to each. The present results support the relevance of investigating concurrently SZ and BP within the same study and have implications for the modelling of genetic effects.

A search for specific and common susceptibility loci for schizophrenia and bipolar disorder: a linkage study in 13 target chromosomes.

We report the first stage of a genome scan of schizophrenia (SZ) and bipolar disorder (BP) covering 18 candidate chromosomal areas. In addition to testing susceptibility loci that are specific to each disorder, we tested the hypothesis that some susceptibility loci might be common to both disorders. A total of 480 individuals from 21 multigenerational pedigrees of Eastern Québec were evaluated by means of a consensus best-estimate diagnosis made blind to diagnoses in relatives and were genotyped with 220 microsatellite markers. Two-point and multipoint model-based linkage analyses were performed and mod scores (Z, for max Z(max)) are reported. The strongest linkage signals were detected at D18S1145 (in 18q12; Z = 4.03) for BP, and at D6S334 (in 6p 22-24; Z(het) = 3.47; alpha = 0.66) for SZ. Three other chromosomal areas (3q, 10p, and 21q) yielded linkage signals. Chromosomes 3p, 4p, 5p, 5q, 6q, 8p, 9q, 11q, 11p, 12q, 13q, 18p and 22q showed no evidence of linkage. The 18q12 results met the Lander and Kruglyak (1995) criterion for a genome-wide significant linkage and suggested that this susceptibility region may be shared by SZ and BP. The 6p finding provided confirmatory evidence of linkage for SZ. Our results suggest that both specific and common susceptibility loci must be searched for SZ and BP.

On site PCB analysis in support of a transformer rebuilding project.

In December 1997, Emergencies Science Division (ESD) was contracted by Natural Resources Canada (NRCAN) to perform on-site analyses in support of a transformer-rebuilding project at Sault Ste-Marie, Ont. Using a gas chromatograph with electron capture detector (GC/ECD) mounted in a mobile laboratory, PCB analyses were conducted on the original transformer oil, surface wipes, Varsol rinsing of the transformer tank interior and cooling fins. To assess the efficiency and validity of the decontamination process, PCB contamination was monitored closely on the rinse solvent. Surface wipe samples after wash down showed surface concentration of several hundred microg Aroclor 1254/100 cm(2), well below the acceptable limit of 8000 microg/100 cm(2). Because of the relatively large percentage of the internal surface area, the fin banks had to be rinsed exhaustively to meet the decontamination criteria. Final rinses of each of the seven fin banks of transformer 1 still showed presence of PCB, ranging from 80 to 590 ppm (microg/ml) with a mean value of 280 ppm. Upon completion of rebuilding, analysis of the R-Temp retro fill fluid showed 5 ppm at the initial power-up, increasing slightly to 16 ppm after 1 year of operation, which was far below the regulatory limit 50 ppm. The second transformer, by comparison, had a lower mean concentration of 54 ppm in the final fin rinse during decontamination. However, the backfill R-Temp showed an initial concentration of 38 ppm and remained essentially unchanged at 32 ppm after approximately 10 months of operation. Extensive comparison of GC and the quick test Clor-N-Oil kit were also carried out and showed generally good agreement. The use of an on-site GC was crucial in providing rapid and accurate analysis on-site, thus, enabling quick modifications to the decontamination strategies in order to meet the target PCB level. For projects of this nature, a GC/ECD was far superior to quick test kits by providing the selectivity and sensitivity for the diverse nature of the sample media.

Significant linkage for Tourette syndrome in a large French Canadian family.

Family and twin studies provide strong evidence that genetic factors are involved in the transmission of Gilles de la Tourette syndrome (TS) and related psychiatric disorders. To detect the underlying susceptibility gene(s) for TS, we performed linkage analysis in one large French Canadian family (127 members) from the Charlevoix region, in which 20 family members were definitely affected by TS and 20 others showed related tic disorders. Using model-based linkage analysis, we observed a LOD score of 3.24 on chromosome 11 (11q23). This result was obtained in a multipoint approach involving marker D11S1377, the marker for which significant linkage disequilibrium with TS recently has been detected in an Afrikaner population. Altogether, 25 markers were studied, and, for level of significance, we derived a criterion that took into account the multiple testing arising from the use of three phenotype definitions and three modes of inheritance, a procedure that yielded a LOD score of 3.18. Hence, even after adjustment for multiple testing, the present study shows statistically significant evidence for genetic linkage with TS.

Developmental changes in expression of myotonic dystrophy protein kinase in the rat central nervous system.

Myotonic dystrophy protein kinase (DMPK) is the protein product of the genetic locus associated with myotonic dystrophy, in which alterations of muscle excitability, cardiac conduction defects, mental retardation, and cognitive deficiencies are inherited as an autosomal dominant trait. DMPK belongs to a novel protein serine/threonine kinase family, but its regulation and physiological functions have not been specified. In a first step toward understanding the functions of DMPK in the central nervous system, we have characterized its localization and developmental pattern of expression in rat brain and spinal cord by using a monospecific rabbit antiserum produced against bacterially expressed DMPK. Expression of DMPK begins after birth and increases gradually to peak at postnatal day 21 with antibody labeling of neuronal cell types in many regions. After postnatal day 21 and proceeding to the adult, the pattern of expression becomes more restricted, with localization to certain regions or cell groups in the central nervous system. Electron microscopy reveals localization within adult spinal motor neurons to the endoplasmic reticulum and dendritic microtubules. The adult localizations suggest that DMPK may function in membrane trafficking and secretion within neurons associated with cognition, memory, and motor control.

Clinical and methodological factors related to reliability of the best-estimate diagnostic procedure.

OBJECTIVE: The reliability and accuracy of the best-estimate diagnostic procedure were examined, and factors associated with reliability were determined. METHOD: The subjects were 134 members of large multigenerational pedigrees densely affected by bipolar disorders or schizophrenia. Three best-estimate diagnoses were derived: first, by a research psychiatrist and research assistant unblind to the relatives' diagnoses; second, by two blind independent psychiatrists; third, by a panel of four blind psychiatrists. The subjects were characterized on several clinical and methodological variables, which were used to compare the agreements of two types of best-estimate diagnoses with the disagreements. RESULTS: There was satisfactory agreement between the unblind and blind consensus best-estimate diagnoses and between the two blind independent psychiatrists. Latent class analyses revealed that limited sensitivity was the main source of imperfect reliability. Confusability analyses revealed that the most problematic diagnostic distinctions involved schizoaffective disorder, which was confused with schizophrenia, bipolar I disorder, and schizophreniform disorder. Blindness significantly affected diagnostic outcome in latent class analyses. Moreover, for diagnostic disagreements, unblind diagnoses had greater continuity with the most predominant diagnosis in the pedigree than did blind diagnoses. Diagnostic disagreements were associated with the presence of mixed affective and psychotic symptoms, less diagnostic certainty, and shorter duration of illness. CONCLUSIONS: These results suggest that it is possible to identify cases that are more likely to lead to diagnostic disagreements in family and epidemiological studies and that blind diagnoses may help to prevent false positive diagnoses, which may be particularly detrimental to genetic linkage analyses.

6p24-22 region and major psychoses in the Eastern Quebec population. Le Groupe IREP.

Recent reports of a linkage trend in 6p24-22 for schizophrenia (SZ), in different samples, were tempered by the concurrent evidence of negative reports in other samples. In the studies showing positive results, different definitions of affection and a wide spectrum of diagnoses were used. Our objectives were not only to test for linkage at 6p24-22 in the Eastern Quebec population, but also to test whether this putative vulnerability locus was either selectively linked to schizophrenia (SZ), or to bipolar disorder (BP), or to both major psychoses. Parametric and nonparametric linkage analyses with 12 microsatellite markers in 6p24-p22 were performed on a sample of 18 large multigenerational pedigrees (N = 354) either affected by SZ, or by BP, or equally affected by both major psychoses (i.e., mixed pedigrees). Three affection definitions were usually tested in our program: one on schizophrenia (SZ), one on bipolar disorder (BP), and one that comprised SZ and BP under the hypothesis of a susceptibility locus common to both in major psychoses (common locus, CL). The results of parametric analyses did not support a major gene hypothesis. However, in one large mixed pedigree (#151), we observed with the common locus phenotype (CL) lod scores of 2.49 and 2.15, respectively, at the D6S296 and D6S277 loci under a dominant model. Our data suggest the presence of a potential vulnerability locus at 6p24-22 that could be related to both schizophrenia and bipolar affective disorder. These results may be seen as congruent with former studies that used schizoaffective as well as schizophrenia diagnoses as entry criteria for the affected families, and used an affection definition that comprised affective psychoses as well as schizophrenia.

The basis of intra-blood-brain-barrier IgG synthesis.

We hold that the intra-blood-brain-barrier (BBB) IgG synthesis (SYN) rate can be quantitated reliably and validly. Although several formulas distinguish patients with multiple sclerosis from normal controls equally well, only the SYN rate formula has been validated in humans using isotopic tracer techniques. Our formula for the IgG SYN rate is reducible to Reiber's formula; therefore, both can be used to quantify the IgG SYN rate in a manner not possible using the IgG index. Although our SYN rate formula has been validated for a modest range of BBB abnormalities (cerebrospinal fluid/serum albumin ratios), there is evidence to suggest that it may be used even in patients having severe BBB damage. We question the acceptance of unique cerebrospinal fluid IgG bands as indisputable evidence of intra-BBB IgG SYN in the presence of a modest to severely damaged BBB. Finally, the utility of quantitation and detection of intra-BBB IgG SYN by standardized methods in a group of asymptomatic, normal individuals compared with a group of patients with clinical definite multiple sclerosis is presented.

Multimodality evoked potentials and neurophysiological tests in multiple sclerosis. Effects of hyperthermia on test results.

Data on critical frequency of photic driving (CFPD), frequency following response (FFR), and visual, somatosensory (peroneal nerve), and brain-stem auditory evoked potentials (EPs) were obtained from 20 patients who had clinically definite multiple sclerosis and ten healthy normal subjects in a controlled, balanced study under normothermic and hyperthermic (+1 degrees C) conditions with a test-retest interval of one week. Normal subjects' test results showed no changes during hyperthermia. Patients' EP and CFPD data correlated well with history, clinical signs, and symptoms during both normothermia and hyperthermia. The FFR test data were equivocal and not fully analyzed. Data from the four other tests showed additional patient abnormalities during hyperthermia. Multimodality testing increased the number of patient abnormalities compared with single tests, and the number increased further during hyperthermia. Test-retest reproducibility was higher during hyperthermia.

Multiple sclerosis-specific central nervous system antigens (MSG2): a blind study.

A blinded study was designed to determine if a glycoprotein fraction, G2, shown in previous studies to be specific for multiple sclerosis (MS), could be isolated from cryopreserved autopsy central nervous system (CNS) tissue. Coded tissue sections were obtained from the Human Neurospecimen Bank, Los Angeles, Calif.; and the code was broken after all data were analyzed. Multiple sections of the CNS from 23 MS patients, 12 patients with other neurologic diseases (OND), and 10 individuals who died as a sudden death were utilized. Crossed immunoisoelectrophoresis (CIE) of G2 against anti-MS cytosol antibodies to MS-specific CNS antigens (MSG2) and tandem CIE of the G2 fraction with a known MSG2 preparation were carried out. MSG2 was found in one or more CNS sections from 78% of MS patients, all sections from MS spinal cord, and no sections from OND or control individuals. We propose that the MSG2 found in the MS CNS may contain a glycoprotein of a persistent virus, such as measles and/or myelin.

Intra-blood-brain barrier measles virus antibody synthesis in multiple sclerosis patients.

Antibodies to nine viruses were measured in serum and CSF of MS patients, patients with other neurologic diseases (OND), and healthy controls. The extent of antibody production inside the blood-brain barrier (BBB) was determined by making a new correction for BBB permeability. Compared with OND and healthy controls, MS patients as a group had significantly higher corrected CSF:serum antibody ratios for measles virus but not to the other eight viruses studied. The incidence of significantly high CSF:serum ratios for measles antibody in MS patients was 50%, and in the other two control groups it was 0 to 12%. The incidence of corrected antibody ratios to the other eight viruses was not significantly different among the three groups.

Cognition in Parkinson disease: an event-related potential perspective.

Auditory event-related potentials (ERP) elicited in a target detection stimulus paradigm and pattern-shift visual ERPs were studied in 20 male patients with idiopathic Parkinson disease (PD) and 20 age-matched normal controls. Patients showed significantly increased latencies for both the P200 and P300 components of the auditory ERP. Patients and controls showed no significant differences in latency of the visual ERP but patients showed significantly decreased amplitude. Only one of five neuropsychological measures, the Symbol Digit Modalities test (SDMT), showed a significant negative correlation with P300 latency. The significant association between the two measures that showed impairments in the PD patients (P300 latency and SDMT scores) suggested that these measures reflect a common, disrupted aspect of cognitive function in PD.

Endogenous event-related potentials: prospective applications in neuropsychology and behavioral neurology.

The primary neurologic application of event-related potentials (ERP) to date has been of relatively short-latency (less than 100-200 ms), stimulus-dependent components. These so-called exogenous components are used to evaluate the structural, and to a lesser extent, the functional integrity of primary afferent pathways. Another class of ERP, termed endogenous, and involving longer-latency (greater than 100 ms) stimulus-independent components has been utilized by psychologists and cognitive psychophysiologists in the measuring of neurocognitive processes. Although the experimental specification of these neurocognitial processes is still in its infancy, the empirical applications of endogenous ERP's offers considerable promise for objective non-invasive evaluations of cognitive functions now conducted only behaviorally. Initial neurocognitive ERP applications have focused on global mental status in dementia. A brief review is presented of experimental studies of some endogenous ERPs (mainly P300), their hypothesized underlying neurocognitive processes, and initial and potential clinical applications.

Multimodality evoked potentials: clinical applications and assessment of utility.

Visual evoked potentials (VEP), brain stem auditory evoked potentials (BAEP), somatosensory evoked potential (SEP), and long latency event related potentials (ERP) have been used to assess various aspects of the central nervous system. Multimodality evoked potential (MEP) testing uses a combination of these tests in the same clinical setting. In the diagnosis of multiple sclerosis and in the diagnosis of brain death, MEP testing has been shown to be more effective than any one evoked potential test used alone. In head trauma, MEP testing is an effective means of localization and prognostication. There are potential uses for MEP testing in Parkinson's Disease and uremia.

Parkinson's disease: Cogentin with Sinemet, a better response.

1. A randomized, placebo controlled, double-blind cross-over study was conducted to evaluate the clinical efficacy of the anticholinergic agent, benztropine mesylate (CogentinR) in 29 patients with mild to moderate, idiopathic Parkinson disease. 2. Patients were maintained on a stable, therapeutically optimal dosage and schedule of levadopa-carbidopa (Sinemet) throughout the study. 3. Both the neurologist's and the patient's global assessments of treatment efficacy indicated that Sinemet plus benztropine mesylate resulted in significantly greater improvement than Sinemet plus placebo. 4. Qualitative and quantitative evaluations of relevant neurologic functions showed small, but statistically significant improvements for rigidity, finger tapping speed and activities of daily living in patients during the Sinemet plus benztropine mesylate treatment period. 5. At the completion of the study 16 patients chose to continue taking benztropine mesylate as an adjuvant to Sinemet. 6. No important adverse side effects occurred during the study.