Role of myelination in the development of a uniform olivocerebellar conduction time

Purkinje cells generate simultaneous complex spikes as a result of olivocerebellar activity. This synchronization (to within 1 ms) is thought to result from electrotonic coupling of inferior olivary neurons. However, the distance from the inferior olive (IO) varies across the cerebellar cortex. Thus signals generated simultaneously at the IO should arrive asynchronously across the cerebellar cortex, unless the length differences are compensated for. Previously, it was shown that the conduction time from the IO to the cerebellar cortex remains nearly constant at approximately 4 ms in the rat, implying the existence of such compensatory mechanisms. Here, we examined the role of myelination in generating a constant olivocerebellar conduction time by investigating the latency of complex spikes evoked by IO stimulation during development in normal rats and myelin-deficient mutants. In normal rats, myelination not only reduced overall olivocerebellar conduction time, but also disproportionately reduced the conduction time to vermal lobules, which had the longest response latencies prior to myelination. The net result was a nearly uniform conduction time. In contrast, in myelin-deficient rats, conduction time differences to different parts of the cerebellum remained during the same developmental period. Thus myelination is the primary factor in generating a uniform olivocerebellar conduction time. To test the importance of a uniform conduction time for generating synchronous complex spike activity, multiple electrode recordings were obtained from normal and myelin-deficient rats. Average synchrony levels were higher in normal rats than mutants. Thus the uniform conduction time achieved through myelination of olivocerebellar fibers appears to be essential for the normal expression of complex spike synchrony.     

Emergence of a nephropathogenic avian infectious bronchitis virus with a novel genotype in India

We describe the emergence of a nephropathogenic avian infectious bronchitis virus (IBV) with a novel genotype in India. The Indian IBV isolate exhibited a relatively high degree of sequence divergence with reference strains. The highest homology was observed with strain 6/82 (68%) and the least homology with strain Mex/1765/99 (34.3%).     

Space-based inhibition of return in children with spina bifida

Inhibition of return (IOR) refers to an increase in time to react to a target in a previously attended location. Children with spina bifida meningomyelocele (SBM) and hydrocephalus have congenital dysmorphology of the midbrain, a brain region associated with the control of covert orienting in general and with IOR in particular. The authors studied exogenously cued covert orienting in 8- to 19-year-old children and adolescents (84 with SBM and 37 age-matched, typically developing controls). The exogenous cue was a luminance change in a peripheral box that was 50% valid for the upcoming target location. Compared with controls, children with SBM showed attenuated IOR in the vertical plane, a deficit that was associated with midbrain dysmorphology in the form of tectal beaking but not with posterior brain volume loss. The data add to the emerging evidence for SBM deficits in attentional orienting to salient information.     

DNA polymorphism of HLA class II genes in systemic lupus erythematosus

Abstract: We investigated the DNA restriction fragment length polymorphism (RFLP) of the major histocompatibility complex (MHC) genes: HLA-DRB, -DQA, -DQB, -DPB in 24 Danish patients with systemic lupus erythematosus (SLE) and in 102 healthy Danes. A highly significant increase of the frequency of the DR3- and DRw6-associated 7.00 kb DRB Taq I DNA fragment was found in SLE patients compared to normal controls (83.3% vs 35.5%; RR = 9.1, p < 10^-4). The frequencies of the DQA1*0501-associated 4.56 kb DQA Taq I fragment and the DRB3*01/03-associated 9.79 kb Taq I fragment were also found to be significantly increased in SLE patients (70.8% vs 29.7%; RR = 5.8, p < 10^-2 for the DQA fragment and 70.8% vs 36.1%; RR = 4.3, p < 0.05 for the DRB3 fragment). Less extensive and insignificant increases of the frequencies of the DR3-associated DQB and DPB fragments were observed. The frequencies of the DR2-associated DRB, DQA, and DQB fragments were comparable to those found in normal controls.     

Alcoholism and drug abuse in three groups — bipolar I, unipolars and their acquaintances

Objective: Previous work has shown that manic-depressive illness and alcohol abuse are linked. This study further explores the relationship of alcohol and drug abuse in bipolar I patients and unipolar depressives and a comparison group obtained through the acquaintance method. Method: Diagnosis was accomplished according to Research Diagnostic Criteria (RDC): controls=469; bipolars=277; unipolar depressives=678. Systematic data were gathered using the SADS on lifetime and current drug abuse and alcoholism. Both patients and comparison subjects were then followed prospectively for 10 years. First degree family members were interviewed using the RDC family history method. Results: The group of bipolar patients and the group of unipolar patients had higher rates of drug and alcohol abuse than the comparison group when primary and secondary affective disorder patients were combined. However, primary unipolar patients did not have higher rates of alcohol or drug abuse than the comparison group. In contrast, primary bipolar patients had higher rates of alcoholism, stimulant abuse, and ever having abused a drug than the primary unipolar group and the control group. In an evaluation of the bipolar patients, drug abusers were significantly younger at intake and had a significantly younger age of onset of bipolar disorder. There was a significant increase in family history of mania or schizoaffective mania in the drug-abusing bipolar patients as compared to the non-abusing bipolar patients. Limitation: As in all adult samples of patients with affective illness, the chronology of alcohol and substance problems vis-à-vis the onset of illness was determined retrospectively. Conclusions: (1) Alcoholism and drug abuse are more frequent in bipolar than unipolar patients. (2) The drug abuse of bipolar patients tends toward the abuse of stimulant drugs. (3) In a bipolar patient, familial diathesis for mania is significantly associated with the abuse of alcohol and drugs. (4) More provocatively, these findings suggest the hypothesis of a common familial-genetic diathesis for a subtype of bipolar I, alcohol and stimulant abuse. Clinical implications: The present analyses, coupled with two previous ones from the CDS, suggest that drug abuse may precipitate an earlier onset of bipolar I disorder in those who already have a familial predisposition for mania. Furthermore, in dually diagnosed patients with manic-depressive and alcohol/stimulant abuse history, mood stabilization of the bipolar disorder represents a rational approach to control concurrent alcohol and drug problems, and should be studied in systematic controlled trials.     

Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders

Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the "immunocannabinoid" system. This system can be an important signaling pathway for immune modulation. To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation. The CB2 cDNA 188-189 GG/GG polymorphism predicts the substitution of glutamine at amino acid position 63 by arginine. T lymphocytes from CB2 188-189 GG/GG homozygotes had approximately twofold reduction of endocannabinoid-induced inhibition of proliferation compared with cells from CB2 188-189 AA/AA homozygotes. In GG/GG subjects, the reduced endocannabinoid inhibitory response was highly significant for N-arachidonylglycine and nearly significant for 2-arachidonylglycerol, and a specific CB2 receptor antagonist partially blocked these effects. Also, patients with autoimmune diseases had an increased prevalence of the homozygous GG/GG genotype. Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188-189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity. The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses while avoiding CB1 receptor-mediated cannabinoid adverse effects.     

The comparative clinical phenotype and long term longitudinal episode course of bipolar I and II: a clinical spectrum or distinct disorders?

BACKGROUND: The present analyses were designed to compare the clinical characteristics and long-term episode course of Bipolar-I and Bipolar-II patients in order to help clarify the relationship between these disorders and to test the bipolar spectrum hypothesis. METHODS: The patient sample consisted of 135 definite RDC Bipolar-I (BP-I) and 71 definite RDC Bipolar-II patients who entered the NIMH Collaborative Depression Study (CDS) between 1978 and 1981; and were followed systematically for up to 20 years. Groups were compared on demographic and clinical characteristics at intake, and lifetime comorbidity of anxiety and substance use disorders. Subsets of patients were compared on the number and type of affective episodes and the duration of inter-episode well intervals observed during a 10-year period following their resolution of the intake affective episode. RESULTS: BP-I and BP-II had similar demographic characteristics and ages of onset of their first affective episode. Both disorders had more lifetime comorbid substance abuse disorders than the general population. BP-II had a significantly higher lifetime prevalence of anxiety disorders in general, and social and simple phobias in particular, compared to BP-I. Intake episodes of BP-I were significantly more acutely severe. BP-II patietns had a substantially more chronic course, with significantly more major and minor depressive episodes and shorter inter-episode well intervals. BP-II patients were prescribed somatic treatment a substantially lower percentage of time during and between affective episodes. LIMITATIONS: BP-I patients with severe manic course are less likely to be retained in long-term follow-up, whereas the reverse might be true for BP-II patients who are significantly more prone to depression (i.e., patients with less inclination to depression and with good prognosis may have dropped out in greater proportions); this could increase the gap in long term course characteristics between the two samples. The greater chronicity of BP-II may be due, in part, to the fact that the patients were prescribed somatic treatments substantially less often both during and between affective episodes. CONCLUSIONS: The variety in severity of the affective episodes shows that bipolar disorders, similar to unipolar disorders, are expressed longitudinally during their course as a dimensional illness. The similarities of the clinical phenotypes of BP-I and BP-II, suggest that BP-I and BP-II are likely to exist in a disease spectrum. They are, however, sufficiently distinct in terms of long-term course (i.e., BP-I with more severe episodes, and BP-II more chronic with a predominantly depressive course), that they are best classified as two separate subtypes in the official classification systems.     

Behavioral and hypnotic treatments for insomnia subtypes

This investigation compared progressive muscle relaxation plus cognitive distraction (PMR/CD), hypothesized to better improve sleep onset, versus sleep restriction and stimulus control (SR/SC), hypothesized to better improve sleep maintenance, versus a flurazepam (Dalmane) positive contrast condition (MED) and a sleep hygiene education minimal treatment control condition (SHE). Participants with chronic insomnia (N = 53), completed 2 baseline weeks of sleep diaries, and were randomly assigned to a treatment group for 2 more weeks. In the second phase, PMR/CD participants were assigned to 2 weeks of PMR/CD + SR/SC + SHE while SHE participants continued SHE. Results indicated that PMR/CD had greater effect upon sleep onset than SR/SC and SHE, SR/SC had greater effect on sleep maintenance than PMR/CD, and MED was better than the other treatments. In the second phase, the treatment package produced modest additional improvements and SHE performed superior to expectations.     

Delayed Hypersensitivity to Toxoplasma and Unrelated Antigens in Toxoplasma-Infected Mice: Induction and Elicitation of Delayed-Type Hypersensitivity by Antigen-Pulsed Macrophages

Delayed-type hypersensitivity (DTH) to Toxoplasma and unrelated antigens in Toxoplasma-infected BALB/c mice was investigated by the radioisotopic uptake method of Vadas et al. (Int. Arch. Allergy Appl. Immunol. 49: 670-692, 1975). DTH became positive on day 30 of infection and remained positive during chronic infection. The expression of DTH in mice infected with the relatively avirulent C37 strain of the parasite paralleled the Toxoplasma antibody response as detected by the Sabin-Feldman dye test. Mice sensitized with Toxoplasma, keyhole limpet hemocyanin, or sheep erythrocytes during the acute or chronic phase of Toxoplasma infection showed a DTH reaction similar to that of uninfected sensitized controls. No parasite antigens could be detected by immunofluorescence techniques on the surface of Toxoplasma-infected cells. When killed organisms were added to the cell cultures, specks of fluorescence appeared on cells containing intracellular parasites as well as on cells without intracellular organisms. That the antigens may be present in or on macrophages in a form readily recognizable by T cells is suggested by experiments in which we demonstrated that injection of uninfected normal macrophages pulsed with Toxoplasma-soluble antigens into the ears of chronically infected mice elicited a DTH reaction comparable to that observed when 10⁶ Formalin-fixed tachyzoites were used as the test antigen. When macrophages pulsed with Toxoplasma antigen were used in attempts to induce DTH in naive uninfected mice, the intensity of the reaction was similar to that observed in infected mice.