Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations.

BACKGROUND: Catechol-O-methyltransferase (COMT) is a strong candidate gene for schizophrenia and cognitive functions disrupted in this disorder. This report examines the relation of COMT genotypes to performance on a battery of working memory tests differing in the cognitive operations to be performed on the material. METHODS: A large sample of 402 healthy adults were tested on four working memory tests: Spatial Delayed Response (SDR), Word Serial Position Test (WSPT), N-back, and Letter-Number Sequencing. A subsample (n = 246) was tested on the Wisconsin Card Sorting Test (WCST). A saliva swab was used to obtain DNA from all participants. RESULTS: Letter-Number Sequencing, which requires both storage and manipulation of information, was the only working memory test that showed expected differences among COMT genotypes, with the met/met group showing the best performance and the val/val group the poorest performance. As in previous studies, the met/met group also performed better than the val/val group on the WCST. CONCLUSIONS: COMT genotypes were not associated with performance on tests measuring simple storage, maintenance of temporal order or updating of information in working memory. Genotype differences in Letter-Number Sequencing and WCST suggest that higher-order components of processing (e.g., mental manipulation) are more closely related to this gene.     

Experimental induction and ultrastructural characterization of apoptosis in murine acute cutaneous graft-versus-host disease

The skin is a primary target organ in acute graft-versus-host disease (GVHD). Recent results suggest that keratinocytes may undergo apoptosis in acute GVHD, although sequential structural evidence supporting this concept is lacking. The present study was undertaken to document and characterize apoptosis, confirmed by endonuclease-mediated DNA fragmentation, in experimental acute GVHD via sequential analysis of ultrastructure. Furthermore, we sought to define whether apoptosis is effector cell-dependent or -independent, and to document cell types responsible for the scavenging of apoptotic cells. Acute GVHD was produced across minor histocompatibility loci using appropriately matched murine strains and highly purified preparations of donor CD4 ⁺ and CD8 ⁺ T-cell subsets. Transmission electron microscopy was correlated with in situ labeling of double-stranded DNA breaks by the TUNEL (terminal uridine deoxynucleotidyl transferase end ligation) technique. Apoptotic cells were observed in all groups receiving T cells. Although most apoptotic cells were found in apposition with effector lymphocytes, a minority of apoptotic cells were detected at early time-points prior to lymphocytic infiltration. Heterogeneous cells, including macrophages, lymphocytes, Langerhans cells and keratinocytes were involved in scavenging putative target cells undergoing apoptosis. This study confirms the final pathway of target cell injury in acute GVHD to be apoptosis. In acute GVHD, apoptosis can be induced in the presence or absence of local effector cell influx, suggesting at least two mechanisms for the induction of epidermal target cell injury. Received: 13 September 1996     

Partial C4 deficiency in juvenile idiopathic arthritis patients.

OBJECTIVES: C4 is encoded by 2 distinct but closely linked loci within the major histocompatibility complex locus on human chromosome 6. C4A deficiencies have been associated with autoimmune disease and C4B with increased frequency of infection. C4 deficiencies have rarely been associated with juvenile idiopathic arthritis (JIA). Our aim was to investigate the prevalence of deficiencies in C4 allotypes in JIA patients. METHODS: We evaluated 61 patients [35 JIA patients, 15 systemic lupus erythematosus patients, 9 rheumatoid arthritis patients, and 2 mixed connective tissue disease (CTD) patients] for C4 deficiency. Genomic DNA was isolated from whole blood and subjected to polymerase chain reaction using sequence-specific primers for C4 allotypes. RESULTS: We found 5 JIA patients with C4 deficiencies. Two IgM rheumatoid factor-positive JIA polyarthritis patients had C4 deficiencies, one with complete C4A deficiency and another with partial C4A and complete C4B deficiency. Two oligoarthritis patients displayed partial C4B deficiencies, and complete C4B deficiency was revealed in 1 IgM rheumatoid factor-negative polyarthritis patient. Three patients had histories of recurrent infections and 2 demonstrated a more severe disease course. Disease controls showed 8 systemic lupus erythematosus patients had partial C4 deficiencies, whereas no deficiencies were revealed in the rheumatoid arthritis or mixed CTD patients. CONCLUSIONS: Defects in the complement system have been implicated in the pathogenesis of CTD. However, the specific role of C4 in JIA is not clear. We demonstrate partial C4 deficiencies in 5 JIA patients. Our findings suggest an association between C4 deficiency and another CTD, JIA, as well as with disease severity and recurrent infections.     

Individual Memory Change After Anterior Temporal Lobectomy: A Base Rate Analysis Using Regression-Based Outcome Methodology

Summary: Purpose: To characterize patterns of base rate change on measures of verbal and visual memory after anterior temporal lobectomy (ATL) using a newly developed regression-based outcome methodology that accounts for effects of practice and regression towards the mean, and to comment on the predictive utility of baseline memory measures on postoperative memory outcome. Methods: Memory change was operationalized using regression-based change norms in a group of left (n = 53) and right (n = 48) ATL patients. All patients were administered tests of episodic verbal (prose recall, list learning) and visual (figure reproduction) memory, and semantic memory before and after ATL. Results: ATL patients displayed a wide range of memory outcome across verbal and visual memory domains. Significant performance declines were noted for 25–50% of left ATL patients on verbal semantic and episodic memory tasks, while one-third of right ATL patients displayed significant declines in immediate and delayed episodic prose recall. Significant performance improvement was noted in an additional one-third of right ATL patients on delayed prose recall. Base rate change was similar between the two ATL groups across immediate and delayed visual memory. Approximately one-fourth of all patients displayed clinically meaningful losses on the visual memory task following surgery. Robust relationships between preoperative memory measures and nonstandardized change scores were attenuated or reversed using standardized memory outcome techniques. Conclusions: Our results demonstrated substantial group variability in memory outcome for ATL patients. These results extend previous research by incorporating known effects of practice and regression to the mean when addressing meaningful neuropscyhological change following epilepsy surgery. Our findings also suggest that future neuropsychological outcome studies should take steps towards controlling for regression-to-the-mean before drawing predictive conclusions.     

Volumetric MRI of the limbic system: anatomic determinants

The limbic system comprises the hippocampal formation, fornix, mamillary bodies, thalamus, and other integrated structures. It is involved in complex functions including memory and emotion and in diseases such as temporal lobe epilepsy. Volume measurements of the amygdala and hippocampus have been used reliably to study patients with temporal lobe epilepsy but have not extended to other limbic structures. We performed volume measurements of hippocampus, amygdala, fornix and mamillary bodies in healthy individuals. Measurements of the amygdala, hippocampus, fornix and mamillary bodies revealed significant differences in volume between right and left sides (P < 0.001). The intraclass coefficient of variation for measurements was high for all structures except the mamillary bodies. Qualitative image assessment of the same structures revealed no asymmetries between the hemispheres. This technique can be applied to the study of disorders affecting the limbic system. Received: 21 February 1997 Accepted: 6 August 1997     

A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps

We report a collection of tri- and tetranucleotide repeat sequencepolymorphic markers used to construct genome-wide human linkagemaps. Using a strategy of marker selection to create librarieshighly enriched for the presence of specific tandem repeat elements,we have developed over 2000 high heterozygosity, easy-to-usetn- and tetranucieotide short tandem repeat polymorphisms (STRPs).To date, over 1300 of these markers have been genotyped on theCEPH reference families. Additional STRPs were assigned to chromosomesusing human monochromosomal somatic cell hybrids. The linkagemaps constructed with these markers have been integrated withother CEPH genotypes into a comprehensive high density linkagemap. These STRPs have been shown to be robust for genotypingin a variety of laboratories using a variety of methods. Thehigh quality of these STRPs makes them ideal candidates foruse in genome-wide linkage searches. The integration of thesemarkers with physical mapping reagents and other genetic markerswill create a resource for moving from genome-wide linkage searchesto rapid subiocalization of disease loci.     

Circadian and genetic influences on tissue sensitivity and sleep time to ethanol in LS and SS mice

Circadian variations in response to ethanol were studied in long-sleep (LS) and short-sleep (SS) mice. Each LS animal received a 2.5 g/kg intraperitoneal ethanol injection, while the SS animals were injected with 4.1 or 5.0 g/kg. Different groups of mice were assessed for sleep time, waking blood alcohol concentration (BAC), and waking brain ethanol concentration (BREC) at 03.00, 09.00, 15.00, or 21.00 hr. Sleep times, waking BACs, and waking BRECs showed circadian variations in the LS mice. SS animals given the 4.1 g/kg dose showed circadian variations for waking BAC and waking BREC, but not for sleep time. The observed variations in the physiological parameters for these animals may have been confounded by a short sleep time so that they reflected circadian variations in drug absorption and/or distribution rather than in CNS sensitivity. SS mice given the 5.0 g/kg dose slept longer than those given the 4.1 g/kg dose and did not show circadian variations for sleep time, waking BAC, or waking BREC. These results suggest both circadian and genetic influences on tissue sensitivity to ethanol.     

HLA-A1, B8, DRw3 in patients with a distinct form of lupus erythematosus

Subacute cutaneous LE was identified by the presence of widespread nonscarring skin lesions with histologic features of LE. The HLA antigens A1,B8,DRw3 were increased in patients with this condition. The frequency of DRw3 in this group was 77% compared to 24% in controls (p less than 0.001). The relative risk with HLA-DRw3 for the subacute cutaneous LE group was 10.8 (p less than 0.001). HLA-A1,B8 antigens were not increased in discoid LE or in the systemic LE group. The results illustrate the value of identifying homogeneous groups of patients for finding meaningful HLA associations.     

Monoclonal antibodies to human platelet glycoprotein IIb beta that initiate distinct platelet responses

Hybridomas secreting monoclonal antibodies (MoAbs) to human platelet membrane glycoprotein IIb (GPIIb) were prepared by fusing cells of a mouse myeloma line to spleen cells from a BALB/c mouse immunized with purified GPIIb. Six of the hybridomas secreted MoAbs that recognized epitopes on the 23,000-dalton, disulfide-linked subunit of GPIIb, GPIIb beta. All six of these MoAbs agglutinated platelets in the absence of calcium. The agglutination titers of three of the MoAbs, however, were enhanced between 2 and 6 log2 dilutions when titrated in the presence of mmol/L of calcium. The enhancement in titer was the result of MoAb- induced platelet activation followed by platelet aggregation, a reaction that could also be initiated by the monovalent Fab fragments prepared from one of the MoAbs. The MoAbs did not significantly agglutinate platelets from patients with Glanzmann's thrombasthenia, confirming biochemical evidence that there is a paucity of GPIIb beta in the membranes of these cells. Our results show that MoAbs to epitopes on GPIIb beta initiate distinct platelet responses; therefore, they should be useful for studying the ways in which regions of surface glycoproteins are involved in platelet-platelet interactions. In addition, these reagents may prove of value in diagnosing and typing patients with Glanzmann's thrombasthenia.