Studies on the molecular immunogenetics of class II histocompatibility antigens in multiple sclerosis

Serological studies of HLA antigens in a number of different populations over many years have clearly demonstrated that MS is associated with particular products of the Major Histocompatibility Complex Class II region, particularly DR2/Dw2 and DQw1. It is widely accepted that immune mechanisms are responsible for the demyelination seen in MS, and there is a good deal of circumstantial evidence in favour of an autoimmune pathogenesis. Furthermore, it is now well established that MHC gene products play a pivotal role in T cell activation, and this raises the possibility that a true disease susceptibility gene might be encoded in the MHC. It has also been suggested that the rate of disease progression might be influenced by the MHC in a similar way. Since the genes encoded by the MHC exhibit at the genetic level an extraordinary degree of polymorphism, much of which is not detectable using serological techniques, genetic methods have been employed to investigate further the association between MS and the Class II region. An extensive analysis of restriction fragment length polymorphism of the Class II region was carried out in an attempt to identify genetic markers more strongly associated with MS than the classical serological markers. Initial studies using pooled DNA samples from patients and controls from the Grampian region of Northeast Scotland enabled the screening of 14 restriction endonucleases with five HLA-D region probes (DPA, DPB, DQA, DQB and DRB). A small number of discriminatory polymorphisms were observed with the DQ probes, although none with DP or DR. Based on these data, further studies were carried out on individual samples of DNA from 33 MS patients and 48 controls from the Grampian region. By identifying a number of DQA and DQB fragments of known specificity, it could be demonstrated that almost all of the antigens that typed serologically as DR2 and DQw1 were encoded by the Dw2 DQw6 alleles of DR and DQ, and also that these alleles were represented equally in both patients and controls. However, following Msp1 digestion and hybridization to a DQA1 probe a cluster of fragments was observed significantly more frequently in the patients (p<0.001), and furthermore, this association was found to be independent of DR2. These findings were confirmed in an independently conducted collaborative study in Northern Ireland. The DQA restriction fragment duster was further characterized by means of established RFLP allogenotyping systems. The cluster was seen in all DRw8 (DQw4) homozygous cell lines included in the Tenth International Histocompatibility Workshop, and in some DR4 and DR7 lines, but not in caucasoid DR2 lines. In a panel of healthy British donors, the cluster was again seen most commonly in association with DQw4 or E>Qw8. The apparent allelism thus demonstrated by the cluster raised the possibility that disease susceptibility was associated with transcomplementation between the DR2-positive and DQA cluster-positive haplotypes. Since the putative allele marked by the DQA cluster possessed many of the features of DQw4, an allele which is thought to be uncommon in caucasoids, an attempt to demonstrate this directly using monoclonal serology was made. A number of lymphoblastoid cell lines were raised from Scottish MS patients and their families, and studied using the DQw4 β chain-specific antibody HU46. However, the relation between the cluster and HU46 reactivity, though close, was not exact. Although 5 out of 6 HU46-reactive cell lines were cluster-positive, 3 out of 8 cluster-positive lines were HU46 non-reactive. In order to demonstrate that the DQA cluster corresponded to an expressed DQ α polymorphism, attempts were made to raise alloreactive T cell clones against cluster-positive cell lines. Using cloning strategies designed to eliminate the possibility of generating clones against the 'cluster-negative' haplotype, a number of CD4-positive clones were raised and maintained in stable culture. However, analysis of the fine specificities of these clones failed to demonstrate reactivity corresponding exclusively to the DQA cluster. DQα1-encoding exons from 3 cluster-positive Scottish MS patients, 2 unaffected siblings from multiple case families and 2 cluster-positive homozygous cell lines were amplified enzymatically by the polymerase chain reaction, and probed with allele-specific oligonucleotides. The data obtained suggested that in each case, the cluster-positive haplotype contained the DQA allele predicted by the linked DR genotype, and thus that the DQA cluster did not correspond to an expressed member of the DQA allelic series. This conclusion was confirmed by analysing the nucleotide sequences of PCR-amplified DQA α1-encoding exons from selected cluster-positive haplotypes. Taken together, these data suggest that an MS-associated polymorphism, detectable by RFLP analysis, lies in noncoding regions adjacent to the DQA gene

Patient preference as a predictor of outcomes in a pilot trial of person-centred counselling versus low-intensity cognitive behavioural therapy for persistent sub-threshold and mild depression

The aim of this analysis was to explore whether pre-treatment intervention preferences were related to outcomes for patients with persistent sub-threshold and mild depression who received one of two treatment types. Thirty-six patients took part in a two-arm, parallel group, pilot randomized controlled trial that compared short term (3 month and 6 month) outcomes of person-centred counselling (PCC) compared with low-intensity, CBT-based guided self-help (LICBT). Patient preferences for the two interventions were assessed at baseline assessment, and analysed as two independent linear variables (pro-PCC, pro-LICBT). Eight out of 30 interactions between baseline treatment preferences and treatment type were found to be significant at the p &lt; .05 level. All were in the predicted direction, with patients who showed a stronger preference for a treatment achieving better outcomes in that treatment compared with the alternative. However, pro-LICBT was a stronger predictor of outcomes than pro-PCC. The findings provide preliminary support that treatment preferences should be taken into account when providing interventions for patients with persistent sub-threshold and mild depression. It is recommended that further research analyses preferences for different treatment types as independent variables, and examines preferences for format of treatment (e.g. guided self-help vs. face-to-face)

Population Ecology of Caribou Populations without Predators: Southampton and Coats Island Herds

This paper is a review of the ecology of two caribou populations inhabiting predator-free northern islands, Coats and Southampton Island. Findings are analyzed in light of the hypothesis that in absence of pr&eacute;dation or high human harvest, food competition results in delayed puberty, reduced calf production, increased winter starvation of caribou and regulates populations at high densities (&gt;2 km-2). Caribou were hunted to extinction on Southampton Island (Northwest Territories, Canada) by mid-century. In 1967, 48 caribou were captured on neighbouring Coats Island and released on Southampton Island. Southampton Island is characterized by a high per capita winter food availability in summer and in winter. The population on Southampton Island has been increasing at a rapid rate of growth since re-introduction (Lamba=1.27). Fast population growth was possible because females invested early in reproduction and over winter survival rate was high. The population on Coats Island is also characterized by high per capita food availability in summer but low food availability in winter. The population size has undergone some marked fluctuations, abrupt declines followed by relatively rapid recovery and, contrary to predictions, densities were always less than 1 km-2. Low population densities on Coats Island result primarily from low food availability. This review suggests that in the absence of pr&eacute;dation or high human harvest competition for food regulates caribou population abundance. However, caribou numbers can fluctuate markedly among years because inter-annual variation of weather conditions affects forage accessibility in winter. This review also emphasizes the importance of distinguishing between factors that determine absolute population density and variation in density among years (in our case probably plant production and winter weather conditions which influence forage accessibility) from the regulatory factors, processes that stop population increase (competition for winter food leading primarily to density dependent changes in mortality from starvation) when examining population dynamics

Records of Zygopa michaelis Holthuis, 1960 (Decapoda: Anomura: Albuneidae) from the Gulf of Mexico

The albuneid mole crab, Zygopa michaelis Holthuis, 1960, which was originally described from Curaçao and recently reported from the Florida East coast (Gore and Becker 1977), is reported from the Gulf of Mexico off the Florida West coast. Of the seven specimens collected, six were taken in 38 m of water off Fort Myers and one in 42 m on the Florida Middle Ground. All seven specimens occurred in substrata composed primarily of carcareous sand

Co-administration of fish oil with signal transduction inhibitors has anti-migration effects in breast cancer cell lines, in vitro

Background: There is an urgent need for new therapies to treat cancer metastasis. Fish oil, with high omega 3 fatty acid content, has shown anticancer activity and signal transduction inhibitors have shown anti-metastatic properties. Objective: To provide preliminary in vitro data on the anti-migration potential of signal transduction inhibitors and co-administered fish oil. Methods: MCF-7, TamR and FasR breast cancer cell lines were used to determine the effects of combinations of PD98059, LY294002 and fish oil in growth assays. Modulations of p-Src and COX-2, both mediators of motility and invasion, were then determined by Western blotting and IHC to ascertain effects on migration potential. Results: Migration rates for the three cell lines examined were ranked: FasR>TamR>MCF-7 (p <0.05). Addition of fish oil reduced the number of TamR cells migrating after 48h (p <0.05), while the addition of PD98059 and LY294002 also decreased migratory potential of TamR cells (p <0.05). Addition of PD98059 and LY294002 to TamR cells did not result in a significant decrease in p-Src levels; as was the case when PD98059, LY294002 and 4-hydroxytamoxifen were added to MCF-7 cells. However, the co-administration of fish oil markedly reduced p-Src and COX-2 expression in both cell lines. Conclusion: Co-administration of a commercial fish oil with signal transduction inhibitors results in decreased cell migration via an unknown co-operative mechanism and could constitute a novel approach for the treatment of breast cancer metastasis

A Source for Feature-Based Attention in the Prefrontal Cortex

SummaryIn cluttered scenes, we can use feature-based attention to quickly locate a target object. To understand how feature attention is used to find and select objects for action, we focused on the ventral prearcuate (VPA) region of prefrontal cortex. In a visual search task, VPA cells responded selectively to search cues, maintained their feature selectivity throughout the delay and subsequent saccades, and discriminated the search target in their receptive fields with a time course earlier than in FEF or IT cortex. Inactivation of VPA impaired the animals’ ability to find targets, and simultaneous recordings in FEF revealed that the effects of feature attention were eliminated while leaving the effects of spatial attention in FEF intact. Altogether, the results suggest that VPA neurons compute the locations of objects with the features sought and send this information to FEF to guide eye movements to those relevant stimuli

The adult perceptual limen of syllable segregation in typically developing paediatric speech

Inappropriate gaps between syllables are one of the core diagnostic features of both childhood apraxia of speech and acquired apraxia of speech. However, little is known about how listeners perceive and identify inappropriate pauses between syllables (gap detection). Only one previous study has investigated the perception of inappropriate pauses between syllables in typical adult speakers and no investigations of gap detection in children's speech have been undertaken. The purpose of this research was to explore the boundaries of listener gap detection to determine at which gap length (duration) a listener can perceive that an inappropriate pause is present in child speech. Listener perception of between-syllable gaps was explored in an experimental design study using the online survey platform Qualtrics. Speech samples were collected from two typically developing children and digitally manipulated to insert gaps between syllables. Adult listeners (n = 84) were recruited and could accurately detect segregation on 80% of presentations at a duration between 100 and 125 ms and could accurately detect segregation on 90% of presentations at a duration between 125 and 150 ms. Listener musical training, gender and age were not correlated with accuracy of detection, but speech pathology training was, albeit weakly. Male speaker gender, and strong onset syllable stress were correlated with increased accuracy compared to female speaker gender and weak onset syllable stress in some gap conditions. The results contribute to our understanding of speech acceptability in CAS and other prosodic disorders and moves towards developing standardised criteria for rating syllable segregation. There may also be implications for computer and artificial intelligence understanding of child speech and automatic detection of disordered speech based on between syllable segregation