Observations on pine susceptibility to weevils /

"September, 1960."

Tumour susceptibility to innate and adaptive immunotherapy changes during tumour maturation

Immunotherapy of tumours using T cells expanded in vitro has met with mixed clinical success suggesting that a greater understanding of tumour/T-cell interaction is required. We used a HPV16E7 oncoprotein-based mouse tumour model to study this further. In this study, we demonstrate that a HPV16E7 tumour passes through at least three stages of immune susceptibility over time. At the earliest time point, infusion of intravenous immune cells fails to control tumour growth although the same cells given subcutaneously at the tumour site are effective. In a second stage, the tumour becomes resistant to subcutaneous infusion of cells but is now susceptible to both adjuvant activated and HPV16E7-specific immune cells transferred intravenously. In the last phase, the tumour is susceptible to intravenous transfer of HPV16E7-specific cells, but not adjuvant-activated immune cells. The requirement for IFN-gamma and perforin also changes with each stage of tumour development. Our data suggest that effective adoptive T-cell therapy of tumour will need to be matched with the stage of tumour development.

Genetic screening for susceptibility to depression: can we and should we?

Objective: To summarize current knowledge about genetic susceptibility to mood disorders and examine ethical and policy issues that will need to be addressed if robustly replicated susceptibility alleles lead to proposals to screen and intervene with persons at increased genetic risk of developing mood disorders. Method: Empirical studies and reviews of the genetics of unipolar and bipolar depression were collected via MEDLINE and psycINFO database searches. Results: A number of candidate genes for depression have been identified, each of which increases the risk of mood disorders two- or threefold. None of the associations between these alleles and mood disorders have been consistently reported to date. Conclusions: Screening the population for genetic susceptibility to mood disorders is unlikely to be a practically useful policy (given plausible assumptions). Until there are effective treatments for persons at increased risk, screening is arguably unethical. Screening within affected families to advise on risks of developing depression would entail screening children and adolescents, raising potentially serious ethical issues of consent and stigmatization. Genetic research on depression should continue under appropriate ethical guidelines that protect the interests of research participants.

Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia

Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia - and, more recently, for bipolar disorder - on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P = .0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.

Identification of the semaphorin receptor PLXNA2 as a candidate for susceptibility to schizophrenia

The discovery of genetic factors that contribute to schizophrenia susceptibility is a key challenge in understanding the etiology of this disease. Here, we report the identification of a novel schizophrenia candidate gene on chromosome 1q32, plexin A2 (PLXNA2), in a genome-wide association study using 320 patients with schizophrenia of European descent and 325 matched controls. Over 25 000 single-nucleotide polymorphisms (SNPs) located within approximately 14 000 genes were tested. Out of 62 markers found to be associated with disease status, the most consistent finding was observed for a candidate locus on chromosome 1q32. The marker SNP rs752016 showed suggestive association with schizophrenia (odds ratio (OR) = 1.49, P = 0.006). This result was confirmed in an independent case control sample of European Americans (combined OR = 1.38, P = 0.035) and similar genetic effects were observed in smaller subsets of Latin Americans (OR = 1.26) and Asian Americans (OR = 1.37). Supporting evidence was also obtained from two family-based collections, one of which reached statistical significance (OR = 2.2, P = 0.02). High-density SNP mapping showed that the region of association spans approximately 60 kb of the PLXNA2 gene. Eight out of 14 SNPs genotyped showed statistically significant differences between cases and controls. These results are in accordance with previous genetic findings that identified chromosome 1q32 as a candidate region for schizophrenia. PLXNA2 is a member of the transmembrane semaphorin receptor family that is involved in axonal guidance during development and may modulate neuronal plasticity and regeneration. The PLXNA2 ligand semaphorin 3A has been shown to be upregulated in the cerebellum of individuals with schizophrenia. These observations, together with the genetic results, make PLXNA2 a likely candidate for the 1q32 schizophrenia susceptibility locus.

Twin study of adolescent genetic susceptibility to mosquito bites using ordinal and comparative rating data

Ordinal and comparative rating measures of mosquito attraction and mosquito bite frequency and symptoms were administered in a self-report questionnaire format to a sample of 197 monozygotic and 326 dizygotic Australian adolescent twin pairs at age 12 between 1992 and 1999, in order to investigate the environmental and possibly genetic determinants of variation between individuals. Repeat measures were obtained from the twin pairs at age 14. Ordinal variable measures, although providing some support for genetic effects on mosquito susceptibility, were affected by low repeatability. However, analysis of a comparative rating variable compared with your twin, who is bitten by mosquitoes more often? indicated a strong genetic influence on frequency of being bitten by mosquitoes, with no significant differences observed between males and females. Comparative rating questionnaire items are a potentially valuable tool for complementing and improving the results obtained from more conventional absolute measures. (C) 2000 Wiley-Liss, Inc.

Susceptibility to pattern glare following stroke

The aim of this work was to measure susceptibility to pattern glare within a stroke group, employing a direct method of assessment. Twenty stroke subjects, aged 38-85 years, were recruited, along with an age-matched control group (n = 20). Assessment of pattern glare susceptibility was undertaken using the pattern glare test. An abnormal degree of pattern glare is present when individuals score >1 on the mid-high spatial frequency difference variable, a relative score that allows for normalization of the subject, or >3 when viewing the mid spatial frequency grating. Stroke subjects demonstrate elevated levels of pattern glare compared to normative data values and a control population, as determined using the pattern glare test. This was most notable when considering the output measure for the mid-high difference variable. The mean score for the mid-high difference variable was 2.15 SD 1.27 for the stroke subjects versus 0.10 SD 1.12 for the control subjects. When considering the mid-high difference variable, 75% of the stroke group recorded an abnormal level of pattern glare compared to 5% in the control group. This study demonstrates an association between stroke subjects and elevated levels of pattern glare. Cortical hyperexcitability has been shown to present following stroke, and this has been proposed as a plausible explanation for the perceptual distortions experienced by individuals susceptible to pattern glare. Further work to assess the benefits of spectral filters in reducing perceptual distortions in stroke patients is currently underway.

Circadian gene variants and susceptibility to type 2 diabetes:a pilot study

Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs) in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants.

Susceptibility to pattern glare and the effect of spectral filters on rate of reading and visual search in stroke patients

The present thesis investigates pattern glare susceptibility following stroke and the immediate and prolonged impact of prescribing optimal spectral filters on reading speed, accuracy and visual search performance. Principal observations: A case report has shown that visual stress can occur following stroke. The use of spectral filters and precision tinted lenses proved to be a successful intervention in this case, although the parameters required modification following a further stroke episode. Stroke subjects demonstrate elevated levels of pattern glare compared to normative data values and a control group. Initial use of an optimal spectral filter in a stroke cohort increased reading speed by ~6% and almost halved error scores, findings not replicated in a control group. With the removal of migraine subjects reading speed increased by ~8% with an optimal filter and error scores almost halved. Prolonged use of an optimal spectral filter for stroke subjects, increased reading speed by >9% and error scores more than halved. When the same subjects switched to prolonged use of a grey filter, reading speed reduced by ~4% and error scores increased marginally. When a second group of stroke subjects used a grey filter first, reading speed decreased by ~3% but increased by ~3% with prolonged use of an optimal filter, with error scores almost halving; these findings persisted with migraine subjects excluded. Initial use of an optimal spectral filter improved visual search response time but not error scores in a stroke cohort with migraine subjects excluded. Neither prolonged use of an optimal nor grey filter improved response time or reduced error scores in a stroke group; these findings persisted with the exclusion of migraine subjects.

The role of apoptotic cell clearance in a high-lipid environment:links to ageing

Individuals within the aged population show an increased susceptibility to infection, implying a decline in immune function, a phenomenon known as immunosenescence. Paradoxically, an increase in autoimmune disease, such as rheumatoid arthritis, is also associated with ageing, therefore some aspects of the immune system appear to be inappropriately active in the elderly. The above evidence suggests inappropriate control of the immune system as we age. Macrophages, and their precursors monocytes, play a key role in control of the immune system. They play an important role in host defence in the form of phagocytosis, and also link the innate and adaptive immune system via antigen presentation. Macrophages also have a reparative role, as professional phagocytes of dead and dying cells. Clearance of apoptotic cells by macrophages has also been shown to directly influence immune responses in an anti-inflammatory manner. Inappropriate control of macrophage function with regards to dead cell clearance may contribute to pathology as we age. The aims of this study were to assess the impact of lipid treatment, as a model of the aged environment, on the ability of macrophages to interact with, and respond to, apoptotic cells. Using a series of in vitro cell models, responses of macrophages (normal and lipid-loaded) to apoptotic macrophages (normal and lipid-loaded) were investigated. Monocyte recruitment to apoptotic cells, a key process in resolving inflammation, was assessed in addition to cytokine responses. Data here shows, for the first time, that apoptotic macrophages (normal and lipid-loaded) induce inflammation in human monocyte-derived macrophages, a response that could drive inflammation in age-associated pathology e.g. atherosclerosis. Monoclonal antibody inhibition studies suggest the classical chemokine CX3CL1 may be involved in monocyte recruitment to apoptotic macrophages, but not apoptotic foam cells, therefore differential clearance strategies may be employed following lipid-loading. CD14, an important apoptotic cell tethering receptor, was not found to have a prominent role in this process, whilst the role for ICAM-3 remains unclear. Additionally, a small pilot study using macrophages from young (<25) and mid-life (>40) donors was undertaken. Preliminary data was gathered to assess the ability of primary human monocyte-derived macrophages, from young and mid-life donors, to interact with, and respond to, apoptotic cells. MØ from mid-life individuals showed no significant differences in their ability to respond to immune modulation by apoptotic cells compared to MØ from young donors. Larger cohorts would be required to investigate whether immune modulation of MØ by apoptotic cells contribute to inflammatory pathology throughout ageing.

Susceptibility to chlorhexidine amongst multidrug-resistant clinical isolates of Staphylococcus epidermidis from bloodstream infections

We thank the staff of the Aberdeen Clinical Diagnostic Laboratory and the Centre for Genome-Enabled Biology and Medicine of the University of Aberdeen for their dedicated support to this study.