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TLR4 haplotypes in alcohol and opioid dependent populations
Abstracts / Brain, Behavior, and Immunity 24 (2010) S1–S71
anxiety-like, LOA: more anxiety-like). We also performed molecular studies at mRNA level of the IL-2 receptor and imaging studies in the brain to further analyse the physiological changes underlying the behavioural effects upon a single peripheral IL-2 treatment. Results differentially decreased social interaction only in IL-2 treated LOA compared to vehicle LOA rats, but not in IL-2 treated HOA animals. In addition, IL-2 did not affect rectal body temperature or body weight. This suggests an anxiogenic-like effect of IL-2 dependent on pre-existing traits, presumably independent of sickness behaviour. Furthermore, IL-2 treatment showed significant changes in the IL-2 receptor transcription in discrete brain regions involved in anxiety-like behaviours (hippocampus, striatum). Finally, metabolites (e.g., myo-inositol, creatine) detected by 9.4 T MRS were significantly increased upon peripheral IL-2 treatment, in both hippocampus and prefrontal cortex. Support contributed by: DFG PA 818/4-1. doi:10.1016/j.bbi.2010.07.079
Abstract # 297 Intracerebral hemorrhage in African American populations: Pertinent outcomes and risk factors K.C. Colter, R. Gupta, A. Jayam Trouth Howard University College of Medicine, Washington, DC 20001, United States
S25
Background: Animal studies suggested a significant role for cellular immunity in controlling circulating cancer cells, but most patients’ tumor cells seem resistant, in vitro, to NK and CTL cytotoxicity. Addressing this apparent contradiction we search for and identified a unique leukocyte population in rats, marginatingpulmonary (MP)-leukocytes, which exhibit potent NK cytotoxicity. Here we further characterize the MP- and marginating-liver (ML) compartments in naïve and immunostimulated rats. Methods: Animals were treated with poly I-C or saline, and circulating, MP- and ML-leukocytes were collected and analyzed for cellular composition; NK cytotoxicity against various syngeneic, allogeneic, and xenogeneic tumor cells; and cytokine mRNA and their induced production by poly I-C, LPS and CpG. Results: Compared to circulating-leukocytes, MP- and/or ML-leukocytes showed (i) greater proportion of granulocytes, monocytes, and NK cells, (ii) elevated proinflammatory cytokine mRNA levels (IL1b, IFNg, GRAb) and elevated induced productions (IL1b, IL6), (iii) elevated NK cytotoxicity against several syngeneic and xenogeneic NK-resistant target cells, and (iv) uniquely augmented NK cytotoxicity following in vitro activation. Conclusions: It is suggested that the MP- and ML-compartments are characterized by a continuous activated/inflammatory microenvironment, which is further uniquely triggered by systemic or in vitro immunostimulation. If similarly potent MP/ML-compartments exist in patients, then the role of innate immunity in resisting tumor progression has been underestimated, and these unique immune compartments should be targets to PNI studies. doi:10.1016/j.bbi.2010.07.081
Intracerebral hemorrhage (ICH) is a significant cause of death in the African American population in the United States. African Americans are also at a higher risk for this disease than other populations. The current literature is very limited regarding the clinical characteristics, demographics, and outcomes of African American patients with ICH so we investigated these parameters in this study. Medical records and CT scans were reviewed and documented data was collected regarding demographics, risk factors, social habits and co morbidities of all patients admitted to the Howard University Hospital between July 2007 and June 2009. Variables collected included medication usage, poly substance use, site of hemorrhage, and mortality data. Subarachnoid hemorrhage (SAH) was also included in the data collection. Among 45 ICH patients with an average age of 57, 42% were females who also had higher mortality. Seventy-six percent had preexisting hypertension as a risk factor and 52% were either noncompliant or the status was not known regarding their medication intake. Also noticed were increased rates of SAH (9/45) and Intraventricular hemorrhage (IVH, 4/45). The overall mortality was 29% (male 53% vs F 47%). Hypertension remains the most common risk factor in spontaneous ICH and polysubstance abuse was interestingly higher in females. ICH mortality was less as compared to the literature available (50%), but SAH and IVH rates were comparatively increased with IVH mortality being 100%. doi:10.1016/j.bbi.2010.07.080
Abstract # 298 The marginating immune compartments in rats’ lungs and liver: Characteristics of continuous inflammation and unique activation potential R. Melamed, M. Benish, E. Rosenne, Y. Goldfarb, B. Levi, S. Ben-Eliyahu TAU, Tel-Aviv, Israel
Abstract # 299 TLR4 haplotypes in alcohol and opioid dependent populations J.K. Coller, Y. Wu, J.M. White, M.R. Hutchinson, A.A. Somogyi University of Adelaide, Pharmacology, Level 5, Medical School North, Frome Rd, Adelaide, SA 5005, Australia Up to 60% of alcohol and opioid dependence is heritable. The role of immunogenetics has recently been highlighted via the association between interleukin-1 beta genotypes with opioid and alcohol dependence (Liu L et al, Pharmacogenetics and Genomics 2009;19:869–76). This study examined the role of genetic variants in the innate immune receptor, Toll Like receptor 4 (TLR4), in opioid and alcohol dependence. TLR4 haplotypes (specific combinations of A896G and C1196T variants) were determined in 90 opioid and 93 alcohol dependent, and 74 healthy non-dependent controls. Frequencies of the variants between the groups were compared with Fisher’s Exact test with odds ratios (OR) and chi-square tests. There was no difference in variant frequencies (allele or genotype) of either SNP between the dependent and non-dependent control populations: OR 0.86–1.14, p = 0.1. Similarly, there was no difference in the frequencies of the two haplotypes observed between the opioid dependent and non-dependent groups, respectively: AC 95 and 95.3%, GT 5 and 4.7%. In the alcohol dependent group 4 haplotypes were observed, including 2 that were novel: AC (94%), AT (1.1%), GC (0.5%) and GT (4.4%). However, owing to small subject number carrying these novel haplotypes, the difference in the frequency of these across the 3 groups is not yet significant p = 0.49. Nonetheless, these unique TLR4 haplotypes may be associated with alcohol dependence; large-scale replicate studies are ongoing. doi:10.1016/j.bbi.2010.07.082
anxiety-like, LOA: more anxiety-like). We also performed molecular studies at mRNA level of the IL-2 receptor and imaging studies in the brain to further analyse the physiological changes underlying the behavioural effects upon a single peripheral IL-2 treatment. Results differentially decreased social interaction only in IL-2 treated LOA compared to vehicle LOA rats, but not in IL-2 treated HOA animals. In addition, IL-2 did not affect rectal body temperature or body weight. This suggests an anxiogenic-like effect of IL-2 dependent on pre-existing traits, presumably independent of sickness behaviour. Furthermore, IL-2 treatment showed significant changes in the IL-2 receptor transcription in discrete brain regions involved in anxiety-like behaviours (hippocampus, striatum). Finally, metabolites (e.g., myo-inositol, creatine) detected by 9.4 T MRS were significantly increased upon peripheral IL-2 treatment, in both hippocampus and prefrontal cortex. Support contributed by: DFG PA 818/4-1. doi:10.1016/j.bbi.2010.07.079
Abstract # 297 Intracerebral hemorrhage in African American populations: Pertinent outcomes and risk factors K.C. Colter, R. Gupta, A. Jayam Trouth Howard University College of Medicine, Washington, DC 20001, United States
S25
Background: Animal studies suggested a significant role for cellular immunity in controlling circulating cancer cells, but most patients’ tumor cells seem resistant, in vitro, to NK and CTL cytotoxicity. Addressing this apparent contradiction we search for and identified a unique leukocyte population in rats, marginatingpulmonary (MP)-leukocytes, which exhibit potent NK cytotoxicity. Here we further characterize the MP- and marginating-liver (ML) compartments in naïve and immunostimulated rats. Methods: Animals were treated with poly I-C or saline, and circulating, MP- and ML-leukocytes were collected and analyzed for cellular composition; NK cytotoxicity against various syngeneic, allogeneic, and xenogeneic tumor cells; and cytokine mRNA and their induced production by poly I-C, LPS and CpG. Results: Compared to circulating-leukocytes, MP- and/or ML-leukocytes showed (i) greater proportion of granulocytes, monocytes, and NK cells, (ii) elevated proinflammatory cytokine mRNA levels (IL1b, IFNg, GRAb) and elevated induced productions (IL1b, IL6), (iii) elevated NK cytotoxicity against several syngeneic and xenogeneic NK-resistant target cells, and (iv) uniquely augmented NK cytotoxicity following in vitro activation. Conclusions: It is suggested that the MP- and ML-compartments are characterized by a continuous activated/inflammatory microenvironment, which is further uniquely triggered by systemic or in vitro immunostimulation. If similarly potent MP/ML-compartments exist in patients, then the role of innate immunity in resisting tumor progression has been underestimated, and these unique immune compartments should be targets to PNI studies. doi:10.1016/j.bbi.2010.07.081
Intracerebral hemorrhage (ICH) is a significant cause of death in the African American population in the United States. African Americans are also at a higher risk for this disease than other populations. The current literature is very limited regarding the clinical characteristics, demographics, and outcomes of African American patients with ICH so we investigated these parameters in this study. Medical records and CT scans were reviewed and documented data was collected regarding demographics, risk factors, social habits and co morbidities of all patients admitted to the Howard University Hospital between July 2007 and June 2009. Variables collected included medication usage, poly substance use, site of hemorrhage, and mortality data. Subarachnoid hemorrhage (SAH) was also included in the data collection. Among 45 ICH patients with an average age of 57, 42% were females who also had higher mortality. Seventy-six percent had preexisting hypertension as a risk factor and 52% were either noncompliant or the status was not known regarding their medication intake. Also noticed were increased rates of SAH (9/45) and Intraventricular hemorrhage (IVH, 4/45). The overall mortality was 29% (male 53% vs F 47%). Hypertension remains the most common risk factor in spontaneous ICH and polysubstance abuse was interestingly higher in females. ICH mortality was less as compared to the literature available (50%), but SAH and IVH rates were comparatively increased with IVH mortality being 100%. doi:10.1016/j.bbi.2010.07.080
Abstract # 298 The marginating immune compartments in rats’ lungs and liver: Characteristics of continuous inflammation and unique activation potential R. Melamed, M. Benish, E. Rosenne, Y. Goldfarb, B. Levi, S. Ben-Eliyahu TAU, Tel-Aviv, Israel
Abstract # 299 TLR4 haplotypes in alcohol and opioid dependent populations J.K. Coller, Y. Wu, J.M. White, M.R. Hutchinson, A.A. Somogyi University of Adelaide, Pharmacology, Level 5, Medical School North, Frome Rd, Adelaide, SA 5005, Australia Up to 60% of alcohol and opioid dependence is heritable. The role of immunogenetics has recently been highlighted via the association between interleukin-1 beta genotypes with opioid and alcohol dependence (Liu L et al, Pharmacogenetics and Genomics 2009;19:869–76). This study examined the role of genetic variants in the innate immune receptor, Toll Like receptor 4 (TLR4), in opioid and alcohol dependence. TLR4 haplotypes (specific combinations of A896G and C1196T variants) were determined in 90 opioid and 93 alcohol dependent, and 74 healthy non-dependent controls. Frequencies of the variants between the groups were compared with Fisher’s Exact test with odds ratios (OR) and chi-square tests. There was no difference in variant frequencies (allele or genotype) of either SNP between the dependent and non-dependent control populations: OR 0.86–1.14, p = 0.1. Similarly, there was no difference in the frequencies of the two haplotypes observed between the opioid dependent and non-dependent groups, respectively: AC 95 and 95.3%, GT 5 and 4.7%. In the alcohol dependent group 4 haplotypes were observed, including 2 that were novel: AC (94%), AT (1.1%), GC (0.5%) and GT (4.4%). However, owing to small subject number carrying these novel haplotypes, the difference in the frequency of these across the 3 groups is not yet significant p = 0.49. Nonetheless, these unique TLR4 haplotypes may be associated with alcohol dependence; large-scale replicate studies are ongoing. doi:10.1016/j.bbi.2010.07.082