Nonpurging binge eaters versus nonbinge eaters and treatment retention for adult obesity

Dropout from obesity treatment has been a major factor associated with weight control failure, with few reliable predictors of dropouts or completers. Previous studies have tended to treat obese people as a homogeneous group with standard behavior modification-based interventions. Current research indicates there may be subgroups within the obese population, binge eaters and nonbinge eaters, who have different dropout rates. Current studies also recommend focusing on the subset of this subgroup that does not engage in purging (vomiting, laxative abuse, or excessive exercise) to compensate for binge eating. This research uses a secondary dataset (N = 156) from a prospective study in which participants were randomized to a Food Dependency (FD) and a Behavioral Self-Management (BSM) group for weight reduction. Criteria for subjects in the original study included (1) scoring higher on the existing Binge Eating Scale (BES) in order to ensure enrollment of more binge eaters and (2) no compensatory purging behavior for binge eating. Subjects were then reclassified in this study as binge eaters or nonbinge eaters using the more stringent proposed 1994 DSM-IV criteria for Binge Eating Disorder (BED). Subjects were followed for dropout. Variables studied were binge status, age at obesity onset, age at study baseline, class instructor, number of previous weight loss attempts, race, marital status, body mass index (BMI kg/m$\sp2$), type of intervention, work status, educational level, and social support. Stepwise backward regression Cox survival analysis indicated binge status had a consistent, statistically significant protective effect on dropout in which binge eaters were half as likely to dropout versus nonbinge eaters (p = 0.04). Cox proportional hazards analysis indicated no statistical difference in dropout by type of intervention (FD, p = 0.13; BSM, p = 0.80) when controlling for binge status. All other variables did not reach significance, which is consistent with the literature. Implications of these findings suggest that (1) the proposed 1994 DSM-IV criteria for BED is a more useful classification that the existing DSM-III-R criteria, and (2) the identification of subgroups among obese subjects is an important step in dropout and weight loss intervention research. Future research can confirm this finding. ^

Colorectal cancer: An insight on dietary factors

Aim. To assess the relationships between dietary factors and colorectal cancer risk. ^ Methods. We looked at all the systematic reviews published in last ten years on the topic. ^ Results. For fruits-vegetables some studies1 were significant for heterogeneity and others2 were not. In study by Aune at al3 only fruits were significant, although all the studies had protective RR between 0.90 to 0.94. For folate only case-control group of studies, the study by Sanjoaquin et al4 was significant with p heterogeneity being 0.01 and all of them had protective effect with RR between 0.75 to 0.95, for dietary as well as total folate. For fiber study by Park et al5 p was insignificant at 0.14 an RR was 0.84. Vitamin B6 study by Larsson et al6 had significant p with RR 0.90. For dietary fat both Alexander7 and Liu8 concluded that there is insufficient evidence that dietary fat is an independent causative risk factor. Only one study by Norat et al9 out of three was able to achieve significant p heterogeneity for meat. All the studies reported RR between 1.14 to 1.35, clearly implicating meat as culprit for increasing the risk of colorectal cancer. ^ Conclusions. We would recommend the use of fruits and vegetables to be protective against colorectal cancer. Also meat consumption increases the risk of colorectal cancer.^ *Please refer to dissertation for references/footnotes.^

Genetic variants within the Wnt/ B-catenin signaling pathway as indicators of bladder cancer clinical outcomes

The genetic factors that influence bladder cancer clinical outcomes are largely unknown. In this clinical outcomes study, I assessed genetic variations in the Wnt/β-catenin stem-cell pathway genes for association with recurrence and progression. A total of 230 SNPS in 40 genes from the Wnt/β-catenin pathway were genotyped in 419 histologically confirmed non-muscle invasive bladder cancer cases. Several significant associations were observed in the clinical outcomes analysis. Under the dominant model WNT8B: rs4919464 (HR: 1.55, 95% CI: 1.17-2.06, P=2.2x10-3) and WNT8B: rs3793771 (HR: 1.54, 95% CI: 1.09-1.62, P=4.6x10-3 ) were statistically significantly associated with an increase risk of recurrence while two other variants, APC2: rs11668593 (HR: 2.50, 95% CI: 1.43-4.35, P=1.2x10-3) and LRP5 : rs312778 (HR: 1.81, 95% CI: 1.23-2.65, P=2.7x10-3), were significantly associated with recurrence risk under the recessive model of inheritance. Four SNPs in the recessive model were associated with an increased risk of progression (AXIN2: rs1544427, LRP5: rs312778, AXIN1: rs370681, AXIN1: rs2301522). LRP5: rs312778 had the most significant increased risk of progression with a 2.68 (95% CI: 1.52-4.72, P=6.4x10-4)-fold increased risk. Stratification analysis based on treatment regimen (transurethral resection (TUR) and Bacillus Calmette-Guérin (BCG)) was also performed. Individuals with at least one variant in AXIN2: rs2007085 were found to have a 2.09 (95% CI: 1.24-3.52, P=5.4x10-3) -fold increased risk of recurrence in those that received TUR only, and no statistically significant effect was seen in those that received BCG. Individuals who received TUR with at least one variant in LEF1: rs10516550 were found to have a 2.26 (95% CI: 1.22-4.18, P=9.7x10-3)-fold increase risk of recurrence and no statistically significant effect was found in individuals who received BCG. Also, the recessive model of LRP6: rs2302684 in TUR only treatment was shown to have a 1.95 (95%CI: 1.18-3.21, P=8.8x10 -3)-fold increased risk of recurrence, and a suggested protective effect associated with a (HR: 0.83, 95% CI: 0.51-1.37, P=0.468) decreased risk of recurrence. Together, these findings implicate the Wnt/β-catenin stem-cell pathway as playing a role in bladder cancer clinical outcomes and have important implications for personalization of future treatment regimens. ^

Impact of donor-recipient gender and race mismatching on patient survival in patients with end-stage liver diseases undergoing liver transplantation

Background. End-stage liver disease (ESLD) is an irreversible condition that leads to the imminent complete failure of the liver. Orthotopic liver transplantation (OLT) has been well accepted as the best curative option for patients with ESLD. Despite the progress in liver transplantation, the major limitation nowadays is the discrepancy between donor supply and organ demand. In an effort to alleviate this situation, mismatched donor and recipient gender or race livers are being used. However, the simultaneous impact of donor and recipient gender and race mismatching on patient survival after OLT remains unclear and relatively challenging to surgeons. ^ Objective. To examine the impact of donor and recipient gender and race mismatching on patient survival after OLT using the United Network for Organ Sharing (UNOS) database. ^ Methods. A total of 40,644 recipients who underwent OLT between 2002 and 2011 were included. Kaplan-Meier survival curves and the log-rank tests were used to compare the survival rates among different donor-recipient gender and race combinations. Univariate Cox regression analysis was used to assess the association of donor-recipient gender and race mismatching with patient survival after OLT. Multivariable Cox regression analysis was used to model the simultaneous impact of donor-recipient gender and race mismatching on patient survival after OLT adjusting for a list of other risk factors. Multivariable Cox regression analysis stratifying on recipient hepatitis C virus (HCV) status was also conducted to identify the variables that were differentially associated with patient survival in HCV + and HCV − recipients. ^ Results. In the univariate analysis, compared to male donors to male recipients, female donors to male recipients had a higher risk of patient mortality (HR, 1.122; 95% CI, 1.065–1.183), while in the multivariable analysis, male donors to female recipients experienced an increased mortality rates (adjusted HR, 1.114; 95% CI, 1.048–1.184). Compared to white donors to white recipients, Hispanic donors to black recipients had a higher risk of patient mortality (HR, 1.527; 95% CI, 1.293–1.804) in the univariate analysis, and similar result (adjusted HR, 1.553; 95% CI, 1.314–1.836) was noted in multivariable analysis. After the stratification on recipient HCV status in the multivariable analysis, HCV + mismatched recipients appeared to be at greater risk of mortality than HCV − mismatched recipients. Female donors to female HCV − recipients (adjusted HR, 0.843; 95% CI, 0.769–0.923), and Hispanic HCV + recipients receiving livers from black donors (adjusted HR, 0.758; 95% CI, 0.598–0.960) had a protective effect on patient survival after OLT. ^ Conclusion. Donor-recipient gender and race mismatching adversely affect patient survival after OLT, both independently and after the adjustment for other risk factors. Female recipient HCV status is an important effect modifier in the association between donor-recipient gender combination and patient survival.^

Risk factors for inflammatory breast cancer

Background: Inflammatory breast cancer (IBC) is rare and accounts for 2.5% of all invasive breast cancers. The 5-year survival rates are significantly lower than for other types of breast cancer, highlighting the significance of cancer prevention in IBC. The comprehensive multi-disciplinary team Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at University of Texas MD Anderson Cancer Center treats the largest number of Inflammatory Breast patients in a single center. Because of this unique center, large patient resources, and good medical and epidemiological records, we were able to conduct the largest single center case-control and case-case study on IBC. Methods: We identified 246 patients diagnosed with IBC and 397 cancer free patients seen at the Dan L Duncan Cancer Prevention Clinic. Breast cancer reproductive risk factors and lifestyle risk factors were compared between tumor subtypes of IBC patients (Estrogen Receptor positive (ER+) and/or Progesterone Receptor positive (PR+), Human Epidermal Growth Factor 2 positive (HER2+)), and (ER -/PR-/HER2-)) and cancer free controls. Results: Breastfeeding was the only significant risk factor (p<0.01) between tumor subtypes in IBC patients. In the case-control study that included all IBC patients and cancer free patients the descriptive statistics indicate significant difference in BMI, history of smoking, number of children, age of first pregnancy, any breastfeeding and total time breastfeeding (p<0.05). No differences were found in the frequency of other breast cancer risk factors. Conclusion: The associations determined between cancer free controls and IBC patients have identified previously unknown risk factors for IBC. The risk factors identified by the case control study suggest BMI, history of smoking, and the protective effect of breastfeeding as potential modifiable risk factors that can be used to decrease the incidence of IBC. Impact: These results highlight the importance of evaluating epidemiologic risk factors of IBC, which could lead to the identification of distinct etiologic pathways that could be targeted for prevention.^

Inactivation and self -association of CaM kinase: Effects of ATP, substrate binding domains, and isozymic forms

Calcium/calmodulin-dependent protein kinase II (CaM kinase) is a multifunctional Ser/Thr protein kinase, that is highly enriched in brain and is involved in regulating many aspects of neuronal function. We observed that forebrain CaM kinase from crude homogenates, cytosolic fractions and purified preparations inactivates and translocates into the particulate fraction following autophosphorylation. Using purified forebrain CaM kinase as well as recombinant $\alpha$ isozyme, we determined that the formation of particulate enzyme was due to enzyme self-association. The conditions of autophosphorylation determine whether enzyme self-association and/or inactivation will occur. Self-association of CaM kinase is sensitive to pH, ATP concentration, and enzyme autophosphorylation. This process is prevented by saturating concentrations of ATP. However, in limiting ATP, pH is the dominant factor, and enzyme self-association occurs at pH values $\rm{<}7.0.$ Site-specific mutants were produced by substituting Ala for Thr286, Thr253, or Thr305,306 to determine whether these sites of autophosphorylation affect enzyme inactivation and self-association. The only mutation that influenced these processes was Ala286, which removed the protective effect afforded by autophosphorylation in saturating ATP. Enzyme inactivation occurs in the presence and absence of self-association and appears predominantly sensitive to nucleotide concentration, because saturating concentrations of $\rm Mg\sp{2+}/ADP$ or $\rm Mg\sp{2+}/ATP$ prevent this process. These data implicate the ATP binding pocket in both inactivation and self-association. We also observed that select peptide substrates and peptide inhibitors modeled after the autoregulatory domain of CaM kinase prevented these processes. The $\alpha$ and $\beta$ isozymes of CaM kinase were characterized independently, and were observed to exhibit differences in both enzyme inactivation and self-association. The $\beta$ isozyme was less sensitive to inactivation, and was never observed to self-associate. Biophysical characterization, and transmission electron microscopy coupled with image analysis indicated both isozymes were multimeric, however, the $\alpha$ and $\beta$ isozymes appeared structurally different. We hypothesize that the $\alpha$ subunit of CaM kinase plays both a structural and enzymatic role, and the $\beta$ subunit plays an enzymatic role. The ramifications for the functional differences observed for inactivation and self-association are discussed based on potential structural differences and autoregulation of the $\alpha$ and $\beta$ isozymes in both calcium-induced physiological and pathological processes. ^

Potential roles for bcl-2 in the pathogenesis, progression, and treatment of prostate cancer

The most common molecular alterations observed in prostate cancer are increased bcl-2 protein expression and mutations in p53. Understanding the molecular alterations associated with prostate cancer are critical for successful treatment and designing new therapeutic interventions. Hormone-ablation therapy remains the most effective nonsurgical treatment; however, most patients will relapse with hormone-independent, refractory disease. This study addresses how hormone-ablation therapy may increase bcl-2, develops a transgenic model to elucidate the role of bcl-2 multistep prostate carcinogenesis, and assesses how bcl-2 may confer resistance to cell death induction using adenoviral wild-type p53 gene therapy. ^ Two potential androgen response elements were identified in the bcl-2 promoter. Bcl-2 promoter luciferase constructs were transfected into the hormone- sensitive LNCaP prostate cell line. In the presence of dihydrotestosterone, the activity of one bcl-2 promoter luciferase construct was repressed 40% compared to control cells grown in charcoal-stripped serum. Additionally, it was demonstrated that both bcl-2 mRNA and protein were downregulated in the LNCaP cells grown in the presence DHT. This suggests that DHT represses bcl-2 expression through possible direct and indirect mechanisms and that hormone-ablation therapy may actually increases bcl-2 protein. ^ To determine the role of bcl-2 in prostate cancer progression in vivo, probasin-bcl-2 mice were generated where human bcl-2 was targeted to the prostate. Increased bcl-2 expression rendered the ventral prostate more resistant to apoptosis induction following castration. When the probasin-bcl-2 mice were crossed with TRAMP mice, the latency to tumor formation was decreased. The expression of bcl-2 in the double transgenic mice did not affect the incidence of metastases. The double transgenic model will facilitate the study of in vivo effects of specific genetic lesions during the pathogenesis of prostate cancer. ^ The effects of increased bcl-2 protein on wild-type adenoviral p53-mediated cell death were determined in prostatic cell lines. Increased bcl-2 protected PC3 and DU145 cell lines, which possess mutant p53, from p53-mediated cell death and reductions in cell viability. Bcl-2 did not provide the same protective effect in LNCaP cell line, which expresses wild-type p53. This suggests that the ability of bcl-2 to protect against p53-mediated cell death is dependent upon the endogenous status of p53. ^

Subjective well -being as predictor of mortality, heart disease, and obesity: Prospective evidence from the Alameda County Study

Based on the World Health Organization's (1965) definition of health, understanding of health requires understanding of positive psychological states. Subjective Well-being (SWB) is a major indicator of positive psychological states. Up to date, most studies of SWB have been focused on its distributions and determinants. However, study of its consequences, especially health consequences, is lacking. This dissertation research examined Subjective Well-being, as operationally defined by constructs drawn from the framework of Positive Psychology, and its sub-scores (Positive Feelings and Negative Feelings) as predictors of three major health outcomes—mortality, heart disease, and obesity. The research used prospective data from the Alameda County Study over 29 years (1965–1994), based on a stratified, randomized, representative sample of the general public in Alameda County, California (Baseline N = 6928). ^ Multivariate analyses (Survival analyses using sequential Cox Proportional Hazard models in the cases of mortality and heart disease, and sequential Logistic Regression analyses in the case of obesity) were performed as the main methods to evaluate the associations of the predictors and the health outcomes. The results revealed that SWB reduced risks of all-cause mortality, natural-cause mortality, and cardiovascular mortality. Positive feelings not only had an even stronger protective effect against all-cause, natural-cause and cardiovascular mortality, but also predicted decreased unnatural-cause mortality which includes deaths from suicide, homicide, accidents, mental disorders, drug dependency, as well as alcohol-related liver diseases. These effects were significant even after adjusted for age, gender, education, and various physical health measures, and, in the case of cardiovascular mortality, obesity and health practices (alcohol consumption, smoking, and physical activities). However, these two positive psychological indicators, SWB and positive feelings, did not predict obesity. And negative feelings had no significant effect on any of the health outcomes evaluated, i.e., all-cause mortality, natural- and unnatural-cause mortality, cardiovascular mortality, or obesity, after covariates were controlled. These findings were discussed (1) in comparison with relevant existing studies, (2) in terms of their implications in health research and promotion, (3) in terms of the independence of positive and negative feelings, and (4) from a Positive Psychology perspective and its significance in Public Health research and practice. ^

Efecto de la labranza y la cobertura vegetal sobre el escurrimiento y la pérdida de suelo en la región central de la provincia de Buenos Aires

El objetivo de este trabajo fue evaluar a campo la efectividad de diferentes tipos de labranzas junto con distintos grados de cobertura vegetal (CV) del suelo sobre el escurrimiento (E) y la pérdida de suelo (Ps). Se seleccionaron 34 sitios experimentales bajo labranza tradicional (LT) y siembra directa (SD), con diferentes niveles de CV (C1- < 49, C2- 50-79% y C3- > 80%). Se utilizó un diseño experimental completamente aleatorizado con 4 tratamientos y desigual número de repeticiones: 1) SD-C3, 2) LT-C3, 3) LT-C2, y 4) LT-C1, resultante de combinar el tipo de labranza con CV. Se realizó un ANOVA (p ≤ 0,05) y un análisis de contrastes ortogonales: 1) SD-C3 vs LT-C3, 2) LT-C1 vs LT-C2, y 3) C3 vs LT-C2+C1. Al cabo de cada simulación de lluvia se obtuvo el E y Ps. Se determinó: contenido de materia orgánica (CMO), contenido hídrico (CH) y densidad aparente del suelo (DA) en los 10 cm superficiales, y la pendiente (P) del terreno. La LT presentó mayor E y Ps en todos tratamientos evaluados respecto de SD. El mayor E (26,8 mm) se registró en LT-C2, y el menor (0,5 mm) en SD-C3. La Ps mostró igual tendencia que el E con 11,6 y 0,1 g respectivamente. Los contrastes mostraron E estadísticamente diferentes para los tres contrastes, mientras la Ps fue estadísticamente diferente en los contrastes Nº 2 y 3. Escurrimiento y Ps se correlacionaron entre sí (R2 = 0,98) y con P (R2 = 0,83 y 0,72 respectivamente). Los resultados obtenidos demuestran la importancia del efecto protector de la CV del suelo. Sin embargo, el CMO y CH, y la P y DA deben ser considerados también en el proceso de E - erosión del suelo.

Análisis sobre la eficacia de niveles moderados de actividad física para reducir el riesgo de padecer enfermedades cardiovasculares : Un Meta-análisis

Objetivos: a. Determinar la eficacia de la actividad física en la reducción del riesgo de enfermedades cardiovasculares; b. Analizar los cambios relativos en los niveles de riesgo a padecer enfermedades cardiovasculares de acuerdo a diferentes intensidades (baja-moderada) de actividad física. Metodología: Se realizó un Meta-análisisde los estudios encontrados en la base de datos PUBMED. Se calculó el tamaño del efecto medio y se aplicó el test de Eggerpara descartar un posible sesgo de publicación. Al detectarse heterogeneidad, se procedió a realizar un análisis de las variables moderadoras. Resultados: Se obtuvo un tamaño del efecto medio de 0.762 (0.678-0857; 95 por ciento IC). El test de Egger arrojó un p-valor de 0.67 (I.C. 0.95), de manera tal que se confirmó la ausencia de sesgo de publicación. El análisis moderador determinó que los años de seguimiento (p=0.000; 95 por ciento IC) y los países de estudio (p=0.0096; 95 por ciento IC) son significativos. Conclusión: Se puede concluir en que la práctica de actividad física a intensidades moderadas ofrece un efecto protector sobre los individuos que la realizan disminuyendo el riesgo a padecer enfermedades cardiovasculares

Análisis sobre la eficacia de niveles moderados de actividad física para reducir el riesgo de padecer enfermedades cardiovasculares : Un Meta-análisis

Objetivos: a. Determinar la eficacia de la actividad física en la reducción del riesgo de enfermedades cardiovasculares; b. Analizar los cambios relativos en los niveles de riesgo a padecer enfermedades cardiovasculares de acuerdo a diferentes intensidades (baja-moderada) de actividad física. Metodología: Se realizó un Meta-análisisde los estudios encontrados en la base de datos PUBMED. Se calculó el tamaño del efecto medio y se aplicó el test de Eggerpara descartar un posible sesgo de publicación. Al detectarse heterogeneidad, se procedió a realizar un análisis de las variables moderadoras. Resultados: Se obtuvo un tamaño del efecto medio de 0.762 (0.678-0857; 95 por ciento IC). El test de Egger arrojó un p-valor de 0.67 (I.C. 0.95), de manera tal que se confirmó la ausencia de sesgo de publicación. El análisis moderador determinó que los años de seguimiento (p=0.000; 95 por ciento IC) y los países de estudio (p=0.0096; 95 por ciento IC) son significativos. Conclusión: Se puede concluir en que la práctica de actividad física a intensidades moderadas ofrece un efecto protector sobre los individuos que la realizan disminuyendo el riesgo a padecer enfermedades cardiovasculares

Análisis sobre la eficacia de niveles moderados de actividad física para reducir el riesgo de padecer enfermedades cardiovasculares : Un Meta-análisis

Objetivos: a. Determinar la eficacia de la actividad física en la reducción del riesgo de enfermedades cardiovasculares; b. Analizar los cambios relativos en los niveles de riesgo a padecer enfermedades cardiovasculares de acuerdo a diferentes intensidades (baja-moderada) de actividad física. Metodología: Se realizó un Meta-análisisde los estudios encontrados en la base de datos PUBMED. Se calculó el tamaño del efecto medio y se aplicó el test de Eggerpara descartar un posible sesgo de publicación. Al detectarse heterogeneidad, se procedió a realizar un análisis de las variables moderadoras. Resultados: Se obtuvo un tamaño del efecto medio de 0.762 (0.678-0857; 95 por ciento IC). El test de Egger arrojó un p-valor de 0.67 (I.C. 0.95), de manera tal que se confirmó la ausencia de sesgo de publicación. El análisis moderador determinó que los años de seguimiento (p=0.000; 95 por ciento IC) y los países de estudio (p=0.0096; 95 por ciento IC) son significativos. Conclusión: Se puede concluir en que la práctica de actividad física a intensidades moderadas ofrece un efecto protector sobre los individuos que la realizan disminuyendo el riesgo a padecer enfermedades cardiovasculares

Heterologous Expression of a Plant Small Heat-Shock Protein Enhances Escherichia Coli Viability under Heat And Cold Stress Ref.: 1

A small heat-shock protein (sHSP) that shows molecular chaperone activity in vitro was recently purified from mature chestnut (Castanea sativa) cotyledons. This protein, renamed here as CsHSP17.5, belongs to cytosolic class I, as revealed by cDNA sequencing and immunoelectron microscopy. Recombinant CsHSP17.5 was overexpressed in Escherichia coli to study its possible function under stress conditions. Upon transfer from 37°C to 50°C, a temperature known to cause cell autolysis, those cells that accumulated CsHSP17.5 showed improved viability compared with control cultures. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of cell lysates suggested that such a protective effect in vivo is due to the ability of recombinant sHSP to maintain soluble cytosolic proteins in their native conformation, with little substrate specificity. To test the recent hypothesis that sHSPs may be involved in protection against cold stress, we also studied the viability of recombinant cells at 4°C. Unlike the major heat-induced chaperone, GroEL/ES, the chestnut sHSP significantly enhanced cell survivability at this temperature. CsHSP17.5 thus represents an example of a HSP capable of protecting cells against both thermal extremes. Consistent with these findings, high-level induction of homologous transcripts was observed in vegetative tissues of chestnut plantlets exposed to either type of thermal stress but not salt stress

HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy

The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02+ healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02− HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

A physiological role of the adenosine A3 receptor: Sustained cardioprotection

Adenosine released during cardiac ischemia exerts a potent, protective effect in the heart. A newly recognized adenosine receptor, the A3 subtype, is expressed on the cardiac ventricular cell, and its activation protects the ventricular heart cell against injury during a subsequent exposure to ischemia. A cultured chicken ventricular myocyte model was used to investigate the cardioprotective role of a novel adenosine A3 receptor. The protection mediated by prior activation of A3 receptors exhibits a significantly longer duration than that produced by activation of the adenosine A1 receptor. Prior exposure of the myocytes to brief ischemia also protected them against injury sustained during a subsequent exposure to prolonged ischemia. The adenosine A3 receptor-selective antagonist 3-ethyl 5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS1191) caused a biphasic inhibition of the protective effect of the brief ischemia. The concomitant presence of the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) converted the MRS1191-induced dose inhibition curve to a monophasic one. The combined presence of both antagonists abolished the protective effect induced by the brief ischemia. Thus, activation of both A1 and A3 receptors is required to mediate the cardioprotective effect of the brief ischemia. Cardiac atrial cells lack native A3 receptors and exhibit a shorter duration of cardioprotection than do ventricular cells. Transfection of atrial cells with cDNA encoding the human adenosine A3 receptor causes a sustained A3 agonist-mediated cardioprotection. The study indicates that cardiac adenosine A3 receptor mediates a sustained cardioprotective function and represents a new cardiac therapeutic target.