Antigen burden is major determinant of human immunodeficiency virus-specific CD8+ T cell maturation state: potential implications for therapeutic immunization

The majority of untreated human immunodeficiency virus (HIV) type 1-infected individuals ultimately develop uncontrolled viremia and progressive disease. Cytotoxic T lymphocytes (CTLs) are known to play an important role in controlling HIV-1 replication, which has led to an increasing interest in augmenting conventional antiretroviral therapy with therapeutic vaccination. The successful development of a therapeutic vaccine will rely on the ability to correlate an aspect of the immune response with clinical outcome. In this study, the CD8(+) T cell maturation status of antigen-specific cells in models of well and poorly controlled virus infections were compared, to show that a memory phenotype predominates when antigen loads are absent or low. In HIV-1 infection, the emergence of memory CD8(+) T cells was found to occur only in individuals with highly suppressed viral replication for an extended duration. Such assessments of the immune response may provide a refined measure of virus control.     

Family history of diabetes is a major determinant of endothelial function.

OBJECTIVES: We evaluated whether endothelial dysfunction was present in nondiabetic persons with a family history (FH) of diabetes and assessed its relationship with insulin resistance and atherosclerosis risk factors. BACKGROUND: Atherosclerosis is frequently present when type 2 diabetes (T2D) is first diagnosed. Endothelial dysfunction contributes to atherogenesis. METHODS: Oral glucose tolerance and brachial artery flow-mediated, endothelium-dependent vasodilation (EDV) were assessed in 38 nondiabetic subjects; offspring of two parents with T2D (FH+) or with no first-degree relative with diabetes (FH-). RESULTS: Although fasting glucose was higher in FH+ than FH- (5.3 +/- 0.1 mmol/l vs. 4.9 +/- 0.1 mmol/l, p < 0.03), glycemic burden assessed as 2-h or area-under-the-curve glucose after glucose load or glycosylated hemoglobin (HbA1c), and measures of insulin sensitivity or inflammation did not differ. Brachial artery flow-mediated EDV was reduced in FH+ (7.1 +/- 0.9% vs. 11.7 +/- 1.6%, p < 0.02), with no difference in nitroglycerin-induced endothelium-independent vasodilatation. In the combined cohort, only FH+ (r2 = 0.12, p < 0.02) and HbA1c (r2 = 0.14, p < 0.02) correlated with EDV. Insulin resistance, assessed by tertile of homeostasis model assessment of insulin resistance (HOMA-IR), was associated with impaired endothelium-dependent vasodilatation in FH- (p < 0.03, analysis of variance), but not in FH+, as even the most insulin-sensitive FH+ offspring had diminished endothelial function. In multiple regression analysis, including established cardiac risk factors, blood pressure and lipids, HbA1c, and HOMA-IR, FH remained a significant determinant of EDV (p = 0.04). CONCLUSIONS: Bioavailability of nitric oxide is lower in persons with a strong FH of T2D. Glycemic burden, even in the nondiabetic range, can contribute to endothelial dysfunction. Abnormalities of endothelial function may contribute to atherosclerosis before development of overt diabetes.     

Patient Alert to detect ICD lead failure: efficacy, limitations, and implications for future algorithms.

AIMS: An algorithm that alerts implantable cardioverter-defibrillator (ICD) patients, in case of abnormal lead impedance (Patient Alerttrade mark, Medtronic), may help to recognize lead dysfunction. We aimed to determine the utility of Patient Alert for ICD lead-failure detection in a prospective study. METHODS AND RESULTS: Three hundred and sixty ICD patients were followed for 22+/-14 months. Patient Alert was active for pacing impedance <200 and >2000-3000 Omega, and high-voltage conductor impedance <10-20 and >200 Omega. Ten alert events and a total of 29 severe system complications occurred. Patient Alert detected three of 10 ICD lead failures, with a positive predictive value (PPV) of 77.8% for any severe system complication. Retrospective analysis identified 23 patients with a sensing integrity counter (SIC) >300 and revealed an additional four prior undetected lead defects. SIC detected ICD lead failure with 92.9% sensitivity and a PPV of 59.1%. Eight of nine patients with a false-positive SIC had an integrated bipolar lead. Patient Alert combined with SIC detected all ICD lead failures and 71.4% of all severe lead complications. CONCLUSIONS: Patient Alert, based on daily lead-impedance measurement, detected one-third of all ICD lead failures. Combined use with continuous lead integrity monitoring (SIC) increased sensitivity to 100%. Integrated bipolar leads may yield a false-positive SIC. Incorporating SIC and automated pace/sense threshold measurement may improve Patient Alert sensitivity for severe lead complications.     

Dyslipidemia is a major determinant of systemic atherosclerosis in the elderly: An autopsy study

Background:   Assessment of the pathobiological determinants of atherosclerosis is crucial for a better understanding of cardiovascular events.
Methods:   The study was conducted in 178 autopsy cases of in-hospital death (104 men and 74 women; mean age, 81 years), for whom serum lipid values recorded during outpatient follow ups for chronic diseases were available. Severity of the atherosclerosis was semiquantitatively assessed in 10 arteries, and the correlations with age, sex, serum levels of total cholesterol and high-density lipoprotein cholesterol (HDL-C), and the history of hypertension, diabetes mellitus and/or smoking were evaluated.
Results:   The statistically significant risk factors differed between the genders and among the arterial systems. The effect of total cholesterol and HDL-C was more prominent in women than in men. The odds ratio of an elevated total cholesterol value (per 0.1 g/L) for coronary atherosclerosis was 1.56 (95% confidence interval, 1.25–1.95, P  < 0.001) in women and 1.19 (1.07–1.33, P  = 0.002) in men. Hypertension, but not serum lipid profiles, was significantly associated with cerebral atherosclerosis in both genders ( P  < 0.05). Diabetes mellitus and smoking were associated with atherosclerosis in selected arteries.
Conclusion:   Dyslipidemia is a major determinant of atherosclerosis in the elderly, and control of dyslipidemia is still necessary in the elderly population.     

Plasma norepinephrine is a major determinant of hemodynamic alterations with sodium loading.

OBJECTIVE: To assess hemodynamic responses to 3 weeks of sodium loading and to evaluate factors which contribute to hemodynamic alterations. DESIGN: Analysis of patients' central hemodynamic and laboratory variables before and after sodium loading. SETTING: A referral centre. PATIENTS: Thirty-one elderly hypertensives. INTERVENTIONS: Doppler flowmetry and laboratory examinations were performed during different sodium intake; 120 mmol/day for 8 weeks and 344 mmol/day for 3 weeks. RESULTS: Patients were divided into three groups; those in whom sodium loading increased total peripheral resistance (SST); those in whom salt repletion increased cardiac index (SCC); a non-salt-sensitive group (NSS). The overwhelming reaction to salt loading is that, with time, the NSS and SSC groups became part of the SST group. When the SSC patients became SST with sodium loading, serum sodium and plasma arginine vasopressin decreased and haematocrit increased, suggesting that the excretion of sodium and water accompanied with a decrease in circulating plasma volume may be responsible for the hemodynamic alteration from SSC to SST. In those who remained in the SSC group throughout the 3 weeks of salt repletion, plasma norepinephrine decreased on all of days 7, 14 and 21 of the high-sodium diet compared with the regular-sodium regimen, whilst in patients in the SST group on day 21 of the high-sodium diet plasma norepinephrine remained unchanged throughout the 3 weeks of salt loading. CONCLUSIONS: We confirmed a changing pattern of initially high cardiac index giving way to a persistently elevated total peripheral resistance with sodium loading. Plasma norepinephrine proved to be the best predictor of which subjects were or became SST.     

Transferrin is a major determinant of hepcidin expression in hypotransferrinemic mice

As a central regulator of iron metabolism, hepcidin inhibits dietary iron absorption and macrophage iron recycling. Its expression is regulated by multiple factors including iron availability and erythropoietic activity. To investigate the role of transferrin (Tf) in the regulation of hepcidin expression by these factors in vivo, we employed the hypotransferrinemic (hpx) mouse. These Tf-deficient mice have severe microcytic anemia, tissue iron overload, and hepcidin deficiency. To determine the relationship of Tf levels and erythropoiesis to hepcidin expression, we subjected hpx mutant and control mice to a number of experimental manipulations. Treatment of hpx mice with Tf injections corrected their anemia and restored hepcidin expression. To investigate the effect of erythropoiesis on hepcidin expression, we suppressed erythropoiesis with blood transfusions or myeloablation with chemotherapeutic drugs. Transfusion of hpx animals with wild-type red blood cells led to increased hepcidin expression, while hepcidin expression in myeloablated hpx mice increased only if Tf was administered postablation. These results suggest that hepcidin expression in hpx mice is regulated both by Tf-restricted erythropoiesis and by Tf through a mechanism independent of its role in erythropoiesis.     

Sex hormone-binding globulin is a major determinant of the lipid profile: the PRIME study

The prevalence of coronary heart disease is much higher in men than in women and sex hormones might play a role in these differences through their influence on the lipid profile. The aim of this cross-sectional study was to study the relationship between hormonal markers (total testosterone (TT), estradiol (E2), sex-hormone-binding globulin (SHBG)) and plasma lipids in a population-based sample. Subjects were 352 men, 50-59 years old, selected in France (Lille, Strasbourg and Toulouse) and Northern-Ireland (Belfast) who had questionnaires and a medical examination at baseline of the PRIME prospective study (1991-1993). Pearson correlation coefficients and Student's t tests were used to identify factors associated with plasma lipids. Multiple linear regression models were used for multivariate analyses, using triglycerides (TG) (log-transformed) and high density-lipoprotein cholesterol (HDL-C) as dependent variables. SHBG and TT were negatively correlated with TG (p<0.0001 and p<0.05, respectively) and positively correlated with HDL-C (p<0.0001 and p<0.01). E2 was positively correlated with TG (p<0.05). No significant association was found between sex-hormones and LDL-C. In multiple linear regression analyses, SHBG remained independently associated negatively with TG (p<0.01) and positively with HDL-C (p<0.0001) after adjustment for centre of recruitment, age, body mass index, systolic blood pressure, smoking, alcohol intake and physical activity. After further adjustment for insulin, the association between SHBG and HDL-C remained highly significant (p<0.0001). The association between SHBG and TG was weakened but remained also significant. Our results suggest that SHBG might to be a central protein in the hormonal regulation of the lipid profile.     

Asn177 in Escherichia coli thymidylate synthase is a major determinant of pyrimidine specificity.

The substrate preference of recombinant Escherichia coli thymidylate synthase (TS) has been altered from 2'-deoxyuridylate (dUMP) to 2'-deoxycytidylate (dCMP) by site-directed mutagenesis of the codon for Asn177, which was changed to aspartic acid. The side-chain amide of Asn177 forms hydrogen bonds with O4 and N3 of dUMP bound to the crystalline enzyme [Montfort, W. R., Perry, K. M., Fauman, E. B., Finer-Moore, J. S., Maley, G. F., Hardy, L., Maley, F. & Stroud, R. M. (1990) Biochemistry 29, 6964-6977]. This Asn is invariant in all natural sequences for TS known. The values of kcat for the mutant enzyme, TS(N177D), with dCMP and dUMP are, respectively, 0.09 and 0.002 times the value of kcat of wild-type TS with dUMP as substrate. TS(N177D) turns over dCMP at 35 times its rate of dUMP turnover, whereas wild-type TS turns over dCMP at < 10(-5) of its rate of dUMP turnover. Thus Asn177 is a major determinant of the pyrimidine nucleotide specificity of TS. The mutant enzyme, like wild-type TS, forms a covalent complex with 5-fluoro-dUMP in the presence of 5,10-methylenetetrahydrofolate. TS(N177D) also has a newly acquired ability to be transiently inactivated by dUMP. This time-dependent inactivation requires the presence of methylenetetrahydrofolate and may be due to the accumulation of the enzyme in the form of a catalytic intermediate. The likely mechanistic basis for discrimination by TS between dUMP and dCMP is their differing requirements for charge stabilization during covalent catalysis.     

The HGR motif is the antiangiogenic determinant of vasoinhibin: implications for a therapeutic orally active oligopeptide

Angiogenesis - The hormone prolactin acquires antiangiogenic and antivasopermeability properties after undergoing proteolytic cleavage to vasoinhibin, an endogenous prolactin fragment of 123 or...     

Obesity is a major determinant of radiation dose in patients undergoing pulmonary vein isolation for atrial fibrillation.

OBJECTIVES: This study sought to evaluate the impact of obesity on patient radiation dose during atrial fibrillation (AF) ablation procedures under fluoroscopic guidance. BACKGROUND: Obesity is a risk factor for AF and its recurrence after ablation. It increases patient radiation dose during fluoroscopic imaging, but this effect has not been quantified for AF ablation procedures. METHODS: Effective radiation dose and lifetime attributable cancer risk were calculated from dose-area product (DAP) measurements in 85 patients undergoing AF ablation guided by biplane low-frequency pulsed fluoroscopy (3 frames/s). Three dose calculation methods were used (Monte Carlo simulation, dose conversion coefficients, and depth-profile dose curves). RESULTS: Median DAP for all patients was 119.6 Gy x cm2 (range 13.9 to 446.3 Gy x cm2) for procedures with a median duration of 4 h and 83 +/- 26 min of fluoroscopy. Body mass index was a more important determinant of DAP than total fluoroscopy time (r = 0.74 vs. 0.37, p < 0.001), with mean DAP values per hour of fluoroscopy of 58 +/- 40 Gy x cm2, 110 +/- 43 Gy x cm2, and 184 +/- 79 Gy x cm2 in normal, overweight, and obese patients, respectively. The corresponding effective radiation doses for AF ablation procedures were 15.2 +/- 7.8 mSv, 26.7 +/- 11.6 mSv, and 39.0 +/- 15.2 mSv, respectively (Monte Carlo). Use of conversion coefficients resulted in higher effective dose estimates than other methods, particularly in obese patients. Mean attributable lifetime risk of all-cancer mortality was 0.060%, 0.100%, and 0.149%, depending on weight class. CONCLUSIONS: Obese patients receive more than twice the effective radiation dose of normal-weight patients during AF ablation procedures. Obesity needs to be considered in the risk-benefit ratio of AF ablation and should prompt further measures to reduce radiation exposure.     

Cellular zinc content is a major determinant of iron chelator-induced apoptosis of thymocytes.

Desferrioxamine (DFO) and the hydroxypiridinone (HPO) deferiprone (CP20) chelate iron as well as other metals. These chelators are used clinically to treat iron overload, but they induce apoptosis in thymocytes. Thymocyte apoptosis is potentiated by zinc deficiency, suggesting that these iron chelators may induce apoptosis by depleting stores of zinc. Exposure of murine thymocytes to either DFO or deferiprone resulted in significant reductions in the labile intracellular zinc pool. Moreover, increasing intracellular zinc levels, by chronic zinc dietary supplementation to mice or in vitro loading with zinc, abrogated deferiprone-induced murine thymocyte apoptosis. Bidentate hydroxypyridinones such as deferiprone interact with intracellular zinc pools in a manner distinct from that of DFO, which is a hexadentate iron chelator. Whereas deferiprone acts synergistically with the zinc chelator NNNN-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) to induce apoptosis, DFO does not. This difference is most likely due to the ability of HPOs but not DFO to "shuttle" zinc onto acceptors such as metallothioneins. By nature of its structure, DFO is larger than deferiprone and is thus less able to access some intracellular zinc pools. Additionally, metal complexes of DFO are more stable than those of HPOs and thus are less likely to donate zinc to other acceptors. The ability of deferiprone to preferentially access zinc pools was also demonstrated by inhibition of a zinc-containing enzyme phospholipase C, particularly when combined with TPEN. These findings suggest that bidentate iron chelators access intracellular zinc pools not available to DFO and that zinc chelation is a mechanism of apoptotic induction by such chelators in thymocytes.     

Core lipid structure is a major determinant of the oxidative resistance of low density lipoprotein.

The influence of thermally induced changes in the lipid core structure on the oxidative resistance of discrete, homogeneous low density lipoprotein (LDL) subspecies (d, 1.0297-1.0327 and 1.0327-1.0358 g/ml) has been evaluated. The thermotropic transition of the LDL lipid core at temperatures between 15 degrees C and 37 degrees C, determined by differential scanning calorimetry, exerted significant effects on the kinetics of copper-mediated LDL oxidation expressed in terms of intrinsic antioxidant efficiency (lag time) and diene production rate. Thus, the temperature coefficients of oxidative resistance and maximum oxidation rate showed break points at the core transition temperature. Temperature-induced changes in copper binding were excluded as the molecular basis of such effects, as the saturation of LDL with copper was identical below and above the core transition. At temperatures below the transition, the elevation in lag time indicated a greater resistance to oxidation, reflecting a higher degree of antioxidant protection. This effect can be explained by higher motional constraints and local antioxidant concentrations, the latter resulting from the freezing out of antioxidants from crystalline domains of cholesteryl esters and triglycerides. Below the transition temperature, the conjugated diene production rate was decreased, a finding that correlated positively with the average size of the cooperative units of neutral lipids estimated from the calorimetric transition width. The reduced accessibility and structural hindrance in the cluster organization of the core lipids therefore inhibits peroxidation. Our findings provide evidence for a distinct effect of the dynamic state of the core lipids on the oxidative susceptibility of LDL and are therefore relevant to the atherogenicity of these cholesterol-rich particles.     

Pre-treatment IGF-I level is the major determinant of GH dosage in adult GH deficiency

OBJECTIVE: Severe GH deficiency in adults is a definite clinical entity, the effects of which can be reversed by administration of subcutaneous recombinant GH. The ideal dosing regimen and determinants of the maintenance dose have, however, yet to be elucidated. PATIENTS: In an open study of GH replacement we treated 65 GH-deficient adults of mixed adult- and childhood-onset, of mean age 35.5 (range 17-72) years, and comprising 38 females and 27 males, using an individualized low-dose titration regimen aimed at normalization of the serum IGF-I and induction of clinical improvement. RESULTS: Before initiation of GH therapy, median IGF-I SD was significantly lower in female than male patients (- 3.3 vs. - 1.9, P = 0.007) and in childhood-onset compared with adult-onset patients (- 3.9 vs. - 2.0, P < 0.001). Once maintenance dosage had been achieved, the median GH requirement was significantly greater in female than male patients (1.6 vs. 0.8 IU/day, P = 0.013) and childhood-onset compared with adult-onset patients (1.6 vs. 0.8 IU/day, P = 0.019). The median maintenance GH dose for the cohort overall was 1.2 (range 0.4-2.4) IU/day. By univariate analysis a significant negative correlation was observed between the maintenance GH dose and baseline IGF-I SD (r = - 0.63, P < 0.001). No significant correlation was demonstrated between maintenance GH dose and either age or weight. Multiple linear regression analysis using age, gender, weight, time of onset of GH deficiency, peak GH to the insulin tolerance test (ITT) and baseline IGF-I SD as independent variables demonstrated baseline IGF-I SD to account for 51% of the variation in GH dose required to normalize the IGF-I SD (P < 0.001). Those patients with the lower IGF-I SD at initiation of GH therapy required the greater GH dose. None of the other variables studied significantly influenced the maintenance dose. CONCLUSION: We have demonstrated that the GH dose required in an individual is dependent on the serum IGF-I SD before commencement of replacement. In contrast, the severity of GH deficiency as judged by the peak GH response to an ITT was unrelated to the maintenance GH requirement. The effect of age, gender and age at onset of GH deficiency on the final GH dose are accounted for by the lower pretreatment IGF-I SD in young, female and childhood-onset patients relative to older, male and adult-onset patients, respectively.     

Air trapping is a major determinant of persistent airway obstruction in asthmatics

Chronic persistent airway obstruction has been observed in moderate-to-severe asthmatics despite treatment with inhaled corticosteroids. We investigated which airway changes were associated with this obstruction. High-resolution computed tomography (HRCT) was performed at study entry and reexamined at the time of follow-up when the FEV1 reached a maximally constant level after treatment for 1 year or more with inhaled corticosteroids. Bronchial wall area and air trapping extent were compared in the recovered group (n = 18) and the persistent airway obstruction group (n = 14). Bronchial wall area and air trapping of the initial HRCT were similar between the two groups. On follow-up HRCT, air trapping was markedly decreased in the recovered group compared with that on initial HRCT (P = 0.017), whereas bronchial wall area did not change. In the persistent-airway-obstruction group, these two parameters did not change during follow-up. When follow-up HRCT was compared, air trapping was significantly greater in the persistent-airway-obstruction group than in the recovered group (P = 0.003). Difference post-bronchodilator FEV1 value between at initial and 2nd HRCT exam was correlated with difference air trapping value between at initial and 2nd HRCT exam(%) on the follow-up HRCT (P = 0.017). The presence of persistent airflow obstruction were significantly associated with the air trapping % difference between initial and 2nd time (RR = 1.70, P = 0.018). Persistence of AT could be a main contributing factor to chronic persistent airflow obstruction in asthma.