Value of HIV-1 viral load and CD4 lymphocyte count as determinants of progression to AIDS and survival

BACKGROUND: HIV-1 viral load is regarded as a better surrogate marker for progression and death than CD4+ cell counts. Both markers are analysed in a cohort of patients with unknown seroconversion date and advanced HIV infection. PATIENTS AND METHODS: Retrospective cohort analysis of 421 patients, most on antiretroviral therapy, with a median initial CD4+ cell count of 209 x 10(6)/l and a median initial viral load of 4.7 log copies/ml. One thousand two hundred and eighty-six samples were analysed. Univariate and bivariate analysis were performed with initial and sequential CD4+ cell counts and viral load values to estimate the risk of progression and death by Cox regression models. RESULTS: After a median follow up of 763 days, 124 patients developed AIDS and 117 died. Relative risks of progression related to the group that maintained viral load values always < 35,000 copies/ml were: 5-fold (95% CI: 1.4-17.0; p < 0.05) for patients with any viral load value > 35,000 copies/ml but always < 200,000 copies/ml; and 13.6 fold (95% CI: 5.4-34.2; p < 0.0001) for patients who could not maintain viral load < 200.000 copies/ml. CD4+ counts = 100 x 10(6)/l and viral load = 220,000 copies/ml were the threshold values that best fitted to estimate the probability of survival by a bivariate analysis. CONCLUSIONS: The maintenance of sequential viral load values < 35.000 copies/ml is associated with a lower risk of progression. The maintenance of sequential viral load values < 150,000 copies/ml is associated with higher short-term survival rates.     

Association of HLA profiles with early plasma viral load, CD4+ cell count and rate of progression to AIDS following acute HIV-1 infection. Multicenter AIDS Cohort Study

The products of a growing number of genes have been shown to display seemingly contradictory functions; namely, the induction of tumorigenesis and the induction of apoptosis. Heregulin's involvement in oncogenesis occurs through its interactions with members of the EGF receptor tyrosine kinase family. Recently one isoform of heregulin, beta2b, was isolated in an in vitro screen for dominant, apoptosis-inducing genes in kidney epithelial cells. Here we show that heregulin is also capable of mediating apoptosis in human and murine mammary tumor cell lines and murine tumors. Furthermore, through transfection of the human breast cancer cell line MCF-7 with the truncated transmembrane/cytoplasmic segment of the heregulin gene, we show that the intracellular region of the heregulin precursor is sufficient for induction of apoptosis. Through the use of DNA fragmentation assays we also show that apoptosis occurs in cell lines established from heregulin-induced mammary gland tumors. TdT addition of digoxigenin labeled nucleotides to 3' OH ends of DNA breaks recapitulated these results in the actual tumors. Finally, over-expression of heregulin is shown to lead to the down-regulation of Bcl-2, an inhibitor of apoptosis. Conversely, the transfection of Bcl-2 into MCF-7 cells inhibits heregulin-mediated programmed cell death.     

Evaluating the effect of year of seroconversion on HIV progression in cohort studies. Italian Seroconversion Study

OBJECTIVES: To show how a spurious association between the calendar year of seroconversion and HIV progression arises as a result of censoring the follow-up of individuals at their last visit, when the individuals' visits are intermittent. DESIGN: A notional cohort of 1140 seroconverters and a cohort study of 1270 HIV-infected individuals seroconverted between 1985 and 1994, and followed up to December 1995 (the Italian Seroconversion Study cohort). METHODS: Failure times and rate of the patients attending the clinic over the study period were simulated for the notional cohort. Three separate scenarios with different probabilities of making a visit were considered. Standard survival analysis techniques were used to assess the effect of the year of seroconversion on HIV progression. The progression to a CD4 cell count of 200 x 10(6)/l according to the calendar year of seroconversion in the Italian Seroconversion Study was assessed using different censoring strategies. RESULTS: A spurious effect of the year of seroconversion consistently appeared in 100 repeated simulations. When ignoring the visits occurring after the first year of follow-up in the Italian Seroconversion Study cohort, results supported the hypothesis of no effect of the year from seroconversion. CONCLUSIONS: The choice of the censoring strategy is crucial when assessing the effect of year of seroconversion using survival analysis in cohort studies with intermittent visit structure. Different censoring strategies should be considered before firmly concluding that more virulent strains or the use of treatment are modifying the natural history of HIV disease from cohort studies of this nature.     

CD4 cell count as a surrogate endpoint in HIV clinical trials: a meta-analysis of studies of the AIDS Clinical Trials Group

OBJECTIVE: To evaluate initial changes in CD4 cell count as a surrogate endpoint for clinical outcome in HIV-infected patients. DESIGN: Meta-analysis of all relevant Phase II and III randomized clinical trials undertaken by the Adult AIDS Clinical Trials Group. METHODS: Individual patient data were obtained from each clinical trial, and the difference between a pair of treatments in their effect on clinical outcome (AIDS or death, or death alone) during 2 years of follow-up was evaluated. The proportion of treatment effect explained (PTE) was the proportion of this difference explained by the change in CD4 cell count 6 months after starting treatment, evaluated using proportional hazards models. A weighted average PTE across treatment comparisons was obtained. The association between the difference between treatments in clinical outcome, expressed as hazard ratio, and the difference in mean change in CD4 cell count was evaluated using regression analysis. RESULTS: There were 15 clinical trials involving 24 treatment comparisons. The weighted average PTE for both progression to AIDS or death was 0.16 [95% confidence interval (Cl), 0.07-0.26] and for death was 0.10 (95% Cl, 0.00-0.20). There were significant associations between treatment differences in effect on AIDS or death, and on death alone, and the difference in mean change in CD4 cell count. A difference in mean change in CD4 cell count of 30 or 40 x 10(6)/l or more in favor of the test treatment indicated with high probability that there was a corresponding difference in progression to AIDS or death. CONCLUSIONS: The small PTE suggest that other mechanisms of drug action not captured by initial change in CD4 cells are important. CD4 cell count is a weak surrogate endpoint, but has some value as an aid for screening treatments for drug development or preliminary regulatory approval.     

Analysis of factors related to the recent decline in birth rate in Japan

This study was undertaken in an attempt to determine whether regional differences exist for those factors which have affected the decline in the total fertility rate in Japan between 1970 and 1990. Age Stratified analysis of vital statistics of the 20 to 39-year-old female population for the 46 prefectures was performed, and evaluated in relation to urbanization. The parameters examined were birth rate, percentage of married women, rates of birth by married women, and percentage of the work force in the service industry. The results were as follows. 1. Characteristic changes were noted in birth rates for females between 25 and 29 years of age. The reasons are that average marriage age for females shifted from 20-24 to 25-29, causing the birth rates for females between the ages of 25 to 29 years to decline, while not uniformly, but with some regional differences among the 46 prefectures. 2. Urbanization has had a significant effect on the declining birth rate for females grouped by age. The advance of the urbanization process in each prefecture is directly related to the decline in the birth rates for females between 20 to 24 years and 25 to 29 years. The extent of urbanization in each prefecture is inversely related to the rate of birth by married women and the percentage of married women between age 20 to 24 and 25 to 29 in that prefecture. The trend toward delaying marriage and childbirth in the urbanized prefectures appeared to be a major factor leading to the decline in the total fertility rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Unintegrated circular HIV-1 DNA in the peripheral mononuclear cells of HIV-1-infected subjects: association with high levels of plasma HIV-1 RNA, rapid decline in CD4 count, and clinical progression to AIDS

We observed 36 HIV-infected patients to evaluate whether the presence of tandem 2-long terminal repeat circular unintegrated HIV-1 DNA (2-LTR) in peripheral blood mononuclear cells (PBMC) at baseline was associated with acceleration of HIV disease. Detection of 2-LTR at baseline correlated with high plasma HIV-1 RNA levels (p < .01), recovery of culturable HIV-1 from plasma (p = .02), and progression to AIDS during follow-up (p = .01). More patients with 2-LTR (68%) than without 2-LTR (31%) had a decline in CD4 levels of >50 cells/mm3 over the first 18 months of follow-up (p = .04), and the average annual CD4 decline was 35% in patients with 2-LTR compared with 16% in those without 2-LTR (p = 0.06). Detection of 2-LTR in PBMC at baseline was an independent predictor of high plasma HIV-1 RNA levels and subsequent CD4 cell decline in this cohort of patients with predominantly nonsyncytium-inducing (NSI) isolates at baseline. The presence of 2-LTR in PBMC appears to be reflective of ongoing HIV-1 replication, as measured by plasma HIV-1 RNA levels, and identifies persons at risk for immunologic and clinical decline.     

The Italian quality control study for evaluation of CD4 cells in centres involved in the treatment of HIV-1 patients. Italian CD4 Quality Control Group

We report on the experience of establishing a national network for a quality control programme in evaluating CD4 cell counts in most Italian centres involved in the care of patients with HIV disease. The 68 centres were divided according to their geographical location into eight groups, and twice a year (tests A and B) they received three coded whole blood samples (two were replicates of the same sample) obtained from two informed HIV+ patients, one with CD4 counts/mm3 expected to be < 200 and one with values > 300. The medians of the determinations performed by the labs involved in each of the eight areas were taken as the 'true' values for each sample. Unsatisfactory performances for percentage of CD4 cells were identified as a CD4 analysis with residual values > or = +/- 5% and with deviates > or = +/- 2. For absolute numbers of CD4 cells, an unsatisfactory performance was defined as CD4 counts with residual > +/- 100 CD4 cells/mm3 and with deviates > or = +/- 2. The residual value is the CD4 value reported by each lab minus the median value. The deviate is the residual divided by the modified interquartile range (IQR x 0.75). Most of the centres provided reliable results. However, some labs failed to provide satisfactory results for percentages (6.25% of the tested labs for test A and 6.17% for test B) or absolute numbers (16.25% test A and 12.34% test B). Only 3.7% of the labs gave unsatisfactory results in both tests. Four of the unsatisfactory results from the two tests gave an error in absolute numbers > +/- 200 CD4 cells/mm3. Our data suggest that most Italian labs provide reliable results in evaluating the numbers of CD4 cells in HIV-1+ samples, but the importance of running a quality control programme is highlighted by our experience with those centres which provide unsatisfactory data which may lead to incorrect classification of the patients or assessment of treatment.     

Type of punishment as a determinant of resistance to deviation.

Compared the effectiveness of an aversive stimulus, withholding of resources, withdrawal of love, and reasoning, when used alone and when combined with praise, in a standard laboratory punishment paradigm using 120 1st- and 2nd-grade boys and girls as Ss. Resistance to deviation and stability of resistance to deviation were used as the measures of punishment effectiveness. Sex of child, use of praise, and type of punisher were combined in a 2 * 2 * 5 factorial design, with a female as the punitive agent. An aversive stimulus appeared to produce more suppression of deviant behavior, but the effect was not significant for all response measures. The stability of the deviant response pattern varied for each punisher, but the most stable response pattern resulted from the use of an aversive stimulus. Neither use of praise nor sex of child significantly influenced punisher effectiveness. Results are discussed within the framework of anxiety arousal and information content of the punishers, and the practice of grouping various punishers under the categories of sensitization and induction measures is considered. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Replication as a determinant of the intestinal response to rotavirus

Mucosal antibody induction by otherwise identical replication-competent and replication-incompetent rhesus monkey rotaviruses was compared. Although psoralen-inactivated virus induced diarrhea, the magnitude of the intestinal antibody response was severely attenuated compared with that of replicating rotavirus, as determined by assay of mucosal antibody-secreting cells. Rotavirus that was neutralized by monoclonal antibodies (anti-VP4 and -VP7) prior to inoculation was similarly ineffective at induction of specific antibodies in intestinal secretions. In contrast to genetically inactivated virus, antibody-neutralized virus did not induce diarrhea. In this murine model, viral replication is an important determinant of antibody induction. The diarrhea response is blocked by neutralizing antibodies, but the mechanism of action is not exclusively the inhibition of viral replication.     

Presence of the variant mannose-binding lectin alleles associated with slower progression to AIDS. Amsterdam Cohort Study

OBJECTIVE: To examine the association between mannose-binding lectin (MBL) polymorphism and progression to AIDS and death in HIV-1 infection. DESIGN AND METHODS: In 131 HIV-1-infected homosexual seroconverters, survival analyses were performed to determine both the association between MBL genotype and time from HIV-1 seroconversion to AIDS and death, and time from AIDS to death. RESULTS: Of the 131 seroconverters, of whom 61 developed AIDS, 76 were typed as homozygous wild-type and 55 as carriers of variant alleles (52 heterozygous and three homozygous variant alleles). A Survival analyses suggested that HIV-1-infected men with the variant alleles progressed somewhat slower to AIDS [relative hazard (RH), 0.62; 95% confidence interval (CI), 0.36-1.10] and death (RH, 0.73; 95% CI, 0.42-1.25). Interestingly, CD4+ T-cell count determined at the moment of AIDS was found to be significantly lower among persons with the mutation (97 x 10(6)/l versus 204 x 10(6)/l; P=0.03). Furthermore, when AIDS-free times before the diagnosis of an opportunistic infection were compared with those preceding a diagnosis of Kaposi's sarcoma, Kaposi's sarcoma diagnosis was more postponed than that of an opportunistic infection (RH, 0.21; 95% CI, 0.05-0.95; versus RH, 0.67; 95% CI, 0.35-1.27). CONCLUSION: Indications for a weak pre-AIDS protective effect of variant MBL alleles were demonstrated.     

Free pentosidine and neopterin as markers of progression rate in diabetic nephropathy. Collaborative Study Group

Stimulus-induced release of polyunsaturated fatty acids from membranes has been proposed to couple the processes of stimulus perception and oxylipin synthesis in the octadecanoid signaling pathway. This study investigated wound-induced changes in free fatty acids, diacylglycerol, and phospholipids at the site of wounding and at an unwounded area of the same wounded leaf in castor bean (Ricinus communis L.). Increases in free fatty acids and diacylglycerol and decreases in phospholipids were relatively large and continuous at the site of wounding. The changes at the unwounded area were selective and transient, suggesting a regulated activation of lipid turnover in response to wounding. In unwounded cells, the free fatty acids that increased in the early phase of wounding were linolenate and linoleate, which peaked within 5 min after wounding. Diacylglycerols that increased in unwounded cells were the species containing linolenate and linoleate, not those with oleate and stearate. Within 5 min of wounding, the levels of phosphatidylcholine and phosphatidylglycerol, but not other phospholipids, decreased in unwounded cells. These results provide evidence for the wound-induced selective increase in linolenate and linoleate in unwounded cells. The varied susceptibility of different phospholipids to hydrolysis after wounding indicates that phosphatidylcholine and phosphatidylglycerol may serve as substrates that lead to the increase in linolenate and linoleate in the early phase of wound response. The pattern of increases in polyunsaturated fatty acids, diacylglycerol, and phosphatidic acid and of decreases in phospholipids suggests the activation of a PLD-initiated signaling pathway in response to wounding in castor bean.     

Thought confidence as a determinant of persuasion: The self-validation hypothesis.

Previous research in the domain of attitude change has described 2 primary dimensions of thinking that impact persuasion processes and outcomes: the extent (amount) of thinking and the direction (valence) of issue-relevant thought. The authors examined the possibility that another, more meta-cognitive aspect of thinking is also important--the degree of confidence people have in their own thoughts. Four studies test the notion that thought confidence affects the extent of persuasion. When positive thoughts dominate in response to a message, increasing confidence in those thoughts increases persuasion, but when negative thoughts dominate, increasing confidence decreases persuasion. In addition, using self-reported and manipulated thought confidence in separate studies, the authors provide evidence that the magnitude of the attitude-thought relationship depends on the confidence people have in their thoughts. Finally, the authors also show that these self-validation effects are most likely in situations that foster high amounts of information processing activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effect of education on the onset and rate of terminal decline.

Differences in the time of onset and magnitude of terminal decline were examined in three cognitive domains: processing speed, episodic memory, and global function. In addition, cognitive reserve was investigated by testing whether education affected the onset or rate of decline across these domains. Eight hundred ninety-six community-dwelling Australian adults aged ≥ 70 years were assessed up to four times over 12 years, with vital status followed for 17 years. For each of the cognitive measures, a series of change point models were fitted across the 20 years before death to find the optimal point at which terminal decline was distinguished from preterminal decline. Change points were then assessed separately for high- and low-education groups. The change points were 8.5 years for processing speed (95% CI: 6.0–11.2 years), 7.1 years for global function (6.2–9.3), and 6.6 years for episodic memory (5.3–7.1). The rate of decline was two to four times greater in the terminal phase relative to the preterminal phase, depending on the domain. Increased education changed the terminal decline effect differently for each of the three tests, either by significantly hastening the onset of terminal decline and decreasing the rate of decline, or by increasing the rate of either preterminal or terminal decline. Analyses were repeated excluding participants diagnosed with dementia, with no substantive change to the outcomes. In conclusion, the rate and onset of terminal decline varied somewhat across cognitive domains. Education affected terminal decline differently across the domains, but this modification was not consistent with the predictions of cognitive reserve theory. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Proportion of light to cycle as a determinant of critical flicker-fusion frequency.

On the basis of recent studies a meaningful relationship between CFF and the proportion of light to the total cycle (PL) is emerging. Graphs of the Log of time of one dark period to time of one light period "show that increase in time of light, luminance and/or area of test patch, results in a decrease in the time of dark necessary at fusion." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The work costs of earning food as a determinant of patch leaving.

Foraging theorists have long emphasized the role of the energy (work) costs of food items on foraging behavior. However, few experiments have measured this variable or demonstrated that animals are indeed sensitive to work costs. Experiment 1 assessed whether rats (Long-Evans) can use the work costs of food to determine whether a food patch is exhausted. Rats performed a fixed amount of work for each food item (fixed-work [FW] schedule), but food was withheld unpredictably to simulate sudden patch depletion. It was found that rats left patches only when the work costs of unsuccessful searches (giving-up work) exceeded the prevailing costs of food. The time and response costs of unsuccessful food searches (giving-up time and giving-up responses) were not predictive of patch leaving. Experiment 2 showed how rats regulated work in this paradigm by examining the exteroceptive stimuli connected with fulfilling the FW schedule. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of CD4 cell count by a simple enzyme-linked immunosorbent assay using the TRAx CD4 test kit and by flow cytometry and hematology

Measurement of CD4 T-lymphocyte levels is clinically useful in monitoring immune status in a number of conditions, including human immunodeficiency virus (HIV) infection, in which the absolute CD4 count is used to guide therapy. The absolute CD4 count is obtained by multiplying the results of the leukocyte count and the differential with a hematology cell counter and the percentage of CD4+ T lymphocytes determined by flow cytometry. These techniques require expensive, complex instrumentation, and interlaboratory results are difficult to standardize and reproduce. The rapid growth of HIV infection worldwide has increased the need for more-reproducible and cost-effective methods for CD4 T-cell monitoring. The TRAx CD4 test kit is based on a novel adaptation of conventional enzyme-linked immunosorbent assay (ELISA) and permits the simple quantitation of total CD4 protein from whole-blood lysates. In this study, the relationship between total CD4 protein measured in units per milliliter (TRAx) and in cells per microliter (flow cytometry and hematology) was defined in a multisite clinical study using linear regression analysis. Data from 230 HIV-seronegative and 321 HIV-seropositive specimens were used to calibrate the TRAx assay recombinant CD4 standards and controls in equivalent CD4 T lymphocytes per microliter (cells per microliter). The calibration of the TRAx CD4 assay in cells per microliter was validated with a second group of specimens from 17 healthy volunteers and 20 HIV-seropositive patients which were collected and tested under strictly controlled conditions intended to minimize the effects of specimen aging on the results of the reference method. These data were also used to estimate the variability of absolute CD4 count by cytometric methods as well as the precision of the TRAx CD4 result after it was calibrated in cells per microliter. Overall, correlations between the two methods ranged from 0.87 to 0.95. Additional studies demonstrated that the contribution of CD4 protein from monocytes and any soluble CD4 in sera are negligible in the TRAx assay and do not significantly affect results. This new method represents a promising alternative to absolute CD4 T-cell enumeration by flow cytometry and hematology.     

Internal frame of reference as a determinant of the oblique effect.

Studied the oblique effect (preference for stimuli that are oriented vertically or horizontally over those oriented obliquely) using single dots as stimuli in 2 experiments with 20 graduate students and staff of a university and 10 undergraduates, all with normal or corrected vision. These dots were surrounded by either a square or a circle frame that provided information about their position in the visual field. Results of classification, focusing, and discrimination tasks show that the processing of these dots followed the same pattern of results as it did with line stimuli: Dots located on the main axes (vertical and horizontal) were easier to classify than dots located on the oblique axes. The same pattern of results was found in both the square- and circle-frame experiments. It is suggested that an internal frame of reference, aligned with vertical and horizontal, facilitates processing of stimuli located on those axes. (21 ref) (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Social context as a determinant of sex differences in adults' attraction to infants.

70 male and 70 female undergraduates in same- or mixed-sex groups publicly or privately judged pictures of subhuman primate infants and adults for attractiveness. Sex differences were significant but the largest difference between males and females was found when judgments were made in public same-sex groups. Females reported greater attraction to infants relative to their attraction to adults, when judgments were made publicly in all-female groups. Males reported less attraction to infants in all-male public groups than when in private. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Communication modality as a determinant of persuasion: The role of communicator salience.

Reports 2 studies, using a total of 304 university students, in which a likable or unlikable communicator delivered a persuasive message via writing, audiotape, or videotape. In both studies the likable communicator was more persuasive in video- and audiotape than in writing, but the unlikable communicator was more persuasive in writing. Thus, communicator likability was a significant determinant of persuasion only in the broadcast modalities. Other findings suggest that Ss process more communicator cues when exposed to video- and audiotape messages than when exposed to written ones and that communicator-based (rather than message-based) cognitions predicted opinion change primarily in video and audiotape conditions rather than in written ones. It is concluded that video- and audiotapes enhance communicator-related information, so that communicator characteristics exert a disproportionate effect on persuasion when messages are broadcast. Findings are also discussed in relation to "vividness" phenomena. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)