Karim F. Hirji

Shortened telomeres in the expanded CD28- CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis

OBJECTIVE To test the hypothesis that the expanded population of non-proliferative CD28-CD8+ T cells in HIV disease have shortened telomeres, thereby providing evidence that increased rounds of CD8+ cell division occur during HIV disease, possibly leading to replicative senescence and exhaustion of CD8+ T-cell responses. DESIGN CD8+ cells play a central role in control of HIV infection. In late HIV disease, an expanded population of CD28-CD8+ cells with reduced proliferative potential has been documented. A similar population of CD28-CD8+ cells has been identified in ageing humans, where telomere length measurements have suggested that these cells have reached the irreversible state of replicative senescence. METHODS CD8+ cells from HIV-infected and control subjects were sorted by flow cytometry into CD28+ and CD28- fractions. Telomere lengths were determined as mean terminal restriction fragment (TRF) lengths by Southern hybridization. RESULTS The TRF lengths of sorted CD28-CD8+ cells in HIV-infected subjects ranged between 5 and 7 kilobases (kb) and were significantly shorter than TRF lengths of CD28-CD8+ cells in uninfected subjects (P = 0.003). The TRF length in CD28-CD8+ cells from HIV-infected subjects was the same as that observed for centenarian peripheral blood mononuclear cells and is compatible with a state of replicative senescence. CONCLUSIONS The shortened telomeres in the CD28-CD8+ cells in HIV-infected subjects and the poor proliferative potential of these cells identifies CD8+ cell replicative senescence as a newly described feature of HIV disease. Our results provide a mechanism for the loss of CD8+ cell control of viral replication that accompanies advanced HIV disease. Replicative senescence may contribute to exhaustion of the T-cell response as a result of chronic HIV disease. Whether this phenomenon occurs in other chronic viral infections is unknown.

Computing Distributions for Exact Logistic Regression

Abstract Logistic regression is a commonly used technique for the analysis of retrospective and prospective epidemiological and clinical studies with binary response variables. Usually this analysis is performed using large sample approximations. When the sample size is small or the data structure sparse, the accuracy of the asymptotic approximations is in question. On other occasions, singularity of the covariance matrix of parameter estimates precludes asymptotic analysis. Under these circumstances, use of exact inferential procedures would seem to be a prudent alternative. Cox (1970) showed that exact inference on the parameters of a logistic model with binary response requires consideration of the distribution of sufficient statistics for these parameters. To date, however, resorting to the exact method has not been computationally feasible except in a few special situations. This article presents an efficient recursive algorithm that generates the joint and conditional distributions of the sufficient...

Characteristics of women at risk for psychosocial distress in the year after breast cancer.

PURPOSE To provide a detailed description of rehabilitation problems of women, considered to be low risk and at risk for psychosocial morbidity, diagnosed with stage I and II breast cancer 1 month and 1 year after primary treatment. PATIENTS AND METHODS A sample of 227 newly diagnosed breast cancer patients were systematically interviewed by a clinical social worker and classified for risk of psychosocial distress in the year after diagnosis. They completed a battery of standardized instruments to assess quality of life (QL), rehabilitation needs, and psychologic distress. The primary QL instrument, the Cancer Rehabilitation Evaluation System (CARES), provides a detailed listing of rehabilitation needs. Descriptive CARES data are presented with comparisons between the two groups. RESULTS The at-risk women had significantly more problems with greater severity than the low-risk women in all areas (physical, psychosocial, medical interaction, sexual, and marital). While both groups showed improvement over the year following diagnosis, the at-risk group had significantly more problems 1 year later. Many physical problems subside, but problems at the local surgical site, psychologic distress, communication with marital partners, and negative body image are more persistent in the at-risk group 1 year later, while half of both groups continue to have sexual dysfunction. CONCLUSION The detailed listing of problems provided by the CARES may be helpful to clinicians in their interactions with patients. The need for preventive and early intervention for the at-risk patients is underscored.

Quality of life in the first year after breast cancer surgery: rehabilitation needs and patterns of recovery.

Background. Although mortality rates from breast cancer are declining, many breast cancer survivors will experience physical and psychological sequelae that affect their everyday lives. Few prospective studies have examined the rehabilitation needs of newly diagnosed breast cancer patients, and little is known about the predictors of health‐related quality of life (QOL) in this population.Methods. Between 1987 and 1990, 227 women with early stage breast cancer participated in a prospective longitudinal study in which detailed information was collected through interviews, standardized measures of QOL and psychological distress, and clinical evaluation. Comparisons of physical and treatment‐related problems were made according to type of surgical treatment. Multivariate regression analysis was performed to examine the predictors of QOL at one year after surgery.Results. Physical and treatment‐related problems were reported frequently one month after breast cancer surgery, and occurred with equal frequency in women receiving modified radical mastectomy or breast conservation treatment. There were no significant differences in problems reported at one year by type of surgery; however, frequently reported problems include ‘numbness in the chest wall or axilla,’ ‘tightness, pulling or stretching in the arm or axilla,’ ‘less energy or fatigue,’ ‘difficulty in sleeping,’ and ‘hot flashes’. There was no relationship between the type of surgery and mood or QOL. Poorer QOL one year after surgery was significantly associated with greater mood disturbance and body image discomfort one month after surgery, as well as positive lymph node involvement. Although the majority of patients experienced substantial disruptions in the physical and psychosocial dimensions of QOL post‐operatively, most women recovered during the year after surgery, with only a minority (<10%) significantly worsening during that time.Conclusions. At one year after surgery, most women report high levels of functioning and QOL, with no relationship between the type of surgery and QOL. Women who reported lower levels of QOL at one year after diagnosis had greater mood disturbance and poorer body image one month after surgery, as well as lower income and positive axillary nodes.

Natural Killer Cell Immunodeficiency in Hiv Disease is Manifest by Profoundly Decreased Numbers of Cd16 + Cd56+ Cells and Expansion of a Population of Cd16dim Cd56- Cells with Low Lytic Activity

Natural killer (NK) cells were enumerated by three-color immunofluorescence in 255 uninfected and 399 human immunodeficiency virus-infected adults. Several dramatic alterations were observed. First, the median number and percentage of CD16+CD56+ NK cells, the subset that comprises > 90% of the NK cells in healthy adults, were severely decreased (median, 175/mm3 in uninfected controls; 63/mm3 in HIV-infected non-AIDS subjects). Even subjects with > 800 CD4+ cells/mm3 had decreased CD16+CD56+ NK cell levels (97/mm3). Second, the number of CD16+CD56- cells, an NK population that is rare in healthy adults, was elevated (median, 20/mm3 in uninfected controls; 64/mm3 in HIV-seropositive non-AIDS subjects). Third, the expression of CD16 on the NK cells was markedly reduced; some CD56+ cells and virtually all CD56- cells were CD16dim. Fourth, fluorescence-activated cell-sorting studies revealed little NK- or antibody-dependent cellular cytotoxic activity in the CD16dimCD56- cell population. These results indicate that the pathogenesis of HIV disease includes numerical alterations in subpopulations of NK cells. A better understanding of how HIV infection causes this aspect of pathogenesis is needed.

PREDICTING PSYCHOSOCIAL RISK IN PATIENTS WITH BREAST CANCER

Breast cancer is the most common neoplasm in North American women. The psychosocial impact of breast cancer has been extensively studied, and a number of investigators have attempted to characterize women who are at high risk for increased psychosocial morbidity. Although a detailed interview performed by a professional is the clinical standard for psychosocial assessment, such interviews are usually time-consuming and expensive, and thus are rarely performed. This study was designed to develop a strategy for the rapid identification of newly-diagnosed breast cancer patients at risk for psychosocial morbidity. A sample of 227 newly diagnosed breast cancer patients were interviewed systematically by a clinical social worker and were subsequently classified for risk of psychosocial distress in the year after diagnosis. In addition, these women completed a battery of standardized instruments designed to assess quality of life, rehabilitation needs and psychological distress. A logistic regression procedure was used to examine a wide range of variables for their ability to correctly classify the risk of psychosocial distress in this sample. The final model included the Cancer Rehabilitation Evaluation System (CARES) Psychosocial Summary Scale, the Karnofsky Performance Status score and age as the best predictors of psychosocial risk. Subsequently these three variables were used to construct a clinically usable risk prediction model. Additional research should be performed to validate this predictive model.

Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome.

One hundred ninety-six patients with acute myelogenous leukemia (AML) were treated with intensive induction chemotherapy using similar daunorubicin/cytarabine/thioguanine regimens. Treatment results of 44 patients who had a documented preleukemic syndrome or cytopenia present for more than 2 months before developing over AML were compared with 152 patients with de novo AML. Eighteen (41%) patients with preleukemia evolving into AML achieved complete remission compared with 111 (73%) patients with de novo AML (P less than .01). Patients with preleukemia-AML had a significantly longer period to recovery of granulocytes. Multivariate analysis indicated that presence of a previous preleukemic syndrome and advancing age were independent poor prognostic indicators for achieving remission. For patients who achieved remission, disease-free survival and overall survival were also inferior for patients with previous preleukemia; disease-free survival was 17 +/- 17% at 3 years compared with 29 +/- 10% in patients with de novo AML (P = .02). These data indicate that intensive chemotherapy has limited efficacy in patients with AML following a preleukemic syndrome. Durable remissions may be achieved in some patients.

Median unbiased estimation for binary data

Abstract This article compares the accuracy of the median unbiased estimator with that of the maximum likelihood estimator for a logistic regression model with two binary covariates. The former estimator is shown to be uniformly more accurate than the latter for small to moderately large sample sizes and a broad range of parameter values. In view of the recently developed efficient algorithms for generating exact distributions of sufficient statistics in binary-data problems, these results call for a serious consideration of median unbiased estimation as an alternative to maximum likelihood estimation, especially when the sample size is not large, or when the data structure is sparse.

Exact inference for matched case-control studies

In an epidemiological study with a small sample size or a sparse data structure, the use of an asymptotic method of analysis may not be appropriate. In this paper we present an alternative method of analyzing data for case-control studies with a matched design that does not rely on large-sample assumptions. A recursive algorithm to compute the exact distribution of the conditional sufficient statistics of the parameters of the logistic model for such a design is given. This distribution can be used to perform exact inference on model parameters, the methodology of which is outlined. To illustrate the exact method, and compare it with the conventional asymptotic method, analyses of data from two case-control studies are also presented.

Major Expansions of Select CD8+ Subsets in Acute Epstein-Barr Virus Infection: Comparison with Chronic Human Immunodeficiency Virus Disease

CD8+ lymphocyte phenotypes were characterized during acute Epstein-Barr virus (EBV) infection, and a comparison was made to previous studies of human immunodeficiency virus (HIV). This was of interest because CD8+ cells contribute to immunologic control of both infections, but the usual outcome of EBV infection is benign, whereas untreated HIV infection is fatal. During acute EBV infection, CD8+ cells expressed elevated levels of the activation antigens CD38 and HLA-DR, similar to that during chronic HIV infection. Within 16 weeks, when EBV latency is established, CD8+ cell activation had resolved. In contrast, activation persists in HIV infection. Expression of CD38 and HLA-DR on CD8+ cells could be a marker for ongoing viral replication in both infections. Other CD8+ cell alterations observed in this study of acute EBV infection included increases in both CD62L- and CD62L+ CD8+ cells and unique kinetics in the expansion of the CD57+CD8+ cell subset.