Effects of age, HIV, and HIV-associated clinical factors on neuropsychological functioning and brain regional volume in HIV+ patients on effective treatment.

It is yet unclear if people infected with human immunodeficiency virus (HIV+) on stable, combined antiretroviral therapies (cARTs) decline with age at the same or greater rate than healthy people. In this study, we examined independent and interactive effects of HIV, age, and HIV-related clinical parameters on neuropsychological functioning and brain regional volume in a sizable group of Polish HIV+ men receiving cART. We also estimated the impact of nadir CD4 cell count, CD4 cell count during participation in the study, duration of HIV infection, or duration of cART along with age. Ninety-one HIV+ and 95 control (HIV-) volunteers ages 23-75 completed a battery of neuropsychological tests, and 54 HIV+ and 62 HIV- of these volunteers participated in a brain imaging assessment. Regional brain volume in the cortical and subcortical regions was measured using voxel-based morphometry. We have found that HIV and older age were independently related to lower attention, working memory, nonverbal fluency, and visuomotor dexterity. Older age but not HIV was associated with less volume in several cortical and subcortical brain regions. In the oldest HIV+ participants, age had a moderating effect on the relationship between the duration of cART and visuomotor performance, such as that older age decreased speed of visuomotor performance along with every year on cART. Such results may reflect the efficacy of cART in preventing HIV-associated brain damage. They also highlight the importance of monitoring neuropsychological functioning and brain structure in HIV+ patients. This is particularly important in older patients with long adherence to cART.

Depression accounts for executive function deficits in obsessive-compulsive disorder.

OBJECTIVE: To examine the relative impact of depression on executive function deficits in obsessive-compulsive disorder (OCD). BACKGROUND: Existing data suggest that OCD is associated with basal ganglia and orbital frontal dysfunction, and neurobehavioral abnormalities that are putatively associated with these regions have been demonstrated in OCD. Nonetheless, few studies have accounted for the effects of depression, which is a common concurrent symptom among those with OCD. METHOD: A broad battery of neuropsychological tests, including measures of executive function and sensory-motor function, was administered to 20 adults with OCD and 31 control subjects. To assess depressive severity, participants were administered the depression scale from the Minnesota Multiphasic Personality Inventory. RESULTS: Data were analyzed using a regression model in two steps. In step one, patient group was entered, and patients with OCD demonstrated a pattern of executive function and sensory-motor deficits, similar to those shown in previous research. In step two, self-reported depressive symptom severity was entered as a predictor. As a consequence, depression accounted for some executive function deficits, whereas presence of OCD only predicted performance on measures of sensory-motor function. CONCLUSIONS: These data suggest that abnormalities involving executive function in OCD are related to co-morbid depressive severity. However, sensory-motor deficits seem to be more consistent with basal ganglia/orbital frontal dysfunction in OCD.

Cord blood megakaryocytes do not complete maturation, as indicated by impaired establishment of endomitosis and low expression of G1/S cyclins upon thrombopoietin-induced differentiation.

Cord blood (CB) has successfully been used as a stem cell source for haemopoietic reconstitution. However, a significant delay in platelet engraftment is consistently found in CB versus adult peripheral blood (PB) or bone marrow transplants. We sought to determine whether or not CB megakaryocytes have reached terminal maturation and, hence, full thrombopoietic potential. A comparative analysis of megakaryocytes cultured from either CB or PB progenitors in the presence of thrombopoietin (TPO) showed a similar differentiation response, although proliferation was 2.4 times higher in CB than in PB cells. Importantly, the TPO-induced ploidy level was notably different: whereas 82.7% of CB megakaryocytes remained diploid (2N) at the end of the culture, more than 50% of PB megakaryocytes had reached a DNA content equal to or higher than 4N. Western blot and flow cytometry analyses revealed that only polyploid PB megakaryocytes expressed cyclins E, A and B, whereas cyclin D3 was detected in both fetal and adult megakaryocytic nuclei. These data suggest that establishment of endomitotic cycles is impaired in CB megakaryocytes, associated with a differential regulation of G1/S cell cycle factors. We believe that the relative immaturity of fetal megakaryocytes could be a contributing factor to the delayed platelet engraftment in cord blood transplantation.

Clinical utility of the Rorschach Inkblot Method: reframing the debate.

Recent published exchanges have focused on the clinical utility and diagnostic efficiency of the Rorschach Inkblot Method (RIM), but key issues remain unresolved. In this article, 5 principles for evaluating RIM research are offered to help reframe the ongoing debate in this area. These are (a) recognize what the test can and cannot do; (b) choose appropriate outcome criteria to assess RIM effectiveness; (c) use multimethod, multicriterion matrices to place results in an appropriate context; (d) consider limitations in the outcome criteria themselves; and (e) use experimental--not just correlational--data to contrast the results obtained with projective and self-report tests. Coupled with Weiner's (2000a) guidelines for RIM interpretation, the principles outlined here can improve RIM research and practice, and help resolve some longstanding controversies in this area.

Breast cancer survival and in vitro tumor response in the extreme drug resistance assay.

PURPOSE: To determine whether in vitro extreme drug resistance (EDR) assay results for patients with breast carcinoma were associated with clinical outcome after chemotherapy. PATIENTS AND METHODS: EDR assays were performed on tumor tissue obtained from 103 newly diagnosed breast cancer cases. EDR scores of 2 for low, 1 for intermediate, or 0 for extreme drug resistance were determined for each agent tested. In vitro EDR scores for 4-hydroxycyclophosphamide (4HC) and doxorubicin were summed for patients treated with AC, or for 4HC and 5-FU for patients treated with CMF. Treatment selection was blinded to assay results. RESULTS: Median time to progression was significantly shorter for patients with extreme or intermediate in vitro resistance (n = 55, 48 months), compared to patients with low in vitro resistance, (n = 41, 100 months, p = 0.022). Patients demonstrating extreme to intermediate drug resistance also showed poorer survival than the low resistance group (49.5 months vs. not reached, median follow-up 48 months, p =0.011). Summed EDR scores, stage, and number of lymph nodes were significantly associated with survival in univariate and multivariate analysis. Compared to EDR scores of 4, summed EDR scores of 0-1 and summed EDR scores of 2-3 were associated with a relative risk of death of 3.09 (95%, CI 1.05-9.06, Cox proportional hazards model, p = 0.040) and 2.35 (95%, CI 1.07-5.15, Cox proportional hazards model, p = 0.033), respectively. CONCLUSION: Extreme drug resistance testing identified patients with individual patterns of drug resistance prior to therapy. In this cohort of breast cancer patients treated with chemotherapy, summed EDR scores were significantly associated with time to tumor progression and overall survival. EDR results may offer a method for optimizing treatment selection.

Variability in the levels of PML-RAR alpha fusion transcripts detected by the laboratories participating in an external quality control program using several reverse transcription polymerase chain reaction protocols.

BACKGROUND AND OBJECTIVES: The detection of PML-RAR by reverse transcription (RT) polymerase chain reaction (PCR) in acute promyelocytic leukemia (APL) patients who are in hematologic remission influences therapeutic decision making in several trials. In the light of this, the Spanish group has recently designed an external quality assessment program (EQAP) of RT-PCR detection of PML-RAR, which includes a study of sensitivity of the participating laboratories. DESIGN AND METHODS: Eighteen laboratories were involved in the program. Ten laboratories followed the method of Biondi et al., 5 employed that of Borrow et al. and the 3 remaining used other protocols. The sensitivity was studied in five rounds of quality control. The first two shipments consisted of dilutions of NB4 RNA into non-APL RNA. The third round consisted of serial dilutions of the NB4 cell line into HL60 cells. The fourth and five rounds consisted of plasmid dilutions containing the bcr1 and bcr3 PML-RAR isoforms. RESULTS: The results showed that the distinct methods allow detection of the PML-RAR hybrid up to a dilution of 10(-4), and exceptionally, up to 10(-5). The laboratories following the method of Biondi et al. usually detected the 10(-3) dilution and less frequently the 10(-4) one, whereas those using other methods usually detected PML-RAR transcript in the 10(-4) dilution, and less commonly in the 10(-5) dilution. However, each of the PCR methods used by EQAP participating laboratories successfully detected at least 50 copies of PML-RAR alpha fusion transcript in plasmid dilution controls. INTERPRETATION AND CONCLUSIONS: The results point to heterogeneous sensitivity amongst participating laboratories. This may reflect differences in methodology, although variations in sample quality may also account for discrepant findings.

Hypermethylation of the calcitonin gene in acute lymphoblastic leukaemia is associated with unfavourable clinical outcome.

We analysed calcitonin (CALC1) gene hypermethylation using semiquantitative differential polymerase chain reaction in 105 patients with adult (n = 49) and childhood (n = 56) acute lymphoblastic leukaemia (ALL), and studied the association of CALC1 hypermethylation with clinical presentation features and disease outcome. We also investigated the possible relationship between CALC1 methylation status and expression of the cell cycle inhibitor gene p57KIP2. We observed CALC1 hypermethylation in bone marrow cells from 43% (45 out of 105) of ALL patients. Clinical, molecular and laboratory features did not differ significantly between hypermethylated and hypomethylated patients, only T-cell lineage was associated with hypermethylation (14% vs. 47%, P = 0025). Complete remission rate was similar in both groups although hypermethylated patients had a higher relapse rate (68% vs. 19%, P < 0.00001) and mortality rate (55% vs. 36%, P = 0.06) than hypomethylated patients. Estimated disease-free survival (DFS) at 6 years was 66.1% for hypomethylated patients and 5.3% for hypermethylated patients (P < 0,00001). Multivariate analysis from potential prognostic factors demonstrated that CALC1 methylation status was an independent prognostic factor in predicting DFS (P = 0.0001). Separate analysis of adult and childhood ALL patients showed similar results to the whole series. In addition, hypermethylated patients showed downregulation of p57KIP2 expression. Our results suggest that CALC1 gene hypermethylation is associated with an enhanced risk of relapse independently of known poor-prognostic factors and we describe, for the first time, a possible implication of the p57KIP2 gene in the genesis and prognosis of ALL.

The dependent patient in a psychiatric inpatient setting: relationship of interpersonal dependency to consultation and medication frequencies.

To examine the relationship between interpersonal dependency and medical service use in a hospital setting, the number of medical consultations and psychotropic medication prescriptions were compared in matched, mixed-sex samples of 40 dependent and 40 nondependent psychiatric inpatients. Results indicated that dependent patients received more medical consultations and a greater number of medications than did nondependent patients with similar demographic and diagnostic profiles. Implications of these results for theoretical models of interpersonal dependency and for previous research on the dependency-help-seeking relationship are discussed. Practical implications of these findings for work with dependent patients are summarized.

Practice effects on the Wisconsin Card Sorting Test-64 Card version across 12 months.

The Wisconsin Card Sorting Test (WCST: Heaton, Chelune, Talley, Kay, & Curtiss, 1993) is among the most commonly administered measures of executive function. Recently, a short form of the test was developed (WCST-64: Kongs, Thompson, Iverson, & Heaton, 2000), and it affords psychometric properties commensurate with the full version of the test. Yet, similar to other measures of executive function, relatively little is known concerning the effects of repeated administration on the WCST-64. Towards this end, 53 men (age M = 32.38) were administered the WCST-64 twice over 12 months, and scores on several indices improved significantly during this interval. Suggestions concerning the use of these measures in longitudinal research designs and clinical follow-up examinations are offered, and reliable change indices concerning these measures are included.

Meta-analytic methods, the Rorschach, and the MMPI.

In response to concerns described by H. N. Garb, J. M. Wood, M. T. Nezworski, W. M. Grove, and W. J. Stejskal (2001), the authors present the weighted and unweighted means and medians of the effect sizes obtained by J. B. Hiller, R. Rosenthal, R. F. Bornstein, D. T. R. Berry, and S. Brunell-Neuleib (1999). These indices of central tendency are presented separately for Minnesota Multiphasic Personality Inventory (MMPI) and Rorschach effect sizes, both for all the studies in the meta-analysis and for a 10% trimmed sample designed to obtain more robust estimates of central tendency. The variability of these 4 indices is noticeably greater for the MMPI than for the Rorschach. Meta-analysts must compute, compare, and evaluate a variety of indices of central tendency, and they must examine the effects of moderator variables. The authors also comment briefly on the use of phi versus kappa, combining correlated effect sizes and possible hindsight biases.

Neurobehavioural consequences of substance abuse and HIV infection.

Although our understanding of how human immunodeficiency virus (HIV)-related neurobehavioural deficits develop is nascent and preliminary, some clues have emerged which may clarify lingering uncertainties. In particular, HIV seems to yield brain dysfunction by mediating pathological changes upon neuronal function. HIV also compromises immunological integrity, thereby resulting in secondary infections that may further increase brain dysfunction. Notably, many individuals with HIV tend to be current or past abusers of drugs, and, in some cases, their drug use may have actually presented a pathway for initial HIV infection. Similar to HIV, many drugs tend to yield pathological changes upon neuronal function. Further paralleling HIV, some drugs seem to compromise immune function, which in turn may yield secondary detrimental effects upon the brain. Yet, despite the relatively high comorbidity rates of HIV infection and substance abuse, few investigations have addressed the potential interaction between these two factors upon neurobehavioural status. Towards this end, the present paper reviews the existing literature concerning neuropsychological effects of HIV and substance use, and suggests potential mechanisms whereby substance use may potentiate and exacerbate the onset and severity of neurobehavioural abnormalities in HIV infection.

Interpersonal dependency and personality pathology: variations in Rorschach Oral Dependency scores across Axis II diagnoses.

Although several investigations have examined the relationship of Rorschach Oral Dependency (ROD; Masling, Rabie, & Blondheim, 1967) scores to Axis I diagnosis, there has been very little research assessing variations in ROD scores across Axis II personality disorders (PDs). In this study, ROD scores were compared in 5 PD groups (borderline PD inpatients, borderline PD outpatients, avoidant-dependent PD outpatients, narcissistic PD outpatients, and antisocial PD outpatients), and 2 non-PD comparison groups (psychotic disorder inpatients and college students). Borderline PD inpatients had significantly higher ROD scores than borderline PD outpatients, antisocial PD outpatients, and college students; no other between-group differences were found. We discuss implications of these results for research on dependency and Axis II psychopathology and offer suggestions for future studies.

Deconstructing dependency in a five-factor world: a meta-analytic review.

Meta-analysis of studies assessing the relation between interpersonal dependency test scores and five-factor model (FFM) domain scores revealed that dependency scores are positively correlated with FFM Neuroticism and Agreeableness scores and negatively correlated with FFM Extraversion, Openness, and Conscientiousness scores. The magnitudes of these correlations were all in the small-to-moderate range, and comparable score intercorrelations were obtained when participants' dependency levels were assessed by means of a trait dependency questionnaire, dependent personality disorder questionnaire, or dependent personality disorder interview. These findings have implications for researchers' efforts to deconstruct dependency into its basic trait elements and for the dimensional approaches to personality disorders being considered for future versions of the Diagnostic and Statistical Manual of Mental Disorders.

Dependency and suicidality in psychiatric inpatients.

One hundred fifty-two psychiatric inpatients (91 women and 61 men) completed widely used objective (i.e., self-report) and projective measures of interpersonal dependency; scores on these measures were compared to two indices of suicidality derived from patients' chart records (i.e., number of past suicide attempts and physician judgments of suicidality at admission). High objective dependency scores were associated with high suicidality scores in women and men, even when level of depression was controlled for statistically. Projective dependency scores were unrelated to both suicidality indices.

Estimated premorbid intelligence mediates neurobehavioral change in individuals infected with HIV across 12 months.

This study tested whether estimated premorbid intelligence moderates worsening neurobehavioral dysfunction in HIV infection. 155 homosexual men (54 controls, 49 HIV+ asymptomatic, 24 HIV+ symptomatic, 28 AIDS) with stable disease status were tested on measures of executive function at baseline and 12-month follow-up. Premorbid intelligence was estimated on the basis of a demographically-based regression equation (Hamsher, 1984), and participants were classified as average or above-average intelligence. Regardless of disease status, participants with above-average IQ showed no declines on measures of executive function across time. In contrast, among those with average IQ, symptomatic groups showed declines, whereas the asymptomatic group did not. The findings support the hypothesis that estimated premorbid intelligence mediates declines in neuropsychological function in patients with stable HIV status. These findings are consistent with theoretical models of cognitive reserve capacity.

Effects of immunosuppression and disease severity upon neuropsychological function in HIV infection.

Effects of immunosuppression and illness severity upon neuropsychological function were assessed in a group of homosexual men with AIDS across 6 months. Participants included 62 who were seronegative (HIV-), 74 asymptomatic seropositives (HIV+A), 31 symptomatic seropositives (HIV+S), 23 with AIDS defining illnesses (AIDS-DI), and 10 who were diagnosed with AIDS solely on the basis of CD4+ levels falling below 200 /mm3 (AIDS-CD4). Groups were equivalent in age, education, and IQ. None were drug users, and none experienced a change in disease status across the 6-month inter-test interval. There was little evidence of cognitive decline across time. Nonetheless, after collapsing across time intervals, the AIDS-DI group had worse new-learning than all other groups. Additionally, the AIDS-DI demonstrated a greater number of impaired performances than the other participant groups. The data suggest that cognitive impairment in AIDS is unlikely due to independent contributions of immunosuppression and illness. Rather neurobehavioral deficits are more likely attributable to a combination of the two.

Comparative intracellular cytokine production by in vitro stimulated T lymphocytes from human umbilical cord blood (HUCB) and adult peripheral blood (APB).

To date over 400 HUCB transplants have been reported from different centers. It has been suggested that there is a reduced graft-versus-host-disease (GVHD) with HUCB compared to bone marrow transplantation. Since cytokine production by a cell is an indication of the cells function it is important to determinate the differences between APB and HUCB with respect to production of these soluble factors. Our aim was to analyse the intracellular cytokine production by HUCB and APB T lymphocytes with and emphasize on their possible role in GVHD. Heparinized HUCB samples from 8 normal full-term deliveries and 10 normal blood donors were stimulated 4 hours at 37 degrees C and 5% CO2 with phorbol 12-myristate 13-acetate (PMA) and lonomycin in the presence of brefeldine. Afterwards cells were stained with CD3, CD4 or CD8 in different combinations. Finally, after cell permeabilization, cells were stained with Il-2, Il-4 or IFN-gamma. Data acquisition was performed on a FACScan flow cytometer. Compared to APB, HUCB T lymphocytes produced less Il-2, Il-4 and IFN-gamma. In HUCB, Il-2, Il-4 and IFN-gamma were produced predominantly by CD4+ T cells. In APB, Il-2 and Il-4 were also produced predominantly by CD4+ cells compared with CD8+ T lymphocytes, however, IFN-gamma was produced by both CD4+ and CD8+ T cells. These results indicate that there are clear differences in the cytokine profile between T cells in APB and HUCB.

Limited accuracy of premorbid intelligence estimators: a demonstration of regression to the mean.

Regression-based premorbid intelligence estimators have been devised by Barona, Reynolds, and Chastain (1984), Barona and Chastain (1986), Hamsher (1984), Krull, Scott, and Sherer (1995; the Oklahoma Premorbid Intelligence Estimate: OPIE), and Vanderploeg, Schinka, and Axelrod (1996; BEST-3 approach), but little is known of their relative accuracy, particularly in outer ranges of intellectual ability (e.g., below-average, superior, etc.). Towards this end, the Wechsler Adult Intelligence Scale-Revised (WAIS-R) was administered to 150 neurologically normal adults, and estimated VIQ, PIQ, and FSIQ scores were computed according to each regression method. Results showed that methods based solely on demographic factors were most susceptible to meanward regression, rendering them poor estimators of IQ scores in outer ranges. Although the OPIE and BEST-3 performed somewhat better, their accuracy remained relatively weak. The findings suggest that regression-based estimates of premorbid IQ are very susceptible to error, particularly in outer ranges of intellectual function.

A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group.

The Spanish PETHEMA group designed a protocol for newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia (APL) in which induction and consolidation followed the original AIDA regimen, except for the omission of cytarabine and etoposide from consolidation. Induction consisted of 45 mg/m(2) all-trans retinoic acid (ATRA) daily until complete remission (CR) and 12 mg/m(2) idarubicin on days 2, 4, 6, and 8. Patients in CR received 3 monthly chemotherapy courses: idarubicin 5 mg/m(2)/d x 4 (course no. 1), mitoxantrone 10 mg/m(2)/d x 5 (course no. 2), and idarubicin 12 mg/m(2)/d x 1 (course no. 3). Maintenance therapy consisted of 90 mg/m(2)/d mercaptopurine orally, 15 mg/m(2)/wk methotrexate intramuscularly, and, intermittently, 45 mg/m(2)/d ATRA for 15 days every 3 months. Between November 1996 and December 1998, 123 patients with newly diagnosed PML/RARalpha-positive APL from 39 centers were enrolled. A total of 109 patients achieved CR (89%; 95% confidence interval [CI], 83 to 95), 12 died of early complications, and the remaining 2 were resistant. Consolidation treatment was associated with very low toxicity and no deaths in remission were recorded. Molecular assessment of response by reverse transcriptase-polymerase chain reaction (RT-PCR) showed conversion to PCR-negative in 48 of 99 (51%) and 82 of 88 patients (93%) after induction and consolidation, respectively. The 2-year Kaplan-Meier estimates of overall survival and event-free survival were 82% +/- 4% and 79% +/- 4%, respectively. For patients who achieved CR, the 2-year disease-free survival (DFS) was 92% +/- 3%. These data indicate that a significant reduction in toxicity might be obtained in APL using a less intensive consolidation without apparently compromising the antileukemic effect. These results also suggest a minor role for cytarabine and etoposide in the treatment of newly diagnosed PML/RARalpha-positive APL patients.

Relative memory deficits in recurrent versus first-episode major depression on a word-list learning task.

Although memory deficits are associated with major depressive disorder, few studies have identified which patient characteristics predict impairment. Because recurrent depression appears related to more severe cerebral dysfunction, the present study tested whether recurrent depressed individuals have worse memory function than first-episode depressed individuals. Two groups of young-adult, nonpsychotic, depressed inpatients (20 single episode [SE] and 46 recurrent episode [RE]) were administered the California Verbal Learning Test within a broader battery of neuropsychological tests. The groups were equivalent in age, education, estimated IQ, severity of depression, and demographic composition. The RE group demonstrated memory deficits relative to both the SE group and published norms, but no other significant difference was found across the battery. Data indicate that abnormal memory performance is associated with recurrent depression, whereas memory deficits are not prominent in first-episode depressed individuals.