Bruce Shiramizu

Higher frequency of dementia in older HIV-1 individuals: the Hawaii Aging with HIV-1 Cohort.

Background: Antiretroviral therapy has improved survival for HIV-1-infected individuals. The neuroepidemiologic implications of HIV-1 in an aging population are not well known, particularly the prevalence of HIV-associated dementia (HAD). Methods: The authors report a baseline cross-sectional analysis of 202 HIV-1-seropositive individuals enrolled into one of two groups of the Hawaii Aging with HIV Cohort: older (50 or more years old, n = 106) and younger (20 to 39 years old, n = 96). Neuropsychological, neurologic, medical, and laboratory data were obtained at enrollment. Participant cognitive status was classified (research case definitions) using American Academy of Neurology (1991) criteria in a consensus conference of physicians and neuropsychologists. Results: HAD was more frequent in older (25.2%) compared to younger (13.7%) individuals (p = 0.041) corresponding to an OR of 2.13 (95% CI: 1.02 to 4.44) for the older compared to the younger group. After adjusting for education, race, substance dependence, antiretroviral medication status, viral load, CD4 lymphocyte count, and Beck Depression Inventory score, the odds of having HAD among individuals in the older group was 3.26 (1.32 to 8.07) times that of the younger group. Conclusions: Older age is associated with increased HAD in this HIV-1 cohort. Underlying mechanisms are unclear but do not appear related to duration of HIV-1 infection.

Mitochondrial DNA decrease in subcutaneous adipose tissue of HIV-infected individuals with peripheral lipoatrophy.

ObjectiveTo determine whether the peripheral fat wasting (lipodystrophy), which is seen in association with highly active antiretroviral therapy (HAART) that includes a nucleoside reverse transcriptase inhibitor (NRTI), is associated with a decrease in subcutaneous adipose tissue mitochondrial DNA (mtDNA) content or with large mtDNA deletions or insertions. DesignA four cohort cross-sectional study. MethodsThe mtDNA content of subcutaneous fat tissue from the neck, abdomen and thigh was determined by polymerase chain reaction utilizing the amplification of three different mtDNA fragments. The results from HIV-infected patients with peripheral fat wasting following more than 6 months of NRTI-containing HAART were compared with the results from three different control cohorts: HIV-infected patients with a similar treatment history without lipodystrophy; HIV-infected patients naive to antiretroviral therapy and HIV sero-negative participants. ResultsA decrease in mtDNA content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts. No large mitochondrial deletions or insertions were found. ConclusionsLipodystrophy with peripheral fat wasting following treatment with NRTI-containing HAART is associated with a decrease in subcutaneous adipose tissue mtDNA content.

A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A report from the Children's Oncology Group

To estimate the response rate and therapy related toxicities of the anti‐CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B‐cell non‐Hodgkin lymphoma and mature B‐cell acute lymphoblastic leukemia (B‐ALL).

Circulating proviral HIV DNA and HIV-associated dementia

Objective:Individuals continue to develop HIV-1-associated dementia (HAD) despite treatment with highly active antiretroviral therapy (HAART). Monocytes/macrophages (M/MΦ) can harbor proviral DNA that is not eradicated by HAART. To determine if HAD is associated with the level of HIV-1 infection within circulating leukocytes, we quantified HIV-1 DNA copy number in peripheral blood mononuclear cells (PBMC), and in PBMC subsets. Design:Cross-sectional analysis within the Hawaii Aging with HIV Cohort comparing participants with HAD to those with normal cognition (NC). Methods:Real-time PCR assays assessing HIV DNA copy number/1 × 106 cells were performed on PBMC and subsets. Results.Individuals with HAD (n = 27) had a median (interquartile range) of 9.11 (37.20) HIV DNA per 1 × 106 PBMC compared to 0.49 (0.89) HIV DNA per 1 × 106 PBMC in individuals with NC (n = 22). Using a univariate analysis in the subset of individuals with undetectable viral load (HAD, n = 11; NC, n = 13), the odds of HAD attributable to HIV DNA copy number was 2.76 (1.28–5.94), P < 0.01. Preliminary analysis of a small subset of patients (n = 5) suggested that the primary source of HIV DNA may be the activated M/MΦ (CD14/CD16) subset. Conclusions.These findings suggest a potentially important association between circulating provirus and HAD.

Evidence for molecular subtypes of HIV-associated lymphoma : division into peripheral monoclonal, polyclonal and central nervous system lymphoma

The pathogenesis of the HIV-associated lymphomas is not well understood. In order to begin characterizing this class of lymphoma, we initiated a molecular genetic study of DNA extracted from 31 diagnostic biopsy specimens from patients diagnosed with AIDS-associated non-Hodgkins lymphoma. Analysis of 25 peripheral lymphomas showed that 14 were monoclonal B-cell processes, while 11 appeared to be of polyclonal origin. Five of the 14 monoclonal lymphomas were found to have rearrangements of the c-myc gene. Epstein-Barr virus (EBV) genomes were found in seven out of 14 monoclonal samples, but only two out of nine polyclonal samples. The six primary central nervous system (CNS) lymphoma samples were more homogeneous than the peripheral samples and all were monoclonal, positive for EBV and lacked detectable c-myc gene rearrangements. This study allows us to subdivide the HIV-associated lymphomas into three major molecular subtypes: (1) monoclonal B-cell process frequently associated with c-myc rearrangement or detectable EBV genomes, (2) polyclonal B-cell process typically without evidence of EBV, and (3) monoclonal primary CNS process associated with EBV genomes and lacking detectable c-myc rearrangement.

Placenta and cord blood mitochondrial DNA toxicity in HIV-infected women receiving nucleoside reverse transcriptase inhibitors during pregnancy.

Recent studies of pregnant women and animal models have raised concerns regarding potentially serious mitochondrial toxicity-related side effects in infants born to mothers who received nucleoside reverse transcriptase inhibitors (NRTIs) during their pregnancy to prevent HIV-1 perinatal transmission. The aim of this study was to assess mitochondrial DNA (mtDNA) content of cord blood and placenta in HIV-infected pregnant women receiving NRTI compared with HIV-negative women, hypothesizing that placenta and cord blood mtDNA copies per cell would be decreased in women on NRTI therapy. Immediately following delivery, placenta and cord blood were obtained from eight HIV-infected pregnant women on NRTIs and five HIV-negative women. Assessment of mtDNA copies per cell was accomplished by quantitative real-time PCR. The mean mtDNA copies per cell from the placenta of the HIV-infected women compared with HIV-negative women was 152 +/- 119 and 880 +/- 136 ( =.0016), respectively. Similarly, the mean mtDNA copies per cell from the cord blood of the HIV-positive women compared with HIV-negative women was 144 +/- 101 and 865 +/- 331 ( =.0026), respectively. There was a statistically significant decrease in mtDNA copies per cell in placenta and cord blood between the HIV-infected women on NRTIs compared with HIV-negative women. Further studies are needed to better understand the morbidity to infants and mothers treated with NRTI to prevent vertical transmission of HIV.

Neuropsychological test profile differences between young and old human immunodeficiency virus-positive individuals

Human immunodeficiency virus (HIV) dementia remains as an important cause of neurological morbidity among HIV-seropositive (HIV+) individuals. Differences in the neuropsychological profiles between older and younger HIV+ individuals have not been examined extensively. The objective of this study was to examine the neuropsychological test performance between old and young HIV+ individuals (a) with and without cognitive impairment (total cohort) and (b) with dementia. One hundred thirty-three older (age ≥ 50 years) HIV+ individuals and 121 younger (age 20 to 39 years) HIV+ individuals were evaluated with a standardized neuropsychological test battery. Differences between age groups in the mean z score for each neuropsychological test were determined. The older HIV+ (total) cohort had greater impairment in tests of verbal memory (P = .006), visual memory (P < .002), verbal fluency (P = .001), and psychomotor speed (P < .001) compared to the young HIV+ (total) cohort. After adjusting for differences in education, older HIV+ patients with dementia (n = 31) had a greater deficit in the Trail Making test Part B (P = 0.02) compared to younger HIV+ patients with dementia (n = 15). Age was associated with lower performance in tests of memory, executive functioning, and motor performance in older HIV+ individuals with and without cognitive impairment (total cohort), compared to younger HIV+ individuals. Among HIV+ patients with dementia, age may be associated with greater impairment in a test of executive functioning. These differences could be a result of advanced age itself or age-associated comorbidities such as coexisting cerebrovascular or neurodegenerative disease.

Lowest ever CD4 lymphocyte count (CD4 nadir) as a predictor of current cognitive and neurological status in human immunodeficiency virus type 1 infection—The Hawaii Aging with HIV Cohort

Low CD4 lymphocyte count was a marker for neurological disease in human immunodeficiency virus type 1 (HIV-1); but is now less common among patients with access to highly active antiretroviral therapy. In this study, the authors determine the reliability of self-reported CD4 nadir and its predictive value for neurological status. The authors identify a high degree of reliability (r = .90). After adjusting for age, current CD4 count, and duration of HIV-1, CD4 nadir relates to a current diagnosis of HIV-associated dimentia (HAD) (odds ratio [OR]: 1.395 (1.106–1.761), P = .005) and distal symmetric polyneuropathy (DSPN) (OR: 1.479 (1.221–1.769, P < .001).

Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report

Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report

Molecular and immunophenotypic characterization of AIDS-associated, Epstein-Barr virus-negative, polyclonal lymphoma.

PURPOSE A molecular analysis of non-Hodgkins lymphomas (NHLs) from patients with AIDS was undertaken to determine the prevalence and immunophenotype of polyclonal B-cell lymphoma. MATERIALS AND METHODS DNA was extracted from 40 diagnostic biopsy specimens obtained from patients seen at University of California, San Francisco (UCSF) between 1986 and 1990. Clonality, infection with Epstein-Barr virus (EBV), and presence of a rearranged c-myc gene were determined by Southern blot analysis. Lymphoma immunophenotypes were determined by frozen-section immunohistochemical analysis. RESULTS The most prevalent genotype of lymphoma in this study was that of polyclonal, EBV-negative tumors with no evidence of c-myc rearrangement (14 of 40; 35%). Monoclonal, EBV-positive tumors with no evidence of c-myc rearrangement comprised the second most prevalent class (10 of 40; 25%), and polyclonal, EBV-positive tumors similar to those seen in transplant patients were observed in only a small subset (three of 40; 8%) of specimens analyzed. The immunophenotype of B cells in the polyclonal EBV-negative subset was equally divided into B-cell-predominant and mixed-phenotype lymphomas, with the latter category containing numerous infiltrating T cells. The B cells in each category were immunoglobulin M-positive (IgM+), CD20+, CD21-. All but one of the polyclonal NHLs had large-cell histology. CONCLUSIONS EBV-negative, AIDS-associated, polyclonal B-cell lymphoma appears to be a new class of human immunodeficiency virus (HIV)-associated disease more prevalent in the current study than any other molecular subclass. The absence of CD21, the EBV receptor, may explain in part the absence of EBV within this polyclonal B-cell population.