Higher risk of AIDS or death in patients with lower CD4 cell counts after virally suppressive HAART

Background The clinical implications of a failure to achieve high CD4 cell counts while receiving virally suppressive highly active antiretroviral therapy (HAART) are uncertain.
Methods We analysed data from HIV-infected men participating in the Multicenter AIDS Cohort Study (MACS) to elucidate associations between CD4 cell counts achieved during virally suppressive HAART and risks of AIDS or death. Inclusion criteria were: CD4 cell count <200 cells/μL before HAART initiation; ≥2 viral load (VL) determinations after HAART initiation; and sustained viral suppression, defined as all VL <50 HIV-1 RNA copies/mL, but allowing a single VL of 50–1000 copies/mL.
Results One hundred and twenty-one men were included; median age was 42 years. After first VL <50 copies/mL, six participants had a new AIDS diagnosis and seven died. The median CD4 cell count change/year (cells/μL) after first VL <50 copies/mL was zero among patients who either developed AIDS or died vs . 39 among those who did not meet either endpoint ( P =0.119). After controlling for time from HAART initiation to first VL <50 copies/mL, age at first VL <50 copies/mL, history of AIDS and antiretroviral therapy (ART) experience before HAART, the hazard ratio for AIDS or death at CD4 cell count of ≤200 vs . >350 cells/μL was 10.7 ( P =0.013), and at CD4 cell count of 201–350 vs . >350 cells/μL was 8.54 ( P =0.014).
Conclusion In this cohort, lower CD4 cell count at the time of viral suppression was associated with increased risk of AIDS or death.     

Prevalence of human T-cell leukemia/lymphoma virus (HTLV) type II infection among high-risk individuals: type-specific identification of HTLVs by polymerase chain reaction

The extent of human T-cell leukemia/lymphoma virus type II (HTLV-II) infection and its rate of spread have been difficult to determine owing to the serological cross-reactivity between HTLV-I and HTLV-II. The present study overcame this problem by directly detecting type-specific proviral sequences by means of the polymerase chain reaction (PCR) and liquid hybridization. Screening was performed on a cohort of primarily white intravenous drug abusers (IVDAs), and individuals of other behaviorally defined risk groups from the New York City area. Eleven percent (19 of 169) of the individuals in these high-risk groups were determined by PCR to have HTLV-II proviral infections. One of these patients displayed an exfoliative erythrodermatitis. Thirteen of the 19 subjects were positive in an HTLV-II enzyme-linked immunosorbent assay (ELISA). The remaining six individuals, although negative in the HTLV- II ELISA, were confirmed as HTLV-II positive by analyzing their DNA with a second HTLV-II-specific primer detector system. Four additional individuals were reactive in the HTLV-II ELISA but were PCR-negative for HTLV-II. PCR analysis for HTLV-I revealed that all four were positive for that virus. Thirty-seven percent (seven of 19) of the HTLV- II PCR-positive subjects were also PCR-positive for HTLV-I, and 84% (16 of 19) of the HTLV-II positive individuals were infected with human immunodeficiency virus (HIV-1). Six individuals were triply infected with HTLV-I, HTLV-II, and HIV-1.     

Detection of HIV-1-infected cells from patients using nonisotopic in situ hybridization

We have demonstrated that a sensitive, nonisotopic in situ hybridization (ISH) assay can be used to detect HIV-infected cells from seropositive, asymptomatic individuals. Our assay is based on the detection of a biotinated HIV DNA probe hybridized to human immunodeficiency virus (HIV)-infected peripheral blood lymphocytes (PBL) using streptavidin and alkaline phosphatase to identify positive cells. This assay is rapid in that it can be performed within a day and is sensitive enough to unambiguously identify a rare, single, positive cell. Patient samples derived from HIV-seropositive hemophiliacs and HIV-seropositive infants were analyzed before and after coculture with normal PBL. The same samples were investigated using a Dupont P24 antigen-capture kit. It was found that ISH always detected the same positive samples as antigen capture, often in shorter times of coculture. In situ hybridization detected over half of our HIV-infected hemophilia patient population as virus positive, whereas the antigen capture assay detected less than one fourth as virus positive. In situ hybridization detected positive cells directly, without coculture, in 12 out of 35 (34%) hemophiliacs and in three out of eight (37%) infants. The speed, sensitivity, and confidence of ISH and nonisotopic detection indicates that it will be useful as a tool for clinical research and diagnosis.     

Production of anti-B monoclonal antibodies (DBB.42, DBA.44, DNA.7, and DND.53) reactive on paraffin-embedded tissues with a new B-lymphoma cell line grafted into athymic nude mice

A new B-lymphoma cell line (DEAU-cell line) was established from a diffuse large-cell lymphoma (centroblastic type) and was successfully grafted in athymic nude mice. Monoclonal antibodies (MoAbs) were generated using splenocytes of DEAU-tumor bearing mice. Before the fusion experiments, cellular immunity of the mice bearing growing DEAU tumors was restored by injection of spleen cells from conventional Balb/C mice. Spleen cells from conventional Balb/C mice immunized with DEAU-cell line were also used for the generation of MoAbs. Four MoAbs (DBB.42 and DBA.44 from normal Balb/C mice, and DNA.7 and DND.53 from athymic nude mice) were investigated because they identified B-cell- associated antigens not destroyed by fixatives. DBB.42 recognized a pan- B cell-associated antigen (molecular weight (mol wt) = 45 Kd). DBA.44 detected a B-cell antigen (mol wt not determined) expressed on a subpopulation of B lymphocytes in the mantle zone of lymphoid follicles. DNA.7 also defined a B-cell antigen (43 Kd) mainly expressed on germinal center cells. Similarly, DND.53 recognized a B-cell antigen (two bands of mol wt 20 Kd and 35 Kd, respectively) mainly expressed on germinal center cells and mantle zone lymphocytes and interdigitating reticulum cells in the paracortical area. Major differences were found in the reactivities of these MoAbs on malignant lymphomas. DBB.42 was positive with almost all B-cell lymphomas and some T-cell lymphomas. Within the group of low-grade B-cell lymphomas, DBA.44 reacted principally with hairy-cell leukemia. DNA.7 reacted mainly with high- grade B-cell lymphomas with a weak positivity in low-grade B-cell lymphomas. DND.53 reacted with all but one B-cell lymphoma, cells of histiocytosis X, and Reed-Sternberg cells. These findings indicate that new MoAbs can be generated by using spleen cells from athymic mice bearing human tumors as well as by new lymphoid cell lines. The MoAbs so generated, as in the present study, are deemed potentially useful for the recognition of B-cell lymphomas in routine diagnostic histopathology. In addition, DND.53 could be of value for the diagnosis of histiocytosis X and the detection of Reed-Sternberg cells in Hodgkin's disease.     

Frequent delayed spontaneous seroclearance of hepatitis B virus after incident HBV infection among adult high‐risk groups

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)‐positive for > 6 months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985‐2002) who had anti‐hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan‐Meier curves. A total of 147 incident HBV infections occurred during follow‐up. On initial HBsAg testing after infection (6‐12 months), 42 (29%) were HBsAg‐positive and 105 (71%) were HBsAg‐negative (‘standard HBsAg seroclearance’). Of the 42 initially HBsAg‐positive individuals, 22 subsequently tested HBsAg‐negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg‐negative and HBV DNA‐negative (‘delayed HBsAg seroclearance’), while 27 remained HBsAg and/or HBV DNA‐positive (‘chronic HBV’). The 5‐year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg‐positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)‐co‐infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at‐risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct‐acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co‐infected MSM/PWUD are warranted prior to treatment initiation.     

Risk and significance of endoscopic/radiological evidence of recurrent Crohn's disease

BACKGROUND & AIMS: The aim of this study was to determine the risk of endoscopic/radiological recurrence of Crohn's disease postoperatively and the long-term outcome. METHODS: A randomized placebo-controlled trial was performed to determine the effectiveness of mesalamine in preventing recurrent Crohn's disease postoperatively. Patients in the control group were examined endoscopically/radiologically before entry into and annually during the trial. Findings were classified as minimal or severe. RESULTS: There were 76 patients (49 men and 37 women; mean age, 37.1 +/- 13.2 years). Fifty (61.7%) had terminal ileal resections. Overall, 55 endoscopic/radiological recurrences were observed in 51 patients (67.1%). Expressed actuarially, the recurrence rate was 27.5% at 1 year (95% confidence interval [CI], 15.8%-37.6%), 60.8% at 2 years (95% CI, 46%-71.3%), and 77.3% at 3 years (95% CI, 62.7%-86.3%). Nineteen (37%) were symptomatic and 12 (24%) were initially asymptomatic but later became symptomatic (mean, 13.0 +/- 8.8 months), whereas 20 (39%) remained asymptomatic (mean, 16.9 +/- 17.4 months). Patients with severe endoscopic/radiological disease were significantly more likely to be or become symptomatic than those with minimal disease (23 of 32 vs. 8 of 19, respectively; P = 0.0437). CONCLUSIONS: This study suggests that postoperative endoscopic/radiological recurrences occur later than previously reported. Furthermore, many of these patients, especially with minimal disease, will remain asymptomatic. (Gastroenterology 1997 Dec;113(6):1823-7)     

A novel deletion of approximately 27 kb including the beta-globin gene and the locus control region 3'HS-1 regulatory sequence: beta zero- thalassemia or hereditary persistence of fetal hemoglobin?

A novel deletion of approximately 27 kb with the 5' breakpoint 1.5 to 2.2 kb upstream of the beta-globin gene, and the 3' breakpoint approximately 24 kb downstream of the beta-globin gene, has been found in five members of two families from Southeast Asia (Vietnam and Cambodia). Six members of another family from China, previously reported from our laboratory, have also been shown to carry this deletion. The patients presented with mild hypochromia and microcytosis, a hemoglobin (Hb) A2 level of approximately 4.0%, and a markedly increased, heterocellularly distributed, Hb F level (14.0 to 26.0%). In vitro globin-chain synthesis showed a mild imbalance with appreciable gamma-chain compensation (alpha/beta + gamma ratio of 1.46). The 3' end of this deletion includes the 3'HS-1, and we hypothesize that removal of this region results in the loss of its gamma-globin gene-silencing effect, which causes a markedly elevated Hb F level with a modest increase in Hb A2 levels, unlike the situation in other deletional beta zero-thalassemias. The possible influence of particular sequence variations in the locus control region 5'HS-2 and the G gamma promoter, present on the chromosome with this deletion, on the overall gamma-globin gene should also be considered.     

胎儿和新生儿同种异体免疫性血小板减少症:进展与持续性争议

胎儿和新生儿同种异体免疫性血小板减少症(AIT)是引起胎儿和新生儿严重血小板减少的最常见原因.母亲针对源自父亲的胎儿血小板抗原的IgG抗体,在妊娠早期就可通过胎盘,通常导致胎儿严重血小板减少.由于一些血小板减少症临界值(50、100或150×109/L)的不同,他们的发生率亦各不相同.但在多数未经选择的人群中,AIT影响1/1 000到1/2 000活产数.在新生儿病房,临床确诊的重症AIT很罕见,可能只有1:10 000分娩数.     

胎儿和新生儿同种异体免疫性血小板减少症:进展与持续性争议

胎儿和新生儿同种异体免疫性血小板减少症(AIT)是引起胎儿和新生儿严重血小板减少的最常见原因.母亲针对源自父亲的胎儿血小板抗原的IgG抗体,在妊娠早期就可通过胎盘,通常导致胎儿严重血小板减少.由于一些血小板减少症临界值(50、100或150×109/L)的不同,他们的发生率亦各不相同.但在多数未经选择的人群中,AIT影响1/1 000到1/2 000活产数.在新生儿病房,临床确诊的重症AIT很罕见,可能只有1:10 000分娩数.     

Hemoglobin-spectrin complexes: interference with spectrin tetramer assembly as a mechanism for compartmentalization of band 1 and band 2 complexes

The irreducible complexation of hemoglobin with spectrin is a natural phenomenon of red blood cell aging, positively correlating with increasing cell density and decreasing cell deformability. The current study begins to address the role of these complexes in the disruption of membrane skeletal physiology and structure. The effect of bound hemoglobin on spectrin dimer self-association was investigated in vitro. The extent of conversion of isolated spectrin dimers to tetramers was evaluated as a function of peroxide-induced globin complexation before the conversion incubations. The incremental accumulation of tetramer was observed to decrease with increasing peroxide concentration used in the globin complexation step. The role of oxidized heme in this process was made apparent by the inability of carboxyhemoglobin to inhibit tetramer accumulation. A Western blot analysis of naturally formed globin-spectrin conjugates demonstrated irreducible complexes of globin with both bands 1 and 2. The complexes are tentatively designated "h1" and "h2". This analysis also demonstrated that h1 is completely extractable from cell ghosts, whereas h2 is only 50% extractable. These findings are incorporated into a hypothesis linking globin-spectrin complexation and the consequent inhibition of spectrin dimer self-association to the clustered band 3 senescence antigen (Low et al, Science 227:531, 1985).