Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors.

New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load <400 copies/mL, and CD4+ count ≥500 cells/µL, the 9-year cumulative incidence of ESRD was higher than that of their HIV-negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV-positive individuals with no comorbidities and well-controlled disease may be considered low-risk kidney donor candidates.

Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection.

Expansion of anti-AFP Th1 and Tc1 responses in hepatocellular carcinoma occur in different stages of disease.

BACKGROUND: alpha-Fetoprotein (AFP) is a tumour-associated antigen in hepatocellular carcinoma (HCC) and is a target for immunotherapy. However, there is little information on the pattern of CD4 (Th1) and CD8 (Tc1) T-cell response to AFP in patients with HCC and their association with the clinical characteristics of patients. METHODS: We therefore analysed CD4 and CD8 T-cell responses to a panel of AFP-derived peptides in a total of 31 HCC patients and 14 controls, using an intracellular cytokine assay for IFN-gamma. RESULTS: Anti-AFP Tc1 responses were detected in 28.5% of controls, as well as in 25% of HCC patients with Okuda I (early tumour stage) and in 31.6% of HCC patients with stage II or III (late tumour stages). An anti-AFP Th1 response was detected only in HCC patients (58.3% with Okuda stage I tumours and 15.8% with Okuda stage II or III tumours). Anti-AFP Th1 response was mainly detected in HCC patients who had normal or mildly elevated serum AFP concentrations (P=0.00188), whereas there was no significant difference between serum AFP concentrations in these patients and the presence of an anti-AFP Tc1 response. A Th1 response was detected in 44% of HCC patients with a Child-Pugh A score (early stage of cirrhosis), whereas this was detected in only 15% with a B or C score (late-stage cirrhosis). In contrast, a Tc1 response was detected in 17% of HCC patients with a Child-Pugh A score and in 46% with a B or C score. CONCLUSION: These results suggest that anti-AFP Th1 responses are more likely to be present in patients who are in an early stage of disease (for both tumour stage and liver cirrhosis), whereas anti-AFP Tc1 responses are more likely to be present in patients with late-stage liver cirrhosis. Therefore, these data provide valuable information for the design of vaccination strategies against HCC.

Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.

Virus-specific CD4+ T helper lymphocytes are critical to the maintenance of effective immunity in a number of chronic viral infections, but are characteristically undetectable in chronic human immunodeficiency virus-type 1 (HIV-1) infection. In individuals who control viremia in the absence of antiviral therapy, polyclonal, persistent, and vigorous HIV-1-specific CD4+ T cell proliferative responses were present, resulting in the elaboration of interferon-gamma and antiviral beta chemokines. In persons with chronic infection, HIV-1-specific proliferative responses to p24 were inversely related to viral load. Strong HIV-1-specific proliferative responses were also detected following treatment of acutely infected persons with potent antiviral therapy. The HIV-1-specific helper cells are likely to be important in immunotherapeutic interventions and vaccine development.

17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens.

The effect of 17 beta-estradiol on interleukin-6 (IL-6) synthesis was examined in murine bone marrow-derived stromal cell lines, normal human bone-derived cells, and nontransformed osteoblast cell lines from mice and rats. In all these cell types IL-6 production was stimulated as much as 10,000-fold in response to the combination of recombinant interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF alpha). Addition of 17 beta-estradiol in the cultures exerted a dose-dependent inhibition of IL-1-, TNF-, and IL-1 + TNF-induced production of bioassayable IL-6. Testosterone and progesterone (but not 17 alpha-estradiol) also inhibited IL-6, but their effective concentrations were two orders of magnitude higher than 17 beta-estradiol. 17 beta-estradiol also decreased the levels of the IL-6 mRNA. In addition, estradiol inhibited both TNF-induced IL-6 production and osteoclast development in primary bone cell cultures derived from neonatal murine calvaria. The TNF-stimulated osteoclast development was also suppressed by a neutralizing monoclonal anti-IL-6 antibody. This in vitro evidence suggests, for the first time, a mechanistic paradigm by which estrogens might exert at least part of their antiresorptive influence on the skeleton.

Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide.

The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappaB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappaB (IkappaB) proteins. NF-kappaB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kappaB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappaB leads to overexpression of the anti-apoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the anti-apoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappaB in certain breast cancer cells. We also demonstrate that NF-kappaB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IkappaBalpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappaB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappaB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of IkappaBalpha by inhibiting NF-kappaB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappaB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 - 4169

A trial of recombinant alpha 2 interferon in the myelodysplastic syndromes: I. Clinical results.

Interferon has been reported to have differentiation promoting effects in certain model systems. Because of this and other potentially beneficial effects, a trial of recombinant alpha 2 interferon was undertaken in myelodysplastic syndromes. The study population consisted of 14 patients, subclassified as two refractory anemia (RA), one RA with ring sideroblasts (RARS), nine RA with excess blasts (RAEB), and two chronic myelomonocytic leukemia (CMMoL). The planned dosage schedule was 2.0 MU/M2 t.i.w. sc x 2 weeks q 4 weeks for at least two cycles. No patient achieved the prospective remission criteria, which included sustained blood count improvements. Transient improvements of platelet counts of greater than 50% in baseline were noted in six patients, and a transient antileukemic effect was noted in one patient with CMMoL. Myelodysplastic syndrome patients were found to be sensitive to the count suppressing effects of alpha 2 interferon with greater than 25% suppression of granulocytes, platelets, or reticulocytes transiently noted in 11 patients and decreasing bone marrow cellularity noted in two while on treatment. Because of these effects, dosage adjustments were frequently instituted in the RA, RARS, and RAEB patients. The average dosages and durations of treatment received were thus 1.48 MU/M2 x 19.4 injections for patients with RA, RARS, and RAEB and 2.25 MU/M2 x 27 injections for the CMMoL patients. Progression to acute myeloid leukemia or RAEB in transformation was noted in five patients, and increasing leukocytosis was noted in one CMMoL patient while on protocol. It cannot be determined at this time whether these transformations were accelerated by alpha 2 interferon or represent selection bias in this study population. Although some evidence of beneficial effects was noted, alpha 2 interferon in this dosage and schedule is not a useful treatment for myelodysplastic syndromes.

Forced over-expression of the myeloid zinc finger gene MZF-1 inhibits apoptosis and promotes oncogenesis in interleukin-3-dependent FDCP.1 cells.

The myeloid zinc finger protein MZF-1 is important in hematopoiesis. Previous studies have found that reducing expression of MZF-1 inhibited G-CSF-driven human marrow colony formation assays. In this study we found that retrovirally overexpressing MZF-1 in IL-3-dependent FDCP.1 cells inhibited their apoptosis when IL-3 was withdrawn. The MZF-1-transduced FDCP.1 cells also formed tumors when injected into congenic mice, whereas control FDCP.1 cells did not.

Studies on the regulation of hemopoiesis.

Normal hemopoietic cell differentiation and proliferation is critically dependent upon marrow stromal elements. Long-term liquid culture of marrow provides a model for the study of stromal function. We evaluated the effects of radiation and 5-fluorouracil (5-FU) on various aspects of long-term murine hemopoietic cell growth and stromal function. Exposure of C57BL/6J murine adherent cells from long-term marrow cultures to varying doses of irradiation (0-1000 rad) in vitro resulted in the elaboration of growth factors stimulating granulocyte, macrophage, megakaryocyte, mixed megakaryocyte-granulocyte macrophage, and blast colonies. This increased production of growth factors appears to be related to the ablation of normal granulocyte production in the culture system since addition of normal stroma to irradiated stroma blocks growth factor production. Two cell types appear to be mediating stromal factor production and support of liquid culture hemopoiesis: a macrophagelike cell and an alkaline-phosphatase-positive epithelioid cell. Exposure of these two cell types to pokeweed mitogen results in marked enhancement of growth factor production. Furthermore, a cell line isolated from normal murine stroma produced an activity capable of acting at an early hemopoietic stem cell level and of inducing secondary marrow cell lines. The establishment of cultures from 5-FU-treated animals revealed that chemotherapy-depleted marrow was capable of establishing adequate stromal function and that the residual surviving stem cells had a higher than normal proliferative rate. In addition, the function of granulocytes derived from this post-5-FU marrow was normal. Thus, it appears that both chemotherapy and radiation exposure of marrow results in an enhanced capacity of stromal elements to produce growth factors and support hemopoiesis and that post-5-FU marrow represents an enriched source of high proliferative potential bone marrow stem cells.

Aerosol pentamidine prophylaxis following Pneumocystis carinii pneumonia in AIDS patients: results of a blinded dose-comparison study using an ultrasonic nebulizer.

PURPOSE: To compare the efficacy and safety of three different doses of prophylactic aerosol pentamidine in patients with one prior episode of Pneumocystis carinii pneumonia (PCP) and the acquired immunodeficiency syndrome. PATIENTS AND METHODS: The design of the study was a double-blind, randomized, dose-comparison clinical trial conducted at 13 medical centers within the United States. In stage I of the trial, patients were randomized to receive either 5 mg, 60 mg, or 120 mg of aerosol pentamidine delivered biweekly with the Fisoneb (Fisons, Inc., Rochester, New York) ultrasonic nebulizer. After 24 weeks of therapy, patients entered stage II of the trial, where the 5-mg group was re-randomized to either the 60-mg or 120-mg group. RESULTS: One hundred seventy-five patients entered stage I of the trial and received prophylaxis for a mean of 123.6 days. Seven assigned to the 5-mg biweekly dosing schedule had a confirmed recurrence of PCP, compared with none in the 60-mg group (p = 0.007) and three in the 120-mg group (p = 0.304). During stage II of the trial, eight patients in the 60-mg group and one additional patient in the 120-mg group had recurrent PCP. After 52 weeks of observation, the likelihood of being PCP-free was 88.0% in the 60-mg group and 93% in the 120-mg group (p = 0.712). Minor adverse events related to aerosol pentamidine administration included cough, taste perversion, chest pain, bronchospasm, and dyspnea. These side effects were more common in the 60-mg and 120-mg treatment groups and resulted in withdrawal from the study by one patient. Serious events were more common after 24 weeks of therapy and included asymptomatic hypoglycemia (five), pancreatitis (two), pneumothorax (one), and extrapulmonary pneumocystosis (one). CONCLUSIONS: These results demonstrate that biweekly administration of 60 mg or 120 mg of aerosol pentamidine significantly decreases PCP recurrence when compared with a 5-mg regimen or findings in historic controls and is generally well tolerated. There is no significant difference in effect or safety between these two dosing regimens in patients followed for at least 52 weeks of therapy.

Mutant H-ras over-expression inhibits a random apoptotic nuclease in myeloid leukemia cells.

Cell suicide, or apoptosis, is now recognized as an essential regulatory step in such diverse developmental processes as embryogenesis, thymocyte restriction, and hematopoiesis. One of the major features of apoptosis is the activation of an endogenous nuclease that cleaves DNA into nucleosomal fragments. Little is known about the activation or specificity of the apoptotic endonuclease. In this study, we investigated signalling pathways and the specificity of the apoptotic nuclease. We found that forced over-expression of activated H-ras inhibited activation of the apoptotic endonuclease. Since a high percentage of myelodysplasias and leukemias have mutations that activate ras, this finding lends insight into how ras might be leukemogenic. In addition, the phorbol ester TPA and a cyclic AMP analogue also slowed activation of this endonuclease. Interestingly, protein synthesis inhibition stimulated the endonuclease activity. In addition, by cloning and sequencing apoptotic fragments we found that the apoptotic nuclease has no sequence specificity. Thus, the apoptotic nuclease inhibited by H-ras over-expression was random in nature.

Sonographic diagnosis of partial hydatidiform mole.

We undertook a study to determine whether partial hydatidiform mole could be distinguished from other cases of first-trimester missed abortion using ultrasound. Scans from 22 cases of pathologically proved partial hydatidiform mole and 33 cases of first-trimester missed abortion were independently reviewed by three radiologists, each unaware of the final pathologic diagnosis. Using a standard data form, each radiologist recorded the dimensions, shape, and contents of the gestational sac, the sonographic appearance of the decidual reaction/placenta and myometrium, and the presence or absence of adnexal cysts. The following two criteria were found to be significantly associated (P less than .05) with the diagnosis of partial mole: 1) ratio of transverse to anteroposterior dimension of the gestational sac greater than 1.5, and 2) cystic changes, irregularity, or increased echogenicity in the decidual reaction/placenta or myometrium. There was high interobserver correlation for both criteria, as measured by the kappa statistic. In 50% of the cases, either both or neither of these criteria were met. When both criteria were met, the frequency of partial mole was 87%; when neither criterion was met, the frequency of missed abortion was 90%. These results indicate that ultrasound can be of value in predicting a high likelihood of partial mole prior to curettage.

Two strategies to increase adherence to HIV antiretroviral medication: life-steps and medication monitoring.

Advances in the medical treatment of HIV have made it clear that adherence to highly active antiretroviral treatment is a crucial feature for treatment success. The present paper had two goals: (1) to examine psychosocial predictors of adherence in persons receiving HIV antiretroviral therapy; (2) to compared two minimal-treatment interventions to increase HIV medication adherence in a subset of persons who self-reported less than perfect adherence. One of the interventions, Life-Steps, is a single-session intervention utilizing cognitive-behavioral, motivational interviewing, and problem-solving techniques. The other intervention, self-monitoring, utilizes a pill-diary and an adherence questionnaire alone. Significant correlates of adherence included depression, social support, adherence self-efficacy, and punishment beliefs about HIV. Depression was a significant unique predictor of adherence over and above the other variables. Both interventions yielded improvement in adherence from baseline, and the Life-Steps intervention showed faster improvements in adherence for persons with extant adherence problems.

Building the dental dream team: behavioral styles in the practice.

There are four different behavioral styles evident in a dental team and in patients. The styles are based on observable behaviors relating to degrees of "assertiveness" and "responsiveness." The Behavioral Style model helps to clarify why some people relate positively with each other and why others may conflict. Using finely tuned observational skills and an understanding of these styles, interpersonal transactions can be more effective, dental teams become more cohesive, and patients will be more satisfied with service provided in the dental practice. Each member of the team should understand his/her own personal style and those of teammates. Once that understanding is gained by all, it may be effectively applied to understanding patients. Behavior modification is at the heart of this concept. Adjusting your own behavior to the needs of others enables a patient to achieve more comfort with the dental team, and they are more likely to hear your verbal messages.

Immersion: building a foundation for long-term patient relationships.

The highest compliment a patient can give a dental staff is to say that they make him or her feel like part of the "family." Building this kind of positive long-term patient relationship begins with the first telephone contact. Taking the time to fully "immerse" the patient in the practice through confidence- and communication-building steps will help create a fulfilling patient-staff relationship.

Post-sexual exposure prophylaxis: a roundtable discussion.

AIDS: Mitchell Katz, Julie Gerberding, and Steve Boswell, experts involved in post-exposure prophylaxis of HIV infection, discuss using such measures to prevent possible sexual transmission of HIV infection. The risk of contracting HIV via sexual exposure is similar to the risk from an occupational needlestick injury; however, the type of sex, i.e., anal vs. vagina or insertive vs. receptive, dictates the degree of risk. Due to uncertainties in predicting the exact risk, the physicians recommend offering prophylaxis to people who have had sex with someone known to be HIV-infected or at high risk for being infected. Minimum program needs to provide effective post-sexual exposure prophylaxis are outlined, including the types of facilities best suited to treat patients. Emergency rooms are convenient; however, staff generally lack the expertise to properly treat these patients. If emergency rooms are used, follow-up should be received at other facilities, such as STD clinics. Persons seeking repeated post-sexual exposure prophylaxis should be dealt with on a case-by-case basis. The public health system or government should bear the treatment costs under the rubric of research.^ieng

Flexibility and traditionality in children's gender roles.

The present study examined the correlates of variability in children's gender-role preferences. A multidimensional test battery assessed the traditionality of preferences of 376 kindergarten and third grade children in five different gender role domains, and elicited information about three significant socialization agents (parents, peers, and media). Parents of the children (N = 358) were also interviewed with regard to their attitudes and sex role socialization practices. Predictions were generated from an existing theoretical developmental model. Boys exhibited stronger sex-typed preferences than did girls. Older girls were more flexible and older boys less flexible than were their younger counterparts. In accordance with prediction, two factors were obtained; the first relevant to current gender-related activities, the other to future expectations. Present-oriented gender preferences correlated best with peer perceptions, whereas future expectations (e.g. job aspirations) were best predicted by media choices. Parental data correlated with children's preferences but not as strongly as did the peer and media scales. Predictability of children's gender-role orientations was reasonably high when a number of factors were included, thus supporting the utility of a multidimensional approach.