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.

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.

Postoperative shoulder surgery initiative (POSSI): an interim report of major shoulder surgery as a day case procedure.

BACKGROUND: There are logistical and financial advantages to undertaking shoulder surgery in a day case setting. However, this approach is limited by postoperative pain being inadequately controlled by oral medication alone. We describe a pilot study investigating the feasibility and acceptance of community based continuous interscalene brachial plexus blockade (CIBPB) to provide effective analgesia for day case shoulder surgery. METHODS: Phase 1 consisted of five patients who received CIBPB for shoulder surgery. Following an overnight hospital stay they were assessed for discharge home with the interscalene catheter in situ. Once the safety and feasibility of the approach was documented, five more patients were recruited to Phase 2. These patients had the adequacy of analgesia assessed in the postoperative period and were discharged home on the same day as surgery. A district nurse visited twice daily and removed the catheter on the third day. Patient satisfaction was assessed using a discovery interview. RESULTS: Nine of the 10 patients experienced good analgesia. One patient was re-admitted because the catheter fell out. No patient experienced complications and the discovery interviews showed that the patients were satisfied with their management and pleased to be treated as a day case. CONCLUSIONS: POSSI proved that it was feasible to manage these patients in the community with support and training of the district nurses. Although extra community nursing hours are required, this technique has the potential for significant cost benefits with at least three bed days saved per patient.

T regulatory cells and the control of allergic disease.

Allergic diseases are caused by the induction of T helper (Th)2 cells and IgE responses specific for common environmental antigens (allergens) in susceptible individuals. There is increasing interest in the role of both naturally occurring and induced regulatory T cell (Treg) populations in preventing these inappropriate immune responses and the underlying sensitisation to allergens. Current evidence suggests that Tregs may actively prevent Th2 responses to allergens occurring in healthy non-atopic individuals and that their function may be impaired in allergic patients. Evidence that existing therapies may act by modulating Treg function is reviewed. Future research aims to understand the mechanisms involved in the generation and function of allergen-specific Tregs. A primary aim is to promote the development of optimised therapeutic regimens with the capacity to provide long-lasting, allergen-specific, inhibitory mechanisms at the time and site of allergen challenge.

Nonadherence to medical appointments is associated with increased plasma HIV RNA and decreased CD4 cell counts in a community-based HIV primary care clinic.

This study examined the association of appointment nonadherence to markers of disease severity using one year of demographic and health information on 995 individuals with HIV in primary care at an urban community health centre. At the latest visit, 106 of 946 valid cases (11.2%) had a CD4 less than or equal to 200, and 454 of 936 valid cases (48.5%) had detectable plasma HIV RNA (greater than 50 copies/ml). Using logistic regression, appointment nonadherence (number of missed appointments) was a significant predictor (p < .03) of having an AIDS-defining CD4 count over and above the effects of number of kept appointments (p < .0001), and whether or not the patient was taking HAART (p < .002). Appointment nonadherence was also a significant predictor (p < .05) of having a detectable viral load over and above the effects of number of kept appointments (p < .003), HAART (p < .0001) and age (p < .004). Looking only at individuals with a detectable viral load at the earliest visit, the only significant unique predictor of improvement to an undetectable viral load at the latest visit was being on HAART (p < .05). Looking at those only with an undetectable viral load at the earliest visit, the only predictor of declining to a detectable viral load was number of kept appointments (p < 003), and being on HAART (p < .05).

Halocarbon and dimethyl sulphide studies around the Mascarene Plateau.

Air-sea exchange is thought to be one of the major routes by which halocarbons and dimethyl sulphide reach the troposphere and stratosphere. Once there, in different ways, they participate in chemical reactions that have implications for ozone depletion and climate change. The gases are released by phytoplankton and other algae, but our present understanding of the sources and sinks is insufficient to establish a balanced global budget. Published data suggest that there are regions of coastal and ocean waters that constitute a major source, but, for halocarbons, in other regions the ocean is a net sink. For example, in many open oceanic areas, the rate of degradation of methyl bromide outweighs production. Here we present data from the Central Indian Ocean, a region considered to be low in terms of biological productivity. Little is known about trace-gas release from the Central Indian Ocean and without such data it is impossible to even hazard a guess at the global ocean source to the atmosphere.

Use of an on-line pager system to increase adherence to antiretroviral medications.

Adherence to antiretroviral therapy is critical for treatment success. Antiretroviral therapy typically requires multiple pills at multiple dosing times. To address this, we tested the feasibility, utility, and efficacy of a customizable reminder system using pagers, which were programmed using web-based technology, to increase and maintain proper adherence in patients with pre-existing adherence problems. After a two-week monitoring period with an electronic pill-cap, participants with less than 90% adherence were randomized to continue monitoring or to receive a pager. The group who received the pagers had greater improvements in adherence from baseline to Week 2 and Week 12 than those who monitored their medications only. However, adherence in both groups at the outcome assessments points was still poor. While the provision of a reminder system helped improve adherence, it is likely that more intensive interventions are required for patients with pre-existing problems.

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.

Multiple effector functions mediated by human immunodeficiency virus-specific CD4(+) T-cell clones.

Mounting evidence suggests that human immunodeficiency virus type 1 (HIV-1) Gag-specific T helper cells contribute to effective antiviral control, but their functional characteristics and the precise epitopes targeted by this response remain to be defined. In this study, we generated CD4(+) T-cell clones specific for Gag from HIV-1-infected persons with vigorous Gag-specific responses detectable in peripheral blood mononuclear cells. Multiple peptides containing T helper epitopes were identified, including a minimal peptide, VHAGPIAG (amino acids 218 to 226), in the cyclophilin binding domain of Gag. Peptide recognition by all clones examined induced cell proliferation, gamma interferon (IFN-gamma) secretion, and cytolytic activity. Cytolysis was abrogated by concanamycin A and EGTA but not brefeldin A or anti-Fas antibody, implying a perforin-mediated mechanism of cell lysis. Additionally, serine esterase release into the extracellular medium, a marker for cytolytic granules, was demonstrated in an antigen-specific, dose-dependent fashion. These data indicate that T helper cells can target multiple regions of the p24 Gag protein and suggest that cytolytic activity may be a component of the antiviral effect of these cells.

Mesenteric and renal oxygen transport during hemorrhage and reperfusion: evaluation of optimal goals for resuscitation.

BACKGROUND: Changes in flow to the gut and the kidney during hemorrhage and resuscitation contribute to organ dysfunction and outcome. We evaluated regional and splanchnic oxygen (O2) flow distribution and calculated oxygen supply distribution during hemorrhage and reperfusion and compared them with global measures. METHODS: Seven anesthetized pigs were instrumented to evaluate global hemodynamics, visceral blood flow, and oxygen transport. Tonometric pH probes were positioned in the stomach and jejunum. Animals were bled to 45 mm Hg for 1 hour. Crystalloids and blood were infused during the following 2 hours to normalize blood pressure, heart rate, urine output, and hemo- globin. RESULTS: During hemorrhage, mesenteric flow and O2 consumption were significantly decreased, whereas systemic consumption remained normal. Renal flow was reduced, but renal O2 consumption remained normal. After resuscitation, despite normal hemodynamics, neither systemic, mesenteric, nor renal O2 delivery returned to baseline. Lactate remained significantly increased. Arterial pH, base excess, and gastric and jejunal pH were all decreased. CONCLUSION: During hemorrhage, the gut is more prone than other regions to O2 consumption supply dependency. After resuscitation, standard clinical parameters do not detect residual O2 debt. Lactate, arterial pH, base excess, and intramucosal gut pH are all markers of residual tissue hypoperfusion.

The evolution of the Fenway Community Health model.

Fenway Community Health was founded by community activists in 1971 in the Fenway neighborhood of Boston, Mass, and within a decade had rapidly expanded its medical services for gay men in response to the AIDS epidemic. Increased expertise and cultural competence in lesbian, gay, bisexual, and transgender (LGBT) care led to expansion of medical services to address broader community concerns, ranging from substance use to parenting issues to domestic and homophobic violence, as well as specialized programs for lesbians, bisexuals, and transgendered individuals. Fenway began as a grassroots neighborhood clinic. In 1975, the center recorded 5000 patient care visits; in 2000, Fenway's clinical departments recorded 50,850 visits by 8361 individuals, including more than 1100 individuals receiving HIV-associated care. The center now has more than 170 staff people responsible for clinical programs, community education, research, administration, planning, and development. Over the past few years, Fenway's annual budget has exceeded $10 million. Fenway has established standards for improved cultural competence about LGBT health issues for other health providers and has developed programs to educate the general community about specific LGBT health concerns. This health center may provide a model of comprehensive LGBT health services that have a local impact.

Control of HIV-1 viremia and protection from AIDS are associated with HLA-Bw4 homozygosity.

Certain HLA-B antigens have been associated with lack of progression to AIDS. HLA-B alleles can be divided into two mutually exclusive groups based on the expression of the molecular epitopes HLA-Bw4 and HLA-Bw6. Notably, in addition to its role in presenting viral peptides for immune recognition, the HLA-Bw4, but not HLA-Bw6, motif functions as a ligand for a natural killer cell inhibitory receptor (KIR). Here, we show that profound suppression of HIV-1 viremia is significantly associated with homozygosity for HLA-B alleles that share the HLA-Bw4 epitope. Furthermore, homozygosity for HLA-Bw4 alleles was also significantly associated with the ability to remain AIDS free and to maintain a normal CD4 T cell count in a second cohort of HIV-1-infected individuals with well defined dates of seroconversion. This association was independent of the presence of a mutation in CC chemokine receptor 5 (CCR5) associated with resistance to HIV-1 infection, and it was independent of the presence of HLA alleles that could potentially confound the results. We conclude that homozygosity for HLA-Bw4-bearing B alleles is associated with a significant advantage and that the HLA-Bw4 motif is important in AIDS pathogenesis.

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.

Identification of novel HLA-A2-restricted human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte epitopes predicted by the HLA-A2 supertype peptide-binding motif.

Virus-specific cytotoxic T-lymphocyte (CTL) responses are critical in the control of human immunodeficiency virus type 1 (HIV-1) infection and will play an important part in therapeutic and prophylactic HIV-1 vaccines. The identification of virus-specific epitopes that are efficiently recognized by CTL is the first step in the development of future vaccines. Here we describe the immunological characterization of a number of novel HIV-1-specific, HLA-A2-restricted CTL epitopes that share a high degree of conservation within HIV-1 and a strong binding to different alleles of the HLA-A2 superfamily. These novel epitopes include the first reported CTL epitope in the Vpr protein. Two of the novel epitopes were immunodominant among the HLA-A2-restricted CTL responses of individuals with acute and chronic HIV-1 infection. The novel CTL epitopes identified here should be included in future vaccines designed to induce HIV-1-specific CTL responses restricted by the HLA-A2 superfamily and will be important to assess in immunogenicity studies in infected persons and in uninfected recipients of candidate HIV-1 vaccines.

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

Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: A randomized controlled trial.

CONTEXT: While interleukin 2 (IL-2) is capable of inducing a marked expansion of the CD4 T-lymphocyte pool, limited data exist on whether IL-2 treatment can add significantly to the immunologic and virologic effects of potent antiretroviral therapy (ART). OBJECTIVE: To determine the rate and magnitude of CD4 cell recovery and viral suppression when using a combination therapy of IL-2 and ART compared with ART alone. DESIGN AND SETTING: Randomized, controlled multicenter trial conducted from April 1996 through April 1998 at 8 clinical sites in the United States. PATIENTS: Eighty-two adult outpatients who were infected with human immunodeficiency virus (HIV) and had baseline CD4 cell counts of 200 x 10(6)/L to 500 x 10(6)/L and baseline RNA levels of fewer than 10,000 copies/mL were randomized; 78 completed the study. INTERVENTIONS: Thirty-nine patients were randomly assigned to receive a combination therapy of subcutaneous IL-2 (administered in 5-day courses every 8 weeks at a starting dosage of 7.5 mIU twice per day) and ART; 43 were to receive ART therapy alone. MAIN OUTCOME MEASURES: Interleukin 2 safety and differential effects on CD4 cell counts, CD4 cell percentages, and plasma HIV RNA levels. RESULTS: The mean (SD) percentage increase in CD4 cell counts at 1 year for patients who received IL-2 was 112% (113%) compared with 18% (35%) in recipients of ART alone (P<.001). Both groups had mean (SD) increases in CD4 cell percentage: from 20.4% (6.3%) to 32.3% (12.4%) for the combination therapy group compared with 20.4% (5.1%) to 23.0% (7.2%) for recipients of ART alone (P<.001). Using a sensitive viral RNA assay, mean viral load changes were -0.28 and 0.09 log(10) copies for IL-2 recipients and control patients, respectively (P=.03). Twenty (67%) of 30 evaluable patients receiving IL-2 achieved final viral loads of fewer than 50 copies/mL compared with 13 (36%) of 36 control patients (P=.02). Toxic effects were common among patients who received IL-2 and were managed with antipyretics, hydration, rest, and dosage reduction as needed. CONCLUSIONS: Intermittent therapy with IL-2 and ART produced a substantially greater increase in CD4 cells and was associated with a larger decrease in viral load than ART alone. Clinical end-point trials will be necessary to determine whether the enhanced viral suppression and CD4 cell increases associated with IL-2 therapy will translate into improved clinical outcomes. JAMA. 2000;284:183-189

External fixation as a bridge to intramedullary nailing for patients with multiple injuries and with femur fractures: damage control orthopedics.

BACKGROUND: The advantages of early fracture fixation in patients with multiple injuries have been challenged recently, particularly in patients with head injury. External fixation (EF) has been used to stabilize pelvic fractures after multiple injury. It potentially offers similar benefits to intramedullary nail (IMN) in long-bone fractures and may obviate some of the risks. We report on the use of EF as a temporary fracture fixation in a group of patients with multiple injuries and with femoral shaft fractures. METHODS: Retrospective review of charts and registry data of patients admitted to our Level 1 trauma center July of 1995 to June of 1998. Forty-three patients initially treated with EF of the femur were compared to 284 patients treated with primary IMN of the femur. RESULTS: Patients treated with EF had more severe injuries with significantly higher Injury Severity Scores (26.8 vs. 16.8) and required significantly more fluid (11.9 vs. 6.2 liters) and blood (1.5 vs. 1.0 liters) in the initial 24 hours. Glasgow Coma Scale score was lower (p < 0.01) in those treated with EF (11 vs. 14.2). Twelve patients (28%) had head injuries severe enough to require intracranial pressure monitoring. All 12 required therapy for intracranial pressure control with mannitol (100%), barbiturates (75%), and/or hyperventilation (75%). Most patients had more than one contraindication to IMN, including head injury in 46% of cases, hemodynamic instability in 65%, thoracoabdominal injuries in 51%, and/or other serious injuries in 46%, most often multiple orthopedic injuries. Median operating room time for EF was 35 minutes with estimated blood loss of 90 mL. IMN was performed in 35 of 43 patients at a mean of 4.8 days after EF. Median operating room time for IMN was 135 minutes with an estimated blood loss of 400 mL. One patient died before IMN. One other patient with a mangled extremity was treated with amputation after EF. There was one complication of EF, i.e., bleeding around a pin site, which was self-limited. Four patients in the EF group died, three from head injuries and one from acute organ failure. No death was secondary to the fracture treatment selected. One patient who had EF followed by IMN had bone infection and another had acute hardware failure. CONCLUSION: EF is a viable alternative to attain temporary rigid stabilization in patients with multiple injuries. It is rapid, causes negligible blood loss, and can be followed by IMN when the patient is stabilized. There were minimal orthopedic complications.

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.