Relationships of emerging biomarkers of cancer cachexia with quality of life, appetite, and cachexia.

PURPOSE: Quality of life (QoL), appetite, cachexia, and biomarkers [albumin, hemoglobin (Hb), neutrophils, lymphocytes, platelets, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin 8 (IL-8), C-X-C motif chemokine ligand 5 (CXCL5) and citrullinated histoneH3 (H3Cit)] were compared for 40 cases with advanced cancer and 40 healthy controls. Baseline differences and significant relationships were explored for biomarkers with QoL, appetite, and cachexia. METHODS: In a prospective case-control, age and sex matched study, the European Organisation for the Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC-QLQ-C30) for QoL, the Functional Assessment of Anorexia and Cachexia Therapy assessment (FAACT A/CS-12) for appetite, and a five-factor cachexia assessment tool for cachexia assessment were performed. Routine hematological measurements and blood chemistry analyses together with ELISA procedures and a Multiplex® bead array platform, were used for biomarker analysis. Descriptive statistics and regression analyses were undertaken. P < 0.05 defined statistical significance. RESULTS: Global health status (QL-G), functional scales (QL-FS), and symptom scales (QL-SS) differed for cases and controls (p < 0.01). In cases, differences were observed for QL-G (p < 0.01), QL-FS (p < 0.01), and QL-SS (p = 0.01) compared to standardized references values. FAACT A/CS-12 scores differed significantly between cases and controls (p < 0.01) and 30% of cases scored "poor" appetites. Cachexia was present in 60% of cases. Albumin, lymphocytes, platelets, Hb, platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), CRP, TNFα, all at p < 0.01, neutrophil to lymphocyte ratio (NLR) (p = 0.02), IL-6 (p < 0.04), and IL-8 (p = 0.02) differed significantly between cases and controls. No difference was found for CXCL5 or H3Cit. Albumin NLR, Hb, PLR, SII, TNFα, IL-8, and CRP showed significant relationships with all aspects of QoL. QL-FS was significantly related to CXCL5 (p = 0.04), significant relationships with FAACT A/CS-12 included: NLR (p = 0.002), Hb (p < 0.001), and PLR (p < 0.01). NLR, PLR, SII, TNFα, IL-6, IL-8, and CRP correlated positively to cachexia and albumin while Hb and lymphocyte count correlated negatively to cachexia. CONCLUSION: CXCL5 and H3Cit were not reliable biomarkers for cancer cachexia, nor significantly related to QoL, appetite or cachexia. Albumin, NLR, Hb, PLR, SII, TNFα, IL-8, and CRP were reliable indicators of QoL, appetite, and cachexia. Future research should include other novel biomarkers namely growth differentiation factor-15 (GDF-15), fibroblast growth factor 21 (FGF-21), fractakline, interferon gamma (IFN-y), IL-16, macrophage colony stimulating factor (M-CSF), and macrophage procoagulant-inducing factor (MPIF).

HIV as a Cause of Immune Activation and Immunosenescence.

Systemic immune activation has emerged as an essential component of the immunopathogenesis of HIV. It not only leads to faster disease progression, but also to accelerated decline of overall immune competence. HIV-associated immune activation is characterized by an increase in proinflammatory mediators, dysfunctional T regulatory cells, and a pattern of T-cell-senescent phenotypes similar to those seen in the elderly. These changes predispose HIV-infected persons to comorbid conditions that have been linked to immunosenescence and inflamm-ageing, such as atherosclerosis and cardiovascular disease, neurodegeneration, and cancer. In the antiretroviral treatment era, development of such non-AIDS-defining, age-related comorbidities is a major cause of morbidity and mortality. Treatment strategies aimed at curtailing persistent immune activation and inflammation may help prevent the development of these conditions. At present, the most effective strategy appears to be early antiretroviral treatment initiation. No other treatment interventions have been found effective in large-scale clinical trials, and no adjunctive treatment is currently recommended in international HIV treatment guidelines. This article reviews the role of systemic immune activation in the immunopathogenesis of HIV infection, its causes and the clinical implications linked to immunosenescence in adults, and the therapeutic interventions that have been investigated.

The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public-private partnerships for the development of new strategies to tackle antibiotic resistance.

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than €660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

Emerging markers of cancer cachexia and their relationship to sarcopenia.

PURPOSE: Emerging biomarkers of cancer cachexia and their roles in sarcopenia and prognosis are poorly understood. Baseline assessments of anthropometrics, sarcopenia, cachexia status and biomarkers of cachexia were measured in patients with advanced cancer and healthy controls. Thereafter, relationships of the biomarkers with cachexia and sarcopenia were explored. METHODS: A prospective case-control design was used, including 40 patients with advanced cancer and 40 gender, age-matched controls. Bioelectrical impedance [skeletal muscle index (SMI)] and hand dynamometry [hand grip strength (HGS)] assessed sarcopenia and a validated tool classified cancer cachexia. Albumin, lymphocyte and platelet counts, haemoglobin, C-reactive protein (CRP), pro-inflammatory cytokines/chemokines and citrullinated histone H3 (H3Cit) were measured. RESULTS: Patients had significantly lower SMI (6.67 kg/m2 versus 7.67 kg/m2, p = < 0.01) and HGS (24.42 kg versus 29.62 kg) compared to controls, with 43% being sarcopenic. Significant differences were found for albumin, lymphocyte and platelet counts, haemoglobin, CRP, and tumour necrosis factor α (TNFα), (p < 0.01). Interleukin (IL)-6 (p < 0.04), IL-8 (p = 0.02), neutrophil/lymphocyte ratio (NLR), p = 0.02, platelet/lymphocyte (PLR) ratio, p < 0.01 and systemic immune inflammatory index (SII), p < 0.01 differed significantly. No difference was observed for CXC motif chemokine ligand 5 [CXCL5 or epithelial neutrophil-activating peptide 78 (ENA78)] or H3Cit. Albumin and haemoglobin correlated negatively with total protein, skeletal muscle mass and SMI (all p < 0.01). The presence of sarcopenia associated significantly with albumin, haemoglobin and CRP. CONCLUSION: Significant relationships and differences of haemoglobin, CRP and albumin supports future use of these biomarkers in cancer cachexia. CXCL5 and H3Cit as valuable biomarkers in cancer cachexia remains to be defined.

Manganese promotes increased formation of hydrogen peroxide by activated human macrophages and neutrophils in vitro.

Although pro-inflammatory mechanisms have been implicated in the pathogenesis of manganese (Mn²âº)-related neurological and respiratory disorders, relatively little is known about the potential of this metal to interact pro-oxidatively with human phagocytes. The primary objective of the current study was to investigate the effects of Mn²âº as MnCl2 (0.5-100 µM) on the generation of the reactive oxygen species (ROS), superoxide, hydrogen peroxide (H2O2), and hypohalous acids by isolated human blood neutrophils and monocyte-derived macrophages following activation of these cells with the chemotactic tripeptide, FMLP (1 µM), or the phorbol ester, PMA (25 ng/mL). Generation of ROS was measured using the combination of oxygen consumption, lucigenin/luminol-enhanced chemiluminescence, spectrofluorimetric detection of oxidation of 2,7-dichlorodihydrofluorescein, radiometric assessment of myeloperoxidase (MPO)-mediated protein iodination, release of MPO by ELISA, and spectrophotometric measurement of nitrite formation. Treatment of activated neutrophils with either FMLP or PMA resulted in significantly decreased reactivity of superoxide in the setting of increased formation of H2O2 and MPO-mediated iodination, with no detectable effects on either oxygen consumption or MPO release. Similar effects of the metal with respect to superoxide reactivity and H2O2 formation were observed with activated macrophages, while generation of NO was unaffected. Taken together with the findings of experiments using cell-free ROS-generating systems, these observations are compatible with a mechanism whereby Mn²âº, by acting as a superoxide dismutase mimetic, increases the formation of H2O2 by activated phagocytes. If operative in vivo, this mechanism may contribute to the toxicity of Mn²âº.

Interactive inhibitory effects of formoterol and montelukast on activated human neutrophils.

The research question addressed in the current study was: do formoterol (1 and 10 nM) and montelukast (2 µM) possess interactive inhibitory effects on activated human neutrophils, particularly in relation to alterations in cyclic AMP and cytosolic Ca²(+) fluxes? Isolated human blood neutrophils were activated with the chemoattractant N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) (1 µM) in combination with cytochalasin B (CB; 3 µM). Fura-2-acetoxymethyl ester-based spectrofluorimetry, lucigenin-enhanced chemiluminescence, colorimetric and flow cytometric procedures were used to measure cytosolic Ca²(+) fluxes, production of superoxide, elastase release and beta-2 integrin (CR3) expression, respectively, while cyclic AMP and leukotriene (LT)B4 were assayed using competitive binding ELISA procedures. Activation of the cells with fMLP/CB resulted in abrupt and sustained increases in cytosolic Ca²(+), as well as release of elastase and production of superoxide and LTB4, and expression of CR3, all of which were attenuated by formoterol and montelukast individually, and especially by the combination of these agents. These anti-inflammatory effects of each agent, as well as the combination, were associated with significant increases in cyclic AMP. The findings of the current study may explain the efficacy of montelukast and formoterol when used in combination with inhaled corticosteroids in the treatment of severe asthma, possibly by controlling neutrophil-driven inflammation of the airways.

Posaconazole attenuates leukotriene B4 release and uptake of calcium by chemoattractant-activated human neutrophils: a potential strategy to control neutrophil-mediated inflammation.

OBJECTIVES: This study was designed to investigate the neutrophil-targeted anti-inflammatory potential of posaconazole (0.1-5 microM, equivalent to 0.7-3.9 mg/L) by measuring the effects of this agent on the release of leukotriene B(4) (LTB(4)) and store-operated uptake of Ca(2+) following stimulation of human neutrophils with platelet-activating factor (200 nM). METHODS: LTB(4) release and uptake of Ca(2+) by the cells were measured using an enzyme immunoassay and fura-2/AM-based spectrofluorimetric procedures, respectively. RESULTS: Treatment of neutrophils with posaconazole resulted in dose-related attenuation of PAF-activated release of LTB(4) and influx of Ca(2+), which attained statistical significance at 1 microM of the antimycotic. CONCLUSIONS: Although primarily an antimycotic, posaconazole possesses secondary anti-inflammatory activities, which may contribute to the therapeutic efficacy of this agent in patients with sepsis.

Leukotrienes C4 and D4 sensitize human neutrophils for hyperreactivity to chemoattractants.

OBJECTIVE AND DESIGN: To investigate the sensitizing effects of the cysteinyl leukotrienes (CysLTs) C(4) and D(4) on the proinflammatory responses of chemoattractant-activated human neutrophils in vitro. MATERIALS: Neutrophils were isolated from venous blood taken from healthy, adult, human volunteers. TREATMENT: Cells were exposed to LTC(4) and LTD(4) (50-300 nM) prior to activation with 1 microM of N-formyl-L-methionyl- L-leucyl-L-phenylalanine (fMLF). METHODS: A fura-2/AM-based spectrofluorimetric procedure, lucigenin-enhanced chemiluminescence (LECL), a colourimetric method and an ELISA procedure, were used to measure Ca(2+) mobilization, superoxide production, elastase and MMP-8 release respectively following activation of LTC(4)/ D(4)-primed neutrophils with fMLF. Superoxide generation was also measured in the presence and absence of the CysLT receptor 1 antagonist, montelukast (100 nM). RESULTS: Exposure of neutrophils to either LTC(4) or LTD(4) alone had modest effects on Ca(2+) mobilization, while superoxide generation and elastase release were unaffected. However, relative to the responses of neutrophils activated with fMLF in the absence of the CysLTs, pre-treatment of the cells with either LTC(4)or LTD(4) resulted in significant, augmentation of fMLF-activated elastase and MMP-8 release and superoxide generation, which was attenuated by montelukast. CONCLUSION: These previously undocumented sensitizing interactions of LTs C(4) and D(4) with neutrophils may contribute to the activation of these cells in acute and chronic inflammation of both atopic and non-atopic aetiology, while identifying a role for montelukast in regulating neutrophil reactivity.

Strategies for screening cord blood for a public cord blood bank in high HIV prevalence regions.

The probability of a Black African finding a matched unrelated donor for a hematopoietic stem cell transplant is minimal due to the high degree of genetic diversity amongst individuals of African origin. This problem could be resolved in part by the establishment of a public cord blood (CB) stem cell bank. The high prevalence of human immunodeficiency virus (HIV) amongst women attending antenatal clinics in sub-Saharan Africa together with the risk of mother-to-child transmission increases the risk of transplant transmissible infection. In addition to screening the mother in a period inclusive of 7 days prior to the following delivery, we propose that all CB units considered for storage undergo rigorous and reliable screening for HIV. The Ultrio-plus® assay is a highly specific and sensitive test for detecting HIV, hepatitis-B and hepatitis-C viruses in peripheral blood. We validated the Ultrio-plus® assay for analytical sensitivity in detecting HIV in CB at the level of detection of the assay. Until more comprehensive and sensitive methods are developed, the sensitivity and reliability of the Ultrio-plus® assay suggest that it could be used for the routine screening of CB units in conjunction with currently recommended maternal screening to reduce the risk of transplant transmissible infection.

Expression of soluble triggering receptor expressed on myeloid cells-1 in childhood CF and non-CF bronchiectasis.

BACKGROUND: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is demonstrating promise as an inflammatory biomarker of acute infection in various pulmonary conditions; including community acquired pneumonia, ventilator associated pneumonia and non-tuberculous mycobacterial infection. INTRODUCTION: The expression of sTREM-1 has been poorly studied in all forms of bronchiectasis, both in the context of cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis. METHOD: Induced sputum samples were collected for sTREM-1 determination in children with HIV-associated bronchiectasis and CF-bronchiectasis. The presence or absence of an exacerbation was noted at study entry. Lung function parameters (FEV1, FVC, FEV1 /FVC, FEF(25-75)) were measured using the Viasys SpiroPro Jaeger Spirometer (Hoechberg, Germany). RESULT: A total of twenty-six children with HIV-associated bronchiectasis and seventeen with CF were included. With respect to sTREM-1, the levels were readily detected in both groups, but were significantly higher in children with HIV-associated bronchiectasis (1244.0 pg/ml (iqr 194.5; 3755.3 pg/ml) and 204.9 pg/ml (iqr 66.9; 653.6 pg/ml) P = 0.003. There was a positive correlation between sTREM-1 and IL-8 as well as sputum neutrophil elastase in the HIV-bronchiectasis group (r = 0.715 and r = 0.630), respectively both P < 0.005. sTREM-1 was not further increased in subjects presenting with an acute pulmonary exacerbation in the HIV-associated bronchiectasis and in CF participants (P = 0.971 and P = 0.481), respectively. In the CF group sTREM-1 strongly correlated with FVC% predicted and FEV1 % predicted (r = 0.950 and r = 0.954), both P < 0.005. CONCLUSION: The pulmonary innate immune functions are over-active in HIV-associated bronchiectasis, with readily detected sTREM-1 values, which were higher than those in CF. sTREM-1 does not correlate with markers of HIV-disease activity but does correlate with markers of neutrophilic inflammation. In CF sTREM-1 has a negative correlation with pulmonary function parameters.

A dose-ranging study to evaluate the safety and efficacy of abacavir alone or in combination with zidovudine and lamivudine in antiretroviral treatment-naive subjects.

OBJECTIVE: To compare antiretroviral efficacy, safety and tolerance of three dosing regimens of the novel nucleoside reverse transcriptase inhibitor, abacavir (1592U89) over 24 weeks and its efficacy in open-label combination with zidovudine and lamivudine. DESIGN: Sixty HIV-1-infected antiretroviral therapy naive subjects (entry criteria; CD4+ cell count > or = 100 cells/mm(3), plasma HIV-1 RNA > or = 30 000 copies/ml), randomized into 20 subjects per cohort received 100, 300 or 600 mg abacavir twice daily. Subjects successfully completing 24 weeks' randomized therapy could switch to open label therapy (abacavir, zidovudine, lamivudine at 300, 300 and 150 mg twice daily, respectively) for a further 24 weeks of studly, as could subjects meeting one or more switch criteria. METHODS: Subjects were assessed for antiretroviral activity by measuring changes in plasma HIV-1 RNA load and CD4+ cell counts. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: At week 4, subjects receiving 300 or 600 mg abacavir twice daily had greater reductions in plasma HIV-1 RNA (median changes -1.55 and -1.61 log10) copies/ml, respectively); differences (P = 0.007 and P < or = 0.001, respectively) than subjects receiving 100 mg abacavir twice daily (median change, -0.63 log10 copies/ml). Differences between the 300 and 600 mg twice daily groups were not clinically or statistically significant. At 24 weeks, analysis showed a median change in plasma HIV-1 RNA of -0.70 and -1.30 log10 copies/ml in the 300 and 600 mg twice daily groups, respectively. During the open label phase in which zidovudine/lamivudine was added to 300 mg abacavir twice daily, a further median reduction in plasma HIV-1 RNA of 1.74 log10 copies/ml was seen. At 48 weeks pooled data from all abacavir-treated subjects showed a sustained reduction in plasma HIV-1 RNA of 2.8 log10) copies/ml; 65% and 43% of subjects had < or = 400 and < or = 50 HIV-1 RNA copies/ml, respectively, and a further median increase of 111 CD4+ cells/mm3 were seen. Abacavir was generally well tolerated with few clinically significant adverse events. Two subjects (3.3%) developed hypersensitivity reactions to abacavir. There were no differences between the groups with regard to serious adverse events. CONCLUSIONS: In terms of antiretroviral therapy naive subjects, treatment with 300 or 600 mg abacavir twice daily was statistically superior to a 100 mg twice daily dose at 4 weeks. Combinations therapy containing abacavir-zidovudine-lamivudine was a highly effective antiretroviral regimen, resulting in substantial reductions in plasma HIV-1 RNA which may be comparable to combinations containing protease inhibitors. Abacavir was generally tolerated.

Cytomegalovirus as a cause of morbidity in heart transplantation. The experience of one center.

The accumulated data from 78 heart transplant recipients surviving for more than one month postoperatively were reviewed; the median duration of follow up was 16 months. Cytomegalovirus (CMV) disease was seen most frequently in recipients of hearts from CMV-seropositive donors, irrespective of the recipient CMV antibody status. CMV-related illness was detected in 13 patients; of the six who developed pneumonitis, five were CMV-seropositive recipients with seropositive donors. CMV was not a common cause of hepatitis or gastrointestinal symptoms.

Dissociation of the PAF-receptor from NADPH oxidase and adenylate cyclase in human neutrophils results in accelerated influx and delayed clearance of cytosolic calcium.

The magnitude and duration of the abruptly occurring increases in cytosolic Ca2+ in human neutrophils following activation with PAF (20 and 200 nM) and FMLP (1 microM), have been compared and related to alterations in NADPH oxidase activity, membrane potential and intracellular cyclic AMP. Cytosolic Ca2+ and membrane potential were measured by spectrofluorimetry, transmembrane fluxes of Ca2+ by radiometric procedures, and NADPH oxidase activity and cyclic AMP by chemiluminescence and radioimmunoassay respectively. Activation of neutrophils with both PAF (200 nM) and FMLP (1 microM) was accompanied by an abrupt increase in cytosolic Ca2+, which was of similar magnitude for each activator (393+/-9 and 378+/-17 nM respectively). Unlike FMLP-activated cells in which Ca2+ was rapidly removed from the cytosol, peak levels of cytosolic Ca2+ were sustained for longer (0.14+/-0.02 vs 1.16+/-0.04 min, P

Platelet-activating factor and lyso-PAF possess direct antimicrobial properties in vitro.

The effects of platelet-activating factor (PAF) and lyso-platelet-activating factor (L-PAF) at concentrations of 0.25-20 microg/ml on potassium transport and growth of gram-positive and gram-negative bacteria have been investigated in vitro and compared with those of lysophosphatidylcholine (LPC). Potassium transport was determined using 86Rb+ as tracer, while growth was measured according to the extent of uptake of radiolabeled amino acids. All of the test phospholipids caused dose-related inhibition of 86Rb+-uptake and growth of gram-positive bacteria, the order of potency being PAF>LPC>L-PAF. Gram-negative bacteria, on the other hand, were less sensitive to the inhibitory effects of the phospholipids on K+ transport and growth. Some, but not all, of the gram-positive and gram-negative bacteria were able to degrade LPC, but not PAF or L-PAF, demonstrating that enzymatic degradation of phospholipids does not explain the differential sensitivity to these agents. The bioactive phospholipids LPC, PAF and L-PAF may represent an oxygen-independent antimicrobial host defense system operative primarily against gram-positive bacteria.

A polymerase chain reaction to detect a spliced late transcript of human cytomegalovirus in the blood of bone marrow transplant recipients.

A reverse transcription (RT) nested polymerase chain reaction (PCR) procedure is described for detecting RNA to a spliced late gene (SLG) of human cytomegalovirus (CMV), the product of which (175 bp) is easily differentiated in agarose gels from the product when the target is unspliced viral RNA or DNA (258 bp). The SLG-RT-PCR has been compared against a semi-quantitative PCR for CMV DNA in buffy-coat specimens collected weekly after bone marrow transplantation from 3 patients and against the results of culturing these specimens for CMV both by conventional virus isolation, based on the detection of cytopathic effect, and by the early detection of infected cells by staining with virus-specific monoclonal antibodies. The detection of CMV RNA by SLG-RT-PCR correlated well with the detection of infective virus but only when the results of both culture methods were combined, in that neither culture method alone was as sensitive as the SLG-RT-PCR. The presence of SLG RNA in the circulation is of value as a marker of active CMV infection.

Hypersensitivity reactions during therapy with the nucleoside reverse transcriptase inhibitor abacavir.

BACKGROUND: Hypersensitivity reactions consist of a variable group of clinical findings and have been described for a wide variety of chemical compounds. OBJECTIVE: This review characterizes the clinical profile of hypersensitivity to the nucleoside reverse transcriptase inhibitor abacavir sulfate. METHODS: We performed a retrospective medical review of pooled adverse events data from approximately 200,000 patients who received abacavir in clinical trials, through expanded-access programs, or by prescription from 1996 through 2000. Screened cases of hypersensitivity were classified as either definitive or probable. Definitive cases were identified when initial symptoms resolved on interruption of abacavir therapy and returned on reintroduction of abacavir therapy. RESULTS: A total of 1803 cases were identified, 1302 in the 30,595 patients participating in clinical trials or the expanded-access program and 501 in patients from the post-marketing experience. On review, 176 (9.8%) of these cases were considered definitive and the remainder probable. Based on the 1302 cases identified in clinical trials or the expanded-access program, the calculated incidence of hypersensitivity was 4.3%. Symptoms reported in > or = 20% of cases of this multiorgan reaction included fever, rash, malaise/fatigue, and gastrointestinal symptoms such as nausea, vomiting, and diarrhea, among others. Respiratory symptoms occurred in 30% of cases and included dyspnea (12%), cough (10%), and pharyngitis (6%). In 90% of cases, hypersensitivity reactions occurred within the first 6 weeks after initiation of abacavir (median time, 11 days); after an initial reaction, rechallenge with abacavir resulted in the reappearance of symptoms within hours of reexposure. Hypotension was present in 25% of these rechallenge reactions. Among patients who received abacavir in clinical trials, the mortality rate was 0.03% (3 per 10,000 patients). CONCLUSIONS: Hypersensitivity to abacavir is an idiosyncratic reaction and a distinct clinical syndrome characterized predominantly by systemic involvement. It can be expected to appear as a treatment-limiting event in approximately 5% of patients. The appearance of clinical symptoms consistent with this syndrome mandates immediate discontinuation of abacavir. Hypersensitivity to abacavir is an absolute contraindication to subsequent treatment with any formulation that includes this agent.

The metaphyseal blanch sign of slipped capital femoral epiphysis.

In the early stage of slipping of the capital femoral epiphysis, the epiphysis slips posteriorly in relation to the neck of the femur. When this occurs, the posterior portion of the femoral head is seen on the anteroposterior radiograph as a crescent-shaped area of increased density overlying the metaphysis adjacent to the epiphyseal plate. This metaphyseal blanch sign suggests that slipping of the capital femoral epiphysis has occurred and that a lateral radiograph should be made to confirm or exclude the diagnosis.

Gluteus medius and minimus insertion advancement for correction of internal rotation gait in spastic cerebral palsy.

The gluteus medius and minimus muscles were transferred in twenty-six patients (forty-two hips) with spastic cerebral palsy. The transfer of the insertion of these muscles from the greater trochanter to the anterior part of the femur was done to change their function from that of inward rotators to that of outward rotators of the hip. In the follow-up period, ranging from three to eleven years, the transferred muscles functioned as outward rotators without sacrificing their abduction strength in 90 per cent of the patients. The failures were due primarily to lack of integrity of the transferred muscle insertion. No increase in valgus angulation of the femoral neck was recorded except when the integrity of the trochanteric apophysis had ben compromised. Additionally, in ten patients (thirteen hips) who were operated on when they were from five to eight years old and were followed to skeletal maturity, the angle of anteversion was reduced to at least 25 degrees (range, 18 to 36 degrees). This procedure is indicated in the patient with spastic cerebral palsy to correct an inward-rotation gait caused by hyperexcitable gluteus medius and minimus muscles. It has been useful in eliminating the problems of clumsiness on running and walking associated with tripping, falling, fatigability, and excessive shoe-wear without compromising the abduction power of the gluteus medius and minimus.

Partial or complete resection of the hemipelvis. An alternative to hindquarter amputation for periacetabular chondrosarcoma of the pelvis.

After excision of the hemipelvis through a combined subnatal and anterior incision preserving the lower extremity, five patients with periacetabular chondrosarcoma, after a follow-up of three to six years, were able to walk with no support or with minimum lateral support and had resumed their preoperative occupations. None had either the instability that might have been anticipated or incapacitating discomfort from the neoarthrosis, and there was no evidence of spread or recurrence of tumor in any of the five patients. The procedure, which has the same basic indications as a hindquarter amputation, is a rewarding substitute for that mutilating operation, although the follow-up is too short and the series is too small to warrant conclusions as to the cure rate.