Importance of radiation time and dose factors on outcome for childhood medulloblastoma

The purpose of this study was to investigate the relationship of posterior fossa radiation therapy duration (PFRTD) and relapse-free survival (RFS) following adjuvant craniospinal RT for childhood medulloblastoma. A retrospective audit was performed assessing all children aged <18 years managed with adjuvant craniospinal RT for medulloblastoma in Australia and New Zealand in 1980-1993. Children receiving prolonged (>180 days) pre-RT chemotherapy were excluded. Data were obtained for potential prognostic factors in domains of patient, tumour and treatment factors. Radiation therapy time factors assessed were PFRTD and time interval from surgery to commencement of RT (SRTD). The end-point assessed was RFS and analysis was performed using Cox regression and Kaplan-Meier survival. One hundred and eighty-nine children were identified from 10 oncology units, with data available from 182 children for analysis. Median follow up was 5.3 years. Seventy-three per cent of children presented with disease confined to the cerebellum; 13% had initial neuraxis disease. Macroscopic resection was described in 54%; 42% received adjuvant chemotherapy. Median RT dose and RT duration to PF was 55 Gy and 45 days, respectively. Seventy-eight relapses occurred with a 10-year actuarial RFS of 58.2% (standard error +/- 4%). On univariate analysis, increasing PF dose (P = 0.002), age >5 years (P = 0.006), and more thorough extent of surgical resection (P = 0.043) were associated with improved RFS; PFRTD (P = 0.20) and SRTD (P = 0.51) were not associated with RFS. On multivariate analysis, although both PF dose (P = 0.004) and extent of surgery (P = 0.045) remained strongly significant, RT duration was now associated with RFS (P = 0.049). Other factors assessed that did not reach significance were patient age, local tumour extent, presence of internal shunt and use of chemotherapy. The importance of local treatment factors was confirmed in this audit with established prognostic factors such as primary tumour macroscopic resection and adequate PF RT dose being associated with RFS. A treatment time effect is weakly suggested, although less significant than RT dose delivered.     

Dysfunctional autogenous hemodialysis fistulas: outcomes after angioplasty--are there clinical predictors of patency?

PURPOSE: To determine the primary and secondary patency rates for fistulas treated with angioplasty, as well as clinical predictors of fistula patency after angioplasty. MATERIALS AND METHODS: The authors reviewed their institutional experience with autogenous fistulas from June 1997 to June 2002. A total of 104 men and 36 women were treated. Mean age +/- standard deviation of patient cohort was 62.4 years +/- 15.6. Patient age and sex, age of fistula at initial intervention, presence of diabetes, side and location of fistula, location of stenosis, and number of venous stenoses dilated were examined. Patency after angioplasty was estimated by using the Kaplan-Meier method, and predictors of patency were examined by using a Cox proportional hazards model. RESULTS: One hundred fifty-one dysfunctional fistulas (94 radiocephalic and 57 brachiocephalic) were treated with angioplasty initially. Clinical success rate was 98.0% (297 of 303 interventions). At 3, 6, and 12 months, respectively, primary patency rates +/- standard errors of the estimate were 73% +/- 6, 51% +/- 7, and 39% +/- 7 for brachiocephalic fistulas and 85% +/- 4, 75% +/- 5, and 62% +/- 5 for radiocephalic fistulas; secondary patency rates were 96% +/- 2.4, 89% +/- 4, and 85% +/- 5 for brachiocephalic fistulas and 91% +/- 3, 88% +/- 3, and 86% +/- 4 for radiocephalic fistulas. For all time points, there was a significant difference in primary (P =.004) but not secondary (P =.45) patency between radiocephalic and brachiocephalic fistulas. Stenosis was most prevalent within 3 cm of the arteriovenous anastomosis in 74 (64%) of the 116 dysfunctional radiocephalic fistulas and at the cephalic arch in 22 (30%) of the 74 dysfunctional brachiocephalic fistulas. The clinical variables examined did not influence outcome. Complications occurred in seven (2.3%) of 303 interventions. CONCLUSION: Patency after angioplasty in dysfunctional autogenous hemodialysis fistulas exceeds that observed in hemodialysis grafts. None of the clinical or anatomic variables examined affected patency outcome.     

Circling behavior elicited from the pedunculopontine nucleus: evidence for the involvement of hindbrain GABAergic projections

Unilateral microinjection of GABA agonists into the pedunculopontine nucleus (PPN) of the rat resulted in contraversive postural asymmetry and circling behavior; GABA antagonist caused ipsiversive asymmetry and circling when applied to the PPN. A hemitransection was placed immediately caudal to substania nigra (SN) and rostral to PPN in order to interrupt all connections between the PPN and ipsilateral forebrain nuclei. After hemitransection, microinjection of GABAergic drugs into the PPN on the hemitransected side produced postural asymmetry and circling identical to that observed in intact rats. The hemitransection resulted in a loss of glutamic acid decarboxylase activity in PPN (25%) not substantially greater than that observed in animals with unilateral destruction of SN, indicating that a major proportion of GABA terminals in PPN are derived from hindbrain sources. It appears that forebrain (that is, nigrotegmental) GABAergic projections are not essential for the GABA-mediated asymmetry elicited from PPN.     

Endoplasmic reticulum–mitochondria coupling: local Ca2+ signalling with functional consequences

Plasma membrane store-operated Ca²⁺ release-activated Ca²⁺ (CRAC) channels are a widespread and conserved Ca²⁺ influx pathway, driving activation of a range of spatially and temporally distinct cellular responses. Although CRAC channels are activated by the loss of Ca²⁺ from the endoplasmic reticulum, their gating is regulated by mitochondria. Through their ability to buffer cytoplasmic Ca²⁺, mitochondria take up Ca²⁺ released from the endoplasmic reticulum by InsP₃ receptors, leading to more extensive store depletion and stronger activation of CRAC channels. Mitochondria also buffer Ca²⁺ that enters through CRAC channels, reducing Ca²⁺-dependent slow inactivation of the channels. In addition, depolarised mitochondria impair movement of the CRAC channel activating protein STIM1 across the endoplasmic reticulum membrane. Because they regulate CRAC channel activity, particularly Ca²⁺-dependent slow inactivation, mitochondria influence CRAC channel-driven enzyme activation, secretion and gene expression. Mitochondrial regulation of CRAC channels therefore provides an important control element to the regulation of intracellular Ca²⁺ signalling.     

Human immune response to outer membrane protein CD of Moraxella catarrhalis in adults with chronic obstructive pulmonary disease

Moraxella catarrhalis is a common cause of lower respiratory tract infection in adults with chronic obstructive pulmonary disease (COPD). The antibody response to outer membrane protein (OMP) CD, a highly conserved surface protein of M. catarrhalis under consideration as a vaccine antigen, was studied in adults with COPD following 40 episodes of infection or colonization. Following infection or colonization, 9 of 40 patients developed new serum immunoglobulin G (IgG) to OMP CD, as measured by enzyme-linked immunosorbent assay. Adsorption assays revealed that a proportion of the serum IgG was directed toward surface-exposed epitopes on OMP CD in six of the nine patients who developed new IgG to OMP CD. Immunoblot assays with fusion peptide constructs indicated that the new antibodies that developed after infection or colonization recognized conformational epitopes, particularly in the carboxy region of the protein. Three of 28 patients developed new mucosal IgA to OMP CD in sputum supernatants. This study establishes that OMP CD is a target of a systemic and mucosal immune response following infection and colonization in some patients with COPD.     

Implementation of the NCAA Sickle Cell Trait Screening Policy: A Survey of Athletic Staff and Student-athletes

Objective

To describe the perspectives and experiences of athletic trainers, coaches, and student-athletes approximately three years post-implementation of the NCAA sickle cell trait (SCT) screening policy.

Immune reconstitution inflammatory syndrome in association with HIV/AIDS and tuberculosis: Views over hidden possibilities

Background  

CD4+ T lymphocyte (CD4) cell count testing is the standard method for determining eligibility for antiretroviral therapy (ART), but is not widely available in sub-Saharan Africa. Total lymphocyte counts (TLCs) have not proven sufficiently accurate in identifying subjects with low CD4 counts. We developed clinical algorithms using TLCs, hemoglobin (Hb), and body mass index (BMI) to identify patients who require ART.     

An indirect immunofluorescence assay using a cell culture-derived antigen for detection of antibodies to the agent of human granulocytic ehrlichiosis.

An indirect immunofluorescence assay for the detection of human antibodies to the agent of human granulocytic ehrlichiosis (HGE) was developed and standardized. Antigen was prepared from a human promyelocytic leukemia cell line (HL-60) infected with a tick-derived isolate of the HGE agent (USG3). Suitable antigen presentation and preservation of cellular morphology were obtained when infected cells were applied and cultured on the slide, excess medium was removed, and cells were fixed with acetone. Use of a buffer containing bovine serum albumin and goat serum reduced background fluorescence, and use of an immunoglobulin G (gamma-specific) conjugate reduced nonspecific binding. The assay readily detected specific antibody from HGE patients and did not detect antibody from healthy individuals. No significant reactivity was noted in sera from patients with high titers of antibodies to other rickettsial species. We were able to identify antibodies reactive to USG3 antigen in samples from areas where HGE is endemic that had tested negative to other rickettsial agents. Animal sera reactive against Ehrlichia equi or Ehrlichia phagocytophila bound to the HGE antigen, indicating that the assay may be useful for veterinary use. Comparability between two different laboratories was assessed by using coded human sera exchanged between laboratories. Results from the two laboratories were similar, indicating that the assay can be easily integrated into use for routine testing for HGE. The assay was then compared to an assay using horse neutrophils infected with ehrlichiae. The two assays gave comparable results, indicating that the cell culture-derived antigen can be used for testing samples that have been previously tested with E. equi as an antigen. The new assay offers several advantages over other immunofluorescence methods that use animal-derived antigen and is suitable for use in testing for human antibodies to the HGE agent.