Biomedical subjects
Publications and source records attributed to J Burgess.
The activity of a novel series of peptidomimetic hematoregulatory compounds, designed based on a pharmacophore model inferred from the structure activity relationships of a peptide SK&F 107647 (1), is reported. These compounds induce a hematopoietic synergistic factor (HSF) which in turn modulates host defense. The compounds may represent novel therapeutic agents in the area of hematoregulation.
The recent cloning of the gene responsible for multiple endocrine neoplasia type 1 (MEN 1) has opened new avenues for both clinical and basic science research in the field of endocrine oncology. A large amount of genetic information, particularly those in relation to germline and somatic mutations, has since been published during the last 2 years. This new knowledge has provided important insights into its gene function. The significance of these advances in relation to clinical management and future directions for research is discussed.
Contaminating tumor cells in peripheral blood stem cell (PBSC) grafts infused for hematopoietic rescue after high-dose chemotherapy could potentially contribute to relapse in BrCa patients. To date the prevalence of PBSC contamination in BrCa patients, as determined by standard immuno-cytochemistry (ICC) assays, has generally been found to be relatively low. However, assay sensitivity may have an important impact on the ability to detect contamination. In this investigation a novel and highly sensitive BrCa cell assay using immunomagnetic enrichment with a panel of antiBrCa monoclonal antibodies (MAbs) and detection by ICC has been characterized. The immunomagnetic enrichment with ICC detection (IE-ICC) assay was directly compared with standard ICC in ability to detect BrCa contamination of PBSC specimens from patients with high-risk stage II/III and metastatic disease. The sensitivity of the IE-ICC assay was approximately 50-fold greater than that of standard ICC. As determined by standard ICC assay, BrCa cells were present in 1/14 patients (7%) and 2/26 (8%) specimens. In contrast, with IE-ICC assay the proportions of positive findings in patients (12/14, 86%) and specimens (19/26, 73%) were significantly higher (p = 0.001 and p < 0.0005, respectively). These preliminary findings suggest that the prevalence of PBSC contamination may be substantially higher than previously appreciated. Consequently, measures to reduce tumor contamination in the graft may have the potential to improve patient outcomes. Higher sensitivity assays such as the IE-ICC assay may play an important role in assessing the risks associated with tumor contamination and the effectiveness of tumor-purging approaches such as positive selection of CD34+ cells and in monitoring patient response to therapy.
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Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.
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This cross-sectional study of stable HIV-infected children was designed to document the immunological manifestations of paediatric HIV infection and to determine whether inexpensive markers of immunosuppression could be identified. Investigations included lymphocyte count and subset analysis, levels of total protein, albumin, immunoglobulins, beta-2 microglobulin and neopterin. The median age of the 74 children studied was 16.5 months and 76% and 39% had subnormal percentage CD4+ counts and absolute CD4+ counts, respectively. According to the Centers for Disease Control (CDC) guidelines, 85% were moderately or severely immunosuppressed. The majority had elevated neopterin, beta-2 microglobulin, IgG, IgM and IgA concentrations. The IgG concentration correlated positively with total globulin, IgG1 and IgG3 concentrations. On bivariate analysis, the absolute CD4+ count correlated positively with total lymphocyte count (r = 0.28 < 0.48 < 0.64) and negatively with total IgG concentration (r = -0.47 < -0.27 < -0.04), IgG1 concentration (r = -0.51 < -0.31 < -0.08), and neopterin concentration (r = -0.49 < -0.28 < -0.04). There was no correlation between CD4+ count, total globulin or beta-2 microglobulin concentration. On multiple linear regression analysis only the total lymphocyte count correlated with CD4+ count. Furthermore, on bivariate analysis total lymphocyte count correlated positively with absolute CD8+ count (r = 0.82 < 0.88 < 0.92). In conclusion, although there was a positive correlation between absolute CD4+ count and total lymphocyte count, the clinical significance is questionable as the total lymphocyte count correlated more strongly with the absolute CD8+ count.
The development of meat-eating habits of 999 Australian children between 1 and 16 years of age stratified across socioeconomic groups, was determined using a 4-day diary and measurement procedures to document intake. The results indicated that a stable pattern of meat-eating behaviour, as regards the frequency and type of meat eaten was established during the period 1-4 years of age and remained until 10-12 years for males and until at least 14-16 years for females. In contrast, the amount of meat consumed increased with age, the greatest increases occurring with adolescent males who ate the largest amounts of beef, chicken and pork. It is suggested that the early establishment of meat-eating habits may reflect a more general effect that may occur with other types of food.
A phase II prospective, randomized, double blind clinical trial of Bradycor, a bradykinin antagonist, was conducted at 31 centers within North America in severely brain injured patients. Patients of Glasgow Coma Score (GCS) 3-8 (n = 139) with at least one reactive pupil were randomized to receive either Bradycor, 3 microg/kg/min or placebo as a continuous intravenous infusion for 5 days, with the infusion beginning within 12 h of the injury. The primary objective was to assess the efficacy of a continuous infusion of Bradycor (3.0 mc/kg/min) in preventing elevation of intracranial pressure (ICP). Other efficacy measures included the effect of Bradycor on the Therapy Intensity Level (TIL), mortality, and functional outcome. A secondary objective was to evaluate the safety of Bradycor in patients with severe brain injury. Randomization was carried out according to a computer generated randomization list. Patients were followed for the first 14 days of hospitalization with long-term outcome assessed at 3 and 6 months after injury. During the infusion and while the ICP monitor was in place, ICP measurements were recorded hourly along with blood pressure and heart rate. A modified version of the TIL was used to record therapeutic interventions hourly, while the ICP was being monitored. Outcome was assessed at 3 and 6 months after injury using the Glasgow Outcome Score (GOS). Bradycor was well tolerated in this patient population, and no adverse events were attributable to the compound. Although positive trends were seen for both ICP and TIL in the Bradycor group, these differences analyzed on a daily basis were not significant. However, a mixed model of variance which included treatment, day, treatment by day interaction, age and GCS revealed that the percentage time ICP of >15 mm Hg on days 4 and 5 was significantly lower in the Bradycor group compared to placebo (p = 0.035). There were fewer deaths in the Bradycor group, which had a 28-day all cause mortality of 20% versus 27% on placebo. Patients treated with Bradycor showed a 10.3% improvement in favorable outcome at 3 months and a 12% improvement in dichotomized GOS at 6 months (p = 0.26). The consistent positive trends seen in ICP, TIL, neuropsychological tests, and, most importantly, 3- and 6-month GOS provide supportive evidence that a bradykinin antagonist may play a neuroprotective role in severe brain injury.
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Our laboratory described a ca. 34-kDa protein of the HeLa S cell surface that bound an antitumor sulfonylurea N-(4-methylphenylsulfonyl)-N'-(4-chlorophenyl) urea (LY181984) with high affinity and that exhibited NADH oxidase and protein disulfide-thiol interchange activities also inhibited by LY181984. The quinone site inhibitor 8-methyl-N-vanillyl-6-noneamide (capsaicin) also blocked these same enzymatic activities. Using capsaicin inhibition as the criterion, the drug-responsive oxidase was released from the surface of HeLa S cells and purified. The activity of the released capsaicin-inhibited oxidase was resistant to heating at 50 degrees C and to protease digestion. After heating and proteinase K digestion, the activity was isolated in >90% yield by FPLC as an apparent 50- to 60-kDa multimer. Final purification by preparative SDS-PAGE yielded a capsaicin-inhibited NADH oxidase activity of a specific activity indicative of >500-fold purification relative to the plasma membrane. The final activity correlated with a ca. 34-kDa band on SDS-PAGE. Matrix-assisted laser desorption mass spectroscopy as well as reelectrophoresis of the 34-kDa band indicated that the ca. 34-kDa material was a stable mixture of 22-, 17-, and 9.5-kDa components which occasionally migrated as a ca. 52-kDa complex. The purified complex tended to multimerize and formed insoluble 10- to 20-nm-diameter amyloid rods. The components of the purified 34-kDa complex were blocked to N-terminal amino acid sequencing and were resistant to further protease digestion. After multimerization into amyloid rods, the protein remained resistant to proteases even under denaturing conditions and to cyanogen bromide either with or without prior alkylation.
The effects of sensor selection and sensor blending on the cardiovascular response to graded exercise was evaluated in 10 patients (age 74 +/- 2 yrs; 7 men and 3 women) implanted with a dual sensor rate adaptive VVIR pacemaker (Vitatron Topaz model 515). Patients underwent three graded exercise tests (GXT) with sensor programming randomly assigned. For a given graded exercise text the pacemaker was programmed into activity sensing (ACT), QT sensing, or dual sensing (ACT = QT). Data were recorded at rest and during each stage of the graded exercise text. Oxygen uptake (VO2) was measured continuously using a Q Plex I system. Heart rate (HR), stroke volume (SV), and cardiac output (Qc) were measured by impedance cardiography. Systolic time intervals were calculated from simultaneous recordings of the ECG, phonocardiogram, and the impedance cardiogram. In response to the GXT no differences in peak VO2 were observed across the three sensor settings. Regardless of the sensor setting Qc increased linearly with each increment in VO2. The HR response to ACT only pacing was significantly higher than in the other two pacing conditions. During ACT only pacing SV failed to rise in response to exercise. The increased exercise Qc during QT and ACT = QT pacing were mediated by significant increases in both HR and SV. The QT and dual pacing conditions were also associated with longer diastolic filling times. The data indicate that the mechanisms responsible for the increase Qc during exercise were different for ACT versus ACT = QT or QT sensor-driven pacing.
OBJECTIVE: To determine the survival patterns of children in Cape Town known to be vertically infected with HIV. DESIGN: Retrospective record review of children diagnosed with symptomatic HIV infection during the period 1 December 1990-31 May 1995. SETTING: Hospitals in the Cape Town metropolitan area. PATIENTS: 193 children were known to be vertically HIV-infected. HIV diagnosis was based on the following criteria: two positive HIV enzyme-linked immunosorbent assays (ELISAs) in children older than 15 months and a positive ELISA together with a positive polymerase chain reaction (PCR) in younger children. The mothers of the children were known to be HIV-positive. On the basis of the presenting clinical findings children were assigned to a disease severity category (A, B or C) according to the Centers for Disease Control and Prevention (CDC)'s 1994 revised classification system for HIV infection in children. OUTCOME MEASURES: Survival was analysed according to the Kaplan-Meier method. Survival time was defined as the length of time between clinical diagnosis of HIV and death or last contact with the health services. Mortality risk in relation to specific variables at diagnosis such as age and clinical manifestations was determined by calculation of odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: The median age at diagnosis was 5 months; 72% of children were aged less than 1 year at diagnosis. According to the CDC clinical classification, 47 (24%) fell into category A, 111 (58%) into category B and 35 (18%) into category C. Of the 193 patients 85 (44%) were alive at the time of review, 65 (34%) had died and 43 (22%) were lost to follow-up. Risk of death was significantly associated with age less than 6 months (OR 4.7, CI 2.1-10.3) and severe disease, i.e. CDC category C (OR 2.7; CI 1.1-6.9) at time of diagnosis. The median survival for all the children from time of diagnosis was 32 months. Infants diagnosed before 6 months of age had significantly shorter median survival (10 months) compared with 36 months for those diagnosed at 7-12 months of age. For the children over the age of 12 months the cumulative proportion surviving at 48 months was 78%. Children with severe disease (category C) had a median survival of 21 months, significantly lower than that in category B (32 months). For the children in category A the cumulative proportion surviving at 48 months was 66%. CONCLUSION: The median survival of children with HIV was 32 months from time of diagnosis, and survival was influenced by age and disease severity.
Noncoded D-amino acids have been designed to replace the quinaldic amide-asparaginyl moiety (P2/P3 ligand) found in several potent human immunodeficiency virus (HIV) protease inhibitors such as LY289612. The substituted nitrogen, optimally an N-methanesulfonyl moiety, served as a CH2CONH2 (asparagine side chain mimic), while the amino acid side chain became the backbone and P3 ligand of these novel inhibitors. Compounds derived from S-aryl-D-cysteine proved to be potent HIV protease inhibitors which also exhibited potent whole cell antiviral activity. Oxidation of the cysteines to the sulfoxide or sulfone oxidation states resulted in significant improvements in potency. For example, the compound derived from N-(methyl-sulfonyl)-2-S-naphthylcysteine sulfone, 17c, was a 3.5 nM inhibitor of HIV protease which inhibited the spread of virus in MT4 cells with an IC50 = 4.3 nM. Compounds 17c,g,i were found to be orally bioavailable in a rat model.
The department of Veterans Affairs (VA) uses a global budgeting process to allocate congressionally appropriated resources to provide medical care to veterans. The Department of Veterans Affairs has developed this process to accommodate the effects of changes in pure inflation, workload, and cost per unit of work in forecasting operating dollars required for facility global budgets. In 1990, VA began shifting to a new method of allocating its global budget called Resource Planning and Management (RPM), based on a capitated system. Facilities receive resources according to their unit costs and the number and type of patients they are expected to serve. A key characteristic of any global budgeting information system is flexibility. The VA information system accesses the portion of each patients's care that is provided at every facility and aggregates this information across all facilities to create a single prorated patient record; the system reconstructs prior years of data into the new patient-centered format to forecast workload. No other health care system in the United States pays for and directly provides such a diverse set of services for such a large population as does VA. Nevertheless, many of the problems VA faces are similar to those of other providers and insurers.
To explore the use of stem/progenitor cells from peripheral blood (PB) for allogeneic transplantation, we have studied the mobilization of progenitor cells in normal donors by growth factors. Normal subjects were administered either granulocyte-macrophage colony-stimulating factor (GM-CSF) at 10 micrograms/kg/d, or G-CSF at 10 micrograms/kg/d, or a combination of G- and GM-CSF at 5 micrograms/kg/d each, administered subcutaneously for 4 days, followed by leukapheresis on day 5. Mononuclear cells expressing CD34 (CD34+ cells) were selectively enriched by affinity labeling using Dynal paramagnetic microspheres (Baxter Isolex; Baxter Healthcare Corp, Santa Ana, CA). The baseline CD34+ cells in peripheral blood before mobilization was 0.07% +/- 0.05% (1.6 +/- 0.7/microL; n = 18). On the fifth day after stimulation (24 hours after the fourth dose), the CD34+ cells were 0.99% +/- 0.40% (61 +/- 14/microL) for the 8 subjects treated with G-CSF, 0.25% +/- 0.25% (3 +/- 3/microL, both P < .01 v G-CSF) for the 5 subjects administered GM-CSF, and for the 5 subjects treated with G- and GM-CSF, 0.65% +/- 0.28% (41 +/- 18/microL, P < .5 v GM-CSF). Parallel to this increase in CD34+ cells, clonogenic assays showed a corresponding increase in CFU-GM and BFU-E. The total number of CD34+ cells collected from the G-CSF group during a 3-hour apheresis was 119 +/- 65 x 10(6) and was not significantly different from that collected from the group treated with G- and GM-CSF (101 +/- 35 x 10(6) cells), but both were greater than that from the group treated with GM-CSF (12.6 +/- 6.1 x 10(6); P < .01 for both comparisons). Analysis of the CD34+ subsets showed that a significantly higher percentage of cells with the CD34+/CD38- phenotype is found after mobilization with G- and GM-CSF. In the G-CSF group, immunomagnetic selection of CD34+ cells permitted the enrichment of the CD34+ cells in the apheresis product to 81% +/- 11%, with a 48% +/- 12% yield and to a purity of 77% +/- 21% with a 51% +/- 15% recovery in the G- and GM-CSF group. T cells were depleted from a mean of 4.5 +/- 2.0 x 10(9) to 4.3 +/- 5.2 x 10(6) after selection, representing 99.9% depletion. We conclude that it is feasible to collect sufficient numbers of PB progenitor cells from normal donors with one to two leukapheresis procedures for allogeneic transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Solubilities and transfer chemical potentials of carboplatin, cisplatin, iproplatin, and several related platinum complexes have been determined in methanol-water mixtures. The range of solvation behaviour is discussed in relation to possible oral administration of complexes of this type.