Prognosis of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer by immunological urinary measurements: statistically weighted syndrome analysis

PURPOSE: The goal of this research was to discover new biological indicators in urine which could be used for short-term prognosis of local Bacillus Calmette-Guerin (BCG) therapy outcome in patients with superficial bladder cancer. PATIENTS AND METHODS: We measured and statistically evaluated soluble immunological molecules in urine from bladder cancer patients (n = 34) receiving BCG intravesically. Urine was collected following each of 6 weekly treatments, processed and assayed. The data base included measurements of interleukin-1 (IL-2, IL-4, IL-6, IL-10, IL-12, soluble intercellular adhesion molecule-1 (sICAM-1), tumour necrosis factor-alpha (TNF alpha), soluble CD14 (sCD14), interferon-gamma (IFN gamma), GM-CSF, volume of urine and its pH. The clinical response was evaluated by urine histology and random quadrant biopsy 3 months after the start of therapy. Patients were divided into 2 groups, with good and poor therapeutic effect. The initial complete response rate was 62% (21/34). The data base was analyzed using traditional multivariate statistical methods and a pattern recognition method which deals with combinatorial-statistical analysis (statistically weighted syndromes (SWS) method) of the gradated features. The SWS method is capable of identifying robust patterns in small "fuzzy" sets with high dimensional objects and some missing values. RESULTS: Only one parameter gave significant differences at p < 0.05, GM-CSF at instillation 6. Repeated measurement analysis of variance, backward stepwise multiple logistic regression and linear discriminant analysis failed to show any significance. However, significant differences in the structure of correlation between features in the groups with and without therapeutic effect were observed and four highly informative variables (the masses of sICAM-1, TNF alpha, sCD14 and pH) relating to 5th-6th installations were selected by SWS. These features provided accurate individual prediction of therapeutic outcome for all our patients. Cross-validation analysis and computer simulation showed the statistically significant stability of the prediction. CONCLUSION: We have selected a set of urinary variables that could be considered as a perspective combination of indicators (syndromes) of outcome of pre-operation BCG therapy of patients with superficial bladder cancer. A larger patient database will provide testing and evaluation of the biological and clinical significance of selected features. The computational syndrome-disease approach should be applicable for the solution of decision-making problems for management of cancer.     

Biosynthesis of progesterone derived neurosteroids by developing avian CNS: in vitro effects on the GABAA receptor complex

Although enthusiasm for measuring health-related quality of life (HRQL) in clinical trials exists, information is limited on the meaning of scores. We examined the relation between scores from the 34-item Medical Outcomes Study HIV Health Survey (MOS-HIV) and the more detailed HIV Overview of Problems-Evaluation System (HOPES) using the responses of 318 HIV-infected outpatients being treated in Los Angeles and Baltimore. With the HOPES problem statements as independent variables, statistically significant predictors of the variation in MOS-HIV scores for the Physical Function, Mental Health, and Energy/Fatigue scales were identified using stepwise regression. Approximately 60% to 70% of the variation in each of the scores was explained by five to seven different HOPES problem statements, with a single item explaining 47% to 59% of the variation. We created illustrative profiles for each of the three MOS-HIV scales using the HOPES items identified in the regressions. Independent of the scale, persons scoring in the top MOS-HIV quartile tended to report few if any problems, whereas a decline in score to the next quartile was characterized by functional difficulties (e.g., "HIV interferes with work"). The onset of specific problems might trigger further evaluation and potential intervention from health care providers to help maintain patient functioning.     

Solution structure of glutathione bound to human glutathione transferase P1-1: comparison of NMR measurements with the crystal structure

The conformation of the bound glutathione (GSH) in the active site of the human glutathione transferase P1-1 (EC 2.5.1.18) has been studied by transferred NOE measurements and compared with those obtained by X-ray diffraction data. Two-dimensional TRNOESY and TRROESY experiments have been performed under fast-exchange conditions. The family of GSH conformers, compatible with TRNOE distance constraints, shows a backbone structure very similar to the crystal model. Interesting differences have been found in the side chain regions. After restrained energy minimization of a representative NMR conformer in the active site, the sulfur atom is not found in hydrogen-bonding distance of the hydroxyl group of Tyr 7. This situation is similar to the one observed in an "atypical" crystal complex grown at low pH and low temperature. The NMR conformers display also a poorly defined structure of the glutamyl moiety, and the presence of an unexpected intermolecular NOE could indicate a different interaction of this substrate portion with the G-site. The NMR data seem to provide a snapshot of GSH in a precomplex where the GSH glutamyl end is bound in a different fashion. The existence of this precomplex is supported by pre-steady-state kinetic experiments [Caccuri, A. M., Lo Bello, M., Nuccetelli, M., Nicotra, M., Rossi, P., Antonini, G., Federici, G., and Ricci, G. (1998) Biochemistry 37, 3028-3034] and preliminary time-resolved fluorescence data.     

Measurement of amide hydrogen exchange by MALDI-TOF mass spectrometry

Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) was used to determine amide proton/deuteron (H/D) exchange rates. The method has broad application to the study of protein conformation and folding and to the study of protein-ligand interactions and requires no modifications of the instrument. Amide protons were allowed to exchange with deuterons in buffered D2O at room temperature, pD 7.25. Exchanged deuterons were "frozen" in the exchanged state by quenching at pH 2.5, 0 degree C and analyzed by MALDI-TOF MS. The matrix mixture consisted of 5 mg/mL alpha-cyano-4-hydroxycinnamic acid, acetonitrile, ethanol, and 0.1% TFA. The matrix was adjusted to pH 2.5, and the chilled MALDI target was rapidly dried. Deuteration of amide protons on cyclic AMP-dependent protein kinase was measured after short times of incubation in deuterium by pepsin protein digestion and MALDI-TOF MS analysis. The unseparated peptic digest was analyzed in a single spectrum of the mixture. From five spectra, H/D exchange rates were determined for some 40 peptides covering 65% of the protein sequence.     

Clinical impact of blood cultures taken in the emergency department

OBJECTIVES: (1) To establish the proportion of blood cultures that yield a positive microbiological culture. (2) To determine what proportion of blood cultures taken in the emergency department impact on patient management. (3) To develop guidelines for the appropriate ordering of blood cultures from patients in the emergency department (ED). METHODS: Retrospective review of all blood cultures taken in the ED of a metropolitan teaching hospital between 26 September 1995 and 30 June 1996. RESULTS: One thousand and sixty two blood cultures were taken from patients in the ED during the study period. Ninety two (9%) returned a positive microbiological culture. Of these, 52 (5%) were "true" positives and 18 (1.6%) resulted in changes in management. CONCLUSIONS: Blood cultures taken in the ED rarely yield positive cultures. Only 1.6% of blood cultures taken in the ED impact on management of patients. Simple strategies could reduce the number of blood cultures ordered with little prospect of patient compromise.     

Differences between completers and early dropouts from 2 HIV intervention trials: a health belief approach to understanding prevention program attrition

OBJECTIVES: The purpose of this study was to identify factors predicting program attrition among participants in human immunodeficiency virus (HIV) risk reduction trials. METHODS: Participants were gay/bisexual men and severely mentally ill adults recruited to take part in HIV risk reduction small-group interventions. Program completers were compared with participants who were assessed at baseline but then failed to attend any sessions. The health belief model provided a framework for selection of possible predictors of program attrition. RESULTS: Younger age was associated with early dropout in both samples. Other predictors among gay/bisexual men included involvement in an exclusive sexual relationship, minority ethnicity, injection drug use, and higher perceived severity of AIDS. Severely mentally ill dropouts were less knowledgeable about safer sex methods and more likely to hold positive outcome expectancies for condom use. CONCLUSIONS: Evaluation of intervention effectiveness among vulnerable population segments is threatened if there is selective attrition. Better methods are needed to attract and maintain participation in HIV prevention programs. Alternatively, wider application of "intention to treat" analysis of intervention outcomes is recommended to minimize selection bias due to program dropout.     

The resting and activation issue of hypofrontality: a single photon emission computed tomography study in neuroleptic-naive and neuroleptic-free schizophrenic female patients

BACKGROUND: Functional neuroimaging findings of "hypofrontality" in schizophrenic patients is still controversial, due to the heterogeneity of methods and patient samples. This study tries to prevent some of these concerns by studying neuroleptic-naive (NN) and neuroleptic-free (NF) young female patients both in resting conditions and during a frontal cognitive activation task. METHODS: Regional cerebral blood flow (rCBF) was studied at rest and during the Wisconsin Card Sorting Test (WCST) in 25 young acute unmedicated schizophrenic female patients (14 NN and 11 NF) and 15 female controls, using single photon emission computed tomography. RESULTS: The schizophrenic and control groups did not differ in rCBF during the baseline condition, but the schizophrenic group failed to activate the frontal lobe during the WCST condition. In addition, the left anterior temporal rCBF at rest correlated with the Scale for the Assessment of Positive Symptoms total score. CONCLUSIONS: The results suggest that hypofrontality in young acute unmedicated schizophrenic patients is a result of an inability to activate frontal regions during cognition, rather than a baseline decrease in frontal activity. Furthermore, positive symptoms seem to be associated with left temporal cortex activity.