A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis.

PURPOSE: This pilot study was designed to evaluate the feasibility of a multicenter, randomized, clinical trial in interstitial cystitis (IC). Secondary objectives were to evaluate the safety and efficacy of oral pentosan polysulfate sodium (PPS), hydroxyzine, and the combination to consider their use in a larger randomized clinical trial. MATERIALS AND METHODS: A 2 x 2 factorial study design was used to evaluate PPS and hydroxyzine. Participants met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC and reported at least moderate pain and frequency for a minimum of 6 months before study entry. The primary end point was a patient reported global response assessment. Secondary end points included validated symptom indexes and patient reports of pain, urgency and frequency. The target sample size was 136 participants recruited during 10 months. RESULTS: A total of 121 (89% of goal) participants were randomized over 18 months and 79% provided complete followup data. The response rate for hydroxyzine was 31% for those treated and 20% for those not treated (p = 0.26). A nonsignificant trend was seen in the PPS treatment groups (34%) as compared to no PPS (18%, p = 0.064). There were no treatment differences for any of the secondary end points. Adverse events were mostly minor and similar to those in previous reports. CONCLUSIONS: The low global response rates for PPS and hydroxyzine suggest that neither provided benefit for the majority of patients with IC. This trial demonstrated the feasibility of conducting a multicenter randomized clinical trial in IC using uniform procedures and outcomes. However, slow recruitment underscored the difficulties of evaluating commonly available IC drugs.

New compensation model improves physician productivity.

In the mid-1990s, Meridia Health System, a hospital system in the Cleveland, Ohio, area began acquiring primary care physician practices to form the core of an integrated delivery system to compete with other providers in the area. Unfortunately, the structure of the physician compensation plan for Meridia's new physician employees caused productivity to decline and losses to mount. Meridia appointed a task force that included physicians to develop a new compensation plan that bases pay on the application of a collection rate percentage to each physician's gross fee-for-service billings. While not perfect, the new compensation plan is helping both Meridia and its physicians achieve their mutual goals of high-quality care, reasonable productivity, and operating efficiency.

Induction of globin synthesis in K562 cells is associated with differential expression of transcription factor genes.

Globin gene switching may be mediated by proteins expressed during different stages of development. Their identification may clarify the mechanisms of the conversion from fetal to adult globin production and lead to new approaches to reversing or retarding the gamma- to beta-globin gene switch. To explore this hypothesis, K562 erythroleukemia cells were induced to differentiate with 1.25, 2.5, and 5 mM sodium butyrate and gene expression was studied after 24, 48, and 72 h. Erythroid differentiation was verified by benzidine staining and by measuring the activity of a transduced A gamma-globin gene promoter linked to a luciferase reporter gene. Using differential display polymerase chain reaction (PCR), total mRNA extracted from induced cells at each time point of induction was reverse transcribed in the presence of A, G, and C anchored primers and 16 arbitrary primers, calculated to amplify approximately 50% of expressed genes. Amplified mRNAs from induced and uninduced cells were separated in polyacrylamide gels and compared. More than 110 cDNA fragments which appeared to represent either up- or downregulated mRNA species in induced K562 cells were identified. Sixty-four of these fragments had more than 95% homology to known GenBank sequences. Seventeen fragments with characteristics of transcription factors were cloned. These include differentiation-related gene-1 (drg-1), PAX 3/forkhead transcription factor, HZF2 which is a Kruppel-related zinc finger protein, three helix-loop-helix proteins (heir-1, Id3, and GOS8), alpha-NAC transcriptional coactivator, LIM domain protein, and trophoblast hypoxia regulating factor. Differential expression of all 17 fragments over 72 h was confirmed by reverse Northern dot blot analysis, semiquantitative PCR using nested primers, and Northern analysis. Erythroid maturation in induced K562 cells is associated with differential expression of numerous genes. Some encode transcription factors that could effect the initiation of HbF synthesis. Almost half of the differentially expressed clones contained cDNAs of unidentified open reading frames and these are the object of continued study.

An in vivo study of phosphorus and glucose metabolism in Alzheimer's disease using magnetic resonance spectroscopy and PET.

OBJECTIVES: To study phosphorus and glucose metabolism in whole-brain slices of otherwise healthy patients with dementia of the Alzheimer type (DAT) and healthy controls. DESIGN: We used proton nuclear magnetic resonance imaging phosphorus spectroscopy and positron emission tomography to study in vivo brain phosphorus and glucose metabolism. PATIENTS: Whole-brain slice phosphorus metabolism was studied in nine drug free patients with mild to moderately severe dementia of the Alzheimer type (DAT) and in eight age- and sex-matched healthy controls. Mean ages (+/- SD) of the patients and controls were 60 +/- 10 years and 64 +/- 16 years, respectively. Positron emission tomography was used to study cerebral glucose metabolism in seven of the patients with DAT and seven of the healthy controls. RESULTS: Patients with DAT had significant brain glucose hypometabolism compared with controls, but there was no significant group difference in any phosphorus metabolite concentration or ratio in the same volume of brain tissue. Also, within patients with DAT there was no correlation between any phosphorus metabolite concentration or ratio and either severity of dementia or glucose metabolism. CONCLUSIONS: We suggest glucose metabolism is reduced early in DAT (reflecting decreased basal synaptic functioning) and is unrelated to a rate limitation in glucose delivery, abnormal glucose metabolism, or abnormal coupling between oxidation and phosphorylation. Normal or near-normal levels of phosphorus metabolites are maintained in mild, moderate, and severe DAT. Therefore, altered high-energy phosphate levels are not a consequence of reduced glucose metabolism in DAT, and do not play a major role in the pathophysiology of the disorder, at least in whole-brain sections.

Alzheimer dementia: quantification of energy metabolism and mobile phosphoesters with P-31 NMR spectroscopy.

To determine whether high-energy phosphate metabolism and mobile phosphoester indexes of membrane metabolism are altered in Alzheimer disease and to help resolve some inconsistencies in the literature, brain phosphate metabolite concentrations and ratios were measured in 11 patients with mild to severe dementia of the probable Alzheimer type and 14 healthy subjects. Fully relaxed, spatially localized, phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy and proton (hydrogen-1) MR imaging were performed. No significant differences were found in the concentrations and relative ratios of phosphocreatine, nucleoside triphosphate, inorganic phosphate, phosphomonoester, and phosphodiesters in whole axial sections through the lateral cerebral ventricles of the brain that could not be accounted for by atrophy. There was no correlation between P-31 NMR indexes and the severity of dementia as assessed with neuropsychologic testing. High-energy phosphate and membrane metabolism, as detected in vivo with P-31 NMR spectroscopy in whole-brain sections, do not appear to play a major role in the disease process, except as a direct consequence of atrophy quantified with H-1 MR imaging.

31P spectroscopic localization using pinwheel NMR excitation pulses.

Spectroscopic imaging with a one-dimensional phase-encoding gradient and surface-coil reception relies on the restricted range of sensitivity of the surface coil to provide localization in the dimensions transverse to the coil axis and consequently suffers from relatively poor localization in these dimensions. A two-dimensional (2D) cylindrically selective excitation pulse with a large spectral bandwidth is presented here to remedy this problem. The gradient waveforms are derived from multiple spirals in k space which form an overall pinwheel pattern, resulting in a pulse which is much shorter than the equivalent single-spiral trajectory. Nonuniform traversal of the spirals further reduces the pulse width under conditions of gradient slew-rate limitations, yielding overall gains in bandwidth of up to about 30 compared with the equivalent single-spiral trajectory traversed at constant angular rate. The accompanying rf waveform is obtained by weighted 2D Fourier transformation of the desired sensitivity profile. A new weighting factor is introduced into the rf waveform to compensate for nonuniform sampling of k space by the pinwheel near the origin. This factor is independent of the weighting used to account for the rate of traversal of the trajectory and is applicable to 2D pulse design in general. Pulse sequences employing pinwheel excitation in conjunction with either phase-encoding or slice-selective inversion are used to produce multiple-voxel and single-voxel localization in a human heart and a phantom. Pinwheel pulses may be used to advantage on moieties with long spin-lattice relaxation times and short transverse relaxation times and are therefore ideal for applications in phosphorus (31P) NMR.

[Antropyloric lithiasic obstruction. A variant of Bouveret's syndrome]. / Obstruction lithiasique antro-pylorique. Une variante du syndrome de Bouveret.

We report about one case of cholecystoduodenal fistula complicated by antropyloric lithiasic obstruction, which was treated surgically with gastrotomy and extraction of the calculus, in an 82-year-old woman. This case represents an anatomic variant of Bouveret's syndrome, which is classically defined as a duodenal lithiasic obstruction. On the basis of this case, the authors discuss the diagnostic and possibly therapeutic merits of digestive endoscopy and define the main clinical, anatomical and evolutive characteristics of this unfrequent complication of biliary lithiasis.

Nutrition, cancer, and aging: an annotated review. I. Diet, carcinogenesis, and aging.

The interrelationships of diet and carcinogenesis are discussed with the focus on aging. To establish whether the elderly are more susceptible to dietary carcinogens and whether dietary prevention of cancer is a reasonable goal for this population, the mechanisms of chemical carcinogenesis, the age-related metabolic and physiologic changes, and the current cancer preventive dietary strategies are reviewed. Vulnerability to dietary carcinogens results from a combination of factors that may increase or decrease the occurrence of cancer in the elderly, and it is, therefore, a very individualized feature, unpredictable when based solely on a subject's age. Dietary prevention of cancer may be effective in advanced age, and the dietary guidelines of the National Academy of Sciences should be implemented in this population.