Topical protection of human esophageal mucosal integrity.

Patients with nonerosive reflux disease exhibit impaired esophageal mucosal integrity, which may underlie enhanced reflux perception. In vitro topical application of an alginate solution can protect mucosal biopsies against acid-induced changes in transepithelial electrical resistance (TER). We aimed to confirm this finding in a second model using 3D cell cultures and to assess prolonged protection in a biopsy model. We assessed the protective effect of a topically applied alginate solution 1 h after application. 3D cell cultures were grown by using an air-liquid interface and were studied in Ussing chambers. The apical surface was "protected" with 200 µl of either alginate or viscous control or was unprotected. The tissue was exposed to pH 3 + bile acid solution for 30 min and TER change was calculated. Distal esophageal mucosal biopsies were taken from 12 patients and studied in Ussing chambers. The biopsies were coated with either alginate or viscous control solution. The biopsies were then bathed in pH 7.4 solution for 1 h. The luminal chamber solution was replaced with pH 2 solution for 30 min. Percentage changes in TER were recorded. In five biopsies fluorescein-labeled alginate solution was used to allow immunohistological localization of the alginate after 1 h. In the cell culture model, alginate solution protected tissue against acid-induced change in TER. In biopsies, 60 min after protection with alginate solution, the acidic exposure caused a -8.3 ± 2.2% change in TER compared with -25.1 ± 4.5% change after protection with the viscous control (P < 0.05). Labeled alginate could be seen coating the luminal surface in all cases. In vitro, alginate solutions can adhere to the esophageal mucosa for up to 1 h and exert a topical protectant effect. Durable topical protectants can be further explored as first-line/add-on therapies for gastroesophageal reflux disease.

Individual crypt genetic heterogeneity and the origin of metaplastic glandular epithelium in human Barrett's oesophagus.

OBJECTIVES: Current models of clonal expansion in human Barrett's oesophagus are based upon heterogenous, flow-purified biopsy analysis taken at multiple segment levels. Detection of identical mutation fingerprints from these biopsy samples led to the proposal that a mutated clone with a selective advantage can clonally expand to fill an entire Barrett's segment at the expense of competing clones (selective sweep to fixation model). We aimed to assess clonality at a much higher resolution by microdissecting and genetically analysing individual crypts. The histogenesis of Barrett's metaplasia and neo-squamous islands has never been demonstrated. We investigated the oesophageal gland squamous ducts as the source of both epithelial sub-types. METHODS: Individual crypts across Barrett's biopsy and oesophagectomy blocks were dissected. Determination of tumour suppressor gene loss of heterozygosity patterns, p16 and p53 point mutations were carried out on a crypt-by-crypt basis. Cases of contiguous neo-squamous islands and columnar metaplasia with oesophageal squamous ducts were identified. Tissues were isolated by laser capture microdissection and genetically analysed. RESULTS: Individual crypt dissection revealed mutation patterns that were masked in whole biopsy analysis. Dissection across oesophagectomy specimens demonstrated marked clonal heterogeneity, with multiple independent clones present. We identified a p16 point mutation arising in the squamous epithelium of the oesophageal gland duct, which was also present in a contiguous metaplastic crypt, whereas neo-squamous islands arising from squamous ducts were wild-type with respect to surrounding Barrett's dysplasia. CONCLUSIONS: By studying clonality at the crypt level we demonstrate that Barrett's heterogeneity arises from multiple independent clones, in contrast to the selective sweep to fixation model of clonal expansion previously described. We suggest that the squamous gland ducts situated throughout the oesophagus are the source of a progenitor cell that may be susceptible to gene mutation resulting in conversion to Barrett's metaplastic epithelium. Additionally, these data suggest that wild-type ducts may be the source of neo-squamous islands.

A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir).

OBJECTIVE: To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639. DESIGN: An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system. RESULTS: The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively). CONCLUSIONS: MK-639 appears to have significant dose-related antiviral activity and is well tolerated.

Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers.

OBJECTIVE: To evaluate the safety and pharmacokinetic interaction between amprenavir (APV) and ritonavir (RTV). METHODS: Three open-label, randomized, two-sequence, multiple-dose studies having the same design (7 days of APV or RTV alone followed by 7 days of both drugs together) used 450 or 900 mg APV with 100 or 300 mg RTV every 12 h with pharmacokinetic assessments on days 7 and 14. Safety was monitored as clinical adverse events (AEs) and laboratory abnormalities. RESULTS: Relative to APV alone, RTV co-administration resulted in a 3.3- to 4-fold and 10.84 to 14.25-fold increase in the geometric least-square (GLS) mean area under the plasma concentration--time curve (AUC(tau,ss)) and minimum concentration (C(min,ss)), respectively. APV 900 mg with RTV 100 mg resulted in a 2.09-fold and 6.85-fold increase in the GLS mean AUC(tau,ss) and C(min,ss), respectively. On day 14, the geometric mean (95% confidence interval) for 450 mg APV AUC(tau,ss) (micro x h/mL) was 23.49 (19.32--28.57) with 300 mg RTV and 35.42 (30.46--44.42) with 100 microg RTV, and for the 900 mg APV with 100 mg RTV 47.11 (39.47--61.24). The 450 mg APV C(min,ss) (microg/ml) were 1.32 (1.05--1.67) and 2.01 (1.70--2.61), and 2.47 (2.08--3.32) for 900 mg APV. The most common AEs were mild and included diarrhea, nausea/vomiting, oral parasthesias, and rash. The triglyceride and cholesterol increased significantly from RTV exposure. CONCLUSION: Adding RTV to APV resulted in clinically and statistically significant increases in APV AUC and C(min) with variable effects on maximum concentration. The two RTV doses had similar effects on APV but AEs were more frequent with 300 mg RTV.

Luteolytic actions of peroxide in rat ovarian cells.

A hallmark of luteolysis is leukocyte infiltration. Phagocytic leukocytes are well known to evoke a burst release of hydrogen peroxide (H2O2) of sufficient magnitude to injure cells. We, therefore, evaluated the effect of H2O2 in isolated rat luteal cells. Peroxide (100 microM; the near-half-maximal dose) markedly inhibited both LH-sensitive cAMP accumulation and progesterone production within 5 min of treatment. Cell levels of ATP were also reduced by H2O2, but not until 10 min after exposure, with more than 50% depletion within 60 min. This depletion of ATP by H2O2 was prevented by nicotinamide or 3-aminobenzamide, inhibitors of DNA repair, but these inhibitors did not prevent the antigonadotropic action of H2O2. cAMP accumulation in response to forskolin was not inhibited by H2O2 when ATP depletion was blocked with 3-aminobenzamide. The specific binding of radiolabeled hCG to isolated cells or the biological activity of LH was not affected by H2O2 pretreatment of the cells. Isobutylmethylxanthine had no effect on abrogation of LH-sensitive cAMP accumulation by H2O2. The actions of H2O2 were not mediated by prostaglandin, since indomethacin was without effect and an increase in prostaglandin F2 alpha production was not seen with H2O2 treatment. The acute luteolytic actions of H2O2 thus appear to be due to a very rapid desensitization of the LH-receptor complex, followed by depletion of ATP. The abrogation of luteotropic support and the injurious consequences of ATP depletion raise the possibility that H2O2 may be a physiological mediator of luteolysis.

The antigonadotropic action of prostaglandin F2 alpha is not mediated by elevated cytosolic calcium levels in rat luteal cells.

We have investigated the role of intracellular calcium in the mechanism of action of prostaglandin F2 alpha (PGF2 alpha) in cultured rat luteal cells. PGF2 alpha (1 microM) maximally inhibited LH-stimulated cAMP accumulation and also initiated a transient release of intracellular calcium. Low doses of the calcium ionophore ionomycin also increased intracellular calcium to a similar extent as PGF2 alpha (1 microM), but did not inhibit LH-stimulated cAMP accumulation. Chelation of intracellular calcium with dimethyl bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) (10 microM) attenuated the transient calcium rise stimulated by PGF2 alpha, but did not affect the inhibitory characteristics of PGF2 alpha on LH-stimulated cAMP accumulation. Treatment of luteal cells with EGTA (1 mM) and ionomycin (500 nM) resulted in depletion of intracellular calcium to such an extent that a subsequent exposure of the luteal cells to PGF2 alpha (1 microM) did not elicit any change in intracellular calcium. Depletion of intracellular calcium and ablation of the calcium response to PGF2 alpha, however, did not affect either the dose response or the time course of inhibition of LH-stimulated cAMP accumulation. We conclude that although intracellular calcium is mobilized by PGF2 alpha in cultured rat luteal cells, the antigonadotropic action of PGF2 alpha on LH-stimulated cAMP accumulation is not mediated by this mechanism.

Transport and selective utilization of adenosine as a prosubstrate for luteinizing hormone-sensitive adenylate cyclase in the luteal cell.

The objective of the present studies was to examine adenosine uptake in the rat luteal cell, to characterize the cellular products after uptake, and to assess the role of adenosine transport and conversion to cAMP in amplification of LH-stimulated cAMP accumulation. Adenosine uptake showed an apparent Km of 7.3 +/- 0.6 microM, and a maximum velocity of 2.2 +/- 1.4 pmol/min X 10(5) cells at 24 C; uptake was temperature dependent (Q10 = approximately 3) and inhibited by dipyridamole (IC50 = 7 microM). Radiolabeled adenosine uptake was inhibited by AMP (IC50 = 14 microM), ATP (IC50 = 16 microM), guanosine (IC50 = 20 microM), inosine (IC50 = 22 microM), ADP (IC50 = 26 microM), and theophylline (IC50 = 5 mM); no inhibition by adenine, hypoxanthine, xanthine, prostaglandin F2 alpha (PGF2 alpha), PGE2, or LH was seen. Cellular products of radiolabeled adenosine uptake were found primarily in the trichloroacetic acid-soluble fraction (88%), and 90% of the radioactivity in this fraction comigrated with adenine nucleotides on electrophoresis; time-dependent incorporation of radioactivity into RNA, DNA, and protein was also seen. Adenosine transport did not appear to be related to the functional state of the luteal cell; for example, no change in the characteristics of uptake was seen in cells obtained from hypophysectomized animals or in cells incubated directly with PGF2 alpha or LH. Adenosine increased cell ATP levels in a dose-dependent manner in parallel with amplification of LH-stimulated cAMP accumulation. A substantial proportion of the total cAMP produced by the cells was derived from extracellular adenosine (40-90%). This response was directly related to the concentration of adenosine, and LH increased the magnitude of cAMP derived from adenosine by about 2-fold. Based on the present studies, adenosine uptake in the luteal cell appears to occur by a dipyridamole-sensitive, phosphorylation-dependent transport system which is independent of pituitary hormones or PG regulation. Moreover, amplification of LH-dependent cAMP accumulation by adenosine appears to be primarily a mass effect due chiefly to utilization of extracellular adenosine by the cell as a prosubstrate for conversion into cAMP by adenylate cyclase.

Adenosine reverses calcium-dependent inhibition of follicle-stimulating hormone action and induction of maturation in cumulus-enclosed rat oocytes.

Previous studies indicate that an increase in calcium in the oocyte-cumulus complex (OCC) appears to be associated with induction of oocyte maturation. In contrast, we previously showed that adenosine augments FSH inhibition of maturation in isolated rat OCC. The objective of the present studies was to assess whether adenosine may inhibit calcium-induced oocyte maturation in rat OCC. Two calcium ionophores (A23187 and ionomycin) were used for these studies. In the intact OCC, both ionophores inhibited FSH-stimulated cAMP accumulation and stimulated germinal vesicle breakdown when spontaneous maturation was inhibited by FSH, but the ionophores had no effect when maturation was inhibited by Bu2 cAMP. In contrast, adenosine amplified FSH-sensitive cAMP accumulation and augmented FSH inhibition of oocyte maturation in the intact OCC. Moreover, adenosine reversed ionophore-dependent inhibition of cAMP accumulation and ionophore induction of oocyte maturation in the intact OCC incubated with FSH. Adenosine, ionophore, or FSH had no effect on oocyte maturation in denuded oocytes. Based on these results we conclude that the ionophores induced oocyte maturation by inhibition of FSH-dependent cAMP accumulation in the cumulus compartment, an effect that was probably calcium mediated. Since adenosine reversed the ionophore effects, we suggest that adenosine antagonizes the inhibitory effect of calcium on cAMP accumulation in cumulus cells and by this mechanism amplifies FSH inhibition of oocyte maturation.

Hormone induction of ascorbic acid transport in immature granulosa cells.

Ascorbic acid serves a vital role as an antioxidant, and like FSH, it inhibits apoptosis of granulosa cells in cultured follicles. In contrast, reactive oxygen species block the action of FSH and induce DNA damage in these cells. As the uptake of ascorbic acid by granulosa cells may be a site for regulation, we examined the nature of this process and whether uptake is under hormone control. Granulosa cells were isolated from immature rats pretreated with estradiol or diethylstilbestrol for 3-4 days and placed in culture. Culture of the cells with either FSH (50 ng/ml) or insulin-like growth factor I (IGF-I; 30 ng/ml) for 48 h increased ascorbic acid uptake by 2.7- and 1.9-fold (P < 0.05), respectively, and the response to FSH plus IGF-I was additive (4.5-fold; P < 0.05). The interval for maximum induction of ascorbic acid transport by FSH was between 4-8 h, whereas a significant response to IGF-I was not seen until 48 h. GnRH (1 microM), phorbol ester (phorbol 12-myristate 13-acetate; 1 microM), and 8-bromo-cAMP (8Br-cAMP; 1 mM) also induced ascorbic acid transport by 1.7-, 1.9-, and 2.3-fold (P < 0.05) within 24 h, and the response to maximal levels of phorbol ester and 8Br-cAMP was synergistic (4.8-fold; P < 0.05). Kinetic analysis showed a similar Michaelis constant (K(m); 50.8 +/- 5.3 microM) and maximum velocity (3.3 +/- 0.4 pmol/10(6) cells.min) for ascorbic acid transport in FSH-, 8Br-cAMP-, or phorbol ester-treated cells. Ouabain (100 microM) or removal of extracellular Na+ significantly inhibited ascorbic acid uptake, as did dinitrophenol (1 mM), an inhibitor of mitochondrial production of ATP. The induction of ascorbic acid transport by FSH, IGF-I, or GnRH was abolished by simultaneous incubation with tyrphostin (AG-18; 80 microM), a specific tyrosine kinase inhibitor, whereas induction was unaffected by an inactive, but chemically similar, compound (A-1; 80 microM). From these results we conclude that ascorbic acid uptake is energy and Na+ dependent and that the induction of ascorbic acid transporters in granulosa cells occurs through multiple hormones that ultimately influence tyrosine-specific protein kinases. The hormone-dependent induction of ascorbic acid accumulation in granulosa cells appears to be an essential process for the development and maintenance of a viable follicle.

Recipes for adult stem cell plasticity: fusion cuisine or readymade?

A large body of evidence supports the idea that certain adult stem cells, particularly those of bone marrow origin, can engraft at alternative locations, particularly when the recipient organ is damaged. Under strong and positive selection pressure these cells will clonally expand/differentiate, making an important contribution to tissue replacement. Similarly, bone marrow derived cells can be amplified in vitro and differentiated into many types of tissue. Despite seemingly irrefutable evidence for stem cell plasticity, a veritable chorus of detractors has emerged, some doubting its very existence, motivated perhaps by more than a little self interest. The issues that have led to this situation include the inability to reproduce certain quite startling observations, and extrapolation from the behaviour of embryonic stem cells to suggest that adult bone marrow cells simply fuse with other cells and adopt their phenotype. Although these issues need resolving and, accepting that cell fusion does appear to allow reprogramming of haemopoietic cells in special circumstances, criticising this whole new field because some areas remain unclear is not good science.

Nonparametric expectation maximization population modeling of ganciclovir.

The use of the nonparametric expectation maximization (NPEM2) program to estimate pharmacokinetic parameters of ganciclovir in a group of patients with human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection was evaluated. A 10-point data set per patient obtained over 8 hours was analyzed. Mean pharmacokinetic parameters obtained included rate constant from the central to the peripheral compartment (KCP,3.1 hr-1), rate constant from the peripheral to the central compartment (KPC, 0.824 hr-1), slope of the volume of distribution to body weight (VS, 0.246 L/kg), and slope of clearance to creatinine clearance (Cl(cr)) and body weight (CLS,0.222L/hr/kg/100 mL/ min Cl(cr). Use of NPEM2 led to identification of a subset of patients with CMV retinitis who had a more rapid clearance of ganciclovir of 0.51 to 0.54 L/hr/kg/100 mL/min Cl(cr). Use of smaller, optimally timed samples of five, four, and three data points per patient produced mean pharmacokinetic parameter results consistent with the full ten-point data set. When Bayesian-derived parameter estimates using a five-point data set were compared with a traditional, nonlinear, least-square analysis of the entire ten-point data set, estimates of clearance were determined to be relatively unbiased and precise. The ability of NPEM2 to estimate pharmacokinetic parameters and to determine the population distribution of the parameters was demonstrated. By using points in the analysis chosen by D-optimal design theory, NPEM2 was able to give consistent parameter estimates with as few as three data points. Determination of the distribution appeared to have been dependent on the time points used, however. The approach of MAP-Bayesian analysis to derive patient-specific estimates using optimal samples and prior estimates from a previous population pharmacokinetic analysis for inclusion in subsequent pharmacodynamic analyses of drug exposure (area under the concentration-time curve) may enable development of exposure-response and exposure-toxicity relationships.

Characterization of rat schwannoma-Schwann cell hybrids.

Sciatic nerve Schwann cells from strain LEC rats, homozygous for the c form of 6-phosphogluconate dehydrogenase (6-PGD), and RN22 rat Schwannoma cells, a subclone of RN2 deficient in hypoxanthine phosphoribosyltransferase and expressing the s form of 6-PGD, were fused to produce 'RNS' hybrid clones which proliferate rapidly in a medium containing hypoxanthine, aminopterin and thymidine (HAT) and express c, s and c/s heterodimeric forms of 6-PGD. RNS cells, like both parents, maintain a high baseline activity of 2', 3'-cyclic nucleotide 3'-phosphohydrolase and, as in RN22, activity of this enzyme is further inducible by 1 mM N6, O2'-dibutyryl 3', 5'-cyclic AMP. The RNS clones resemble normal Schwann cells in the capacity to bind radioiodinated axolemmal fragments to their plasma membranes.

Luteinizing hormone depletes ascorbic acid in preovulatory follicles.

OBJECTIVE: The objective of the present studies was to determine whether luteinizing hormone (LH) depletes ascorbic acid in the preovulatory follicle. DESIGN: Controlled, prospective experimental study. SETTING: University-based research center. ANIMAL(S): Sprague-Dawley female rats. INTERVENTION(S): Follicular growth and ovulation were induced in immature rats by gonadotropin treatment. MAIN OUTCOME MEASURE(S): Analysis of ovary, follicle, and oocyte levels of ascorbic acid by colorimetric analysis and high-pressure liquid chromatography. RESULT(S): Ovarian ascorbic acid was maximally depleted (50%) within 2 h of LH treatment and was sustained for 8 h. Follicle ascorbic acid levels were unchanged 1 h after LH injection but were significantly reduced within 2 h (40%). Incubation of isolated preovulatory follicles for 3 h with hCG or with menadione (a generator of oxygen radicals) reduced ascorbic acid levels. Isolation of cumulus-enclosed or denuded oocytes depleted ascorbic acid to undetectable levels, but follicular ascorbic acid levels were only moderately depleted by isolation and incubation. Accumulation of ascorbic acid by oocytes was significantly enhanced by the presence of intact cumulus cells. CONCLUSION(S): Elevation of LH and the production of oxygen radicals deplete ascorbic acid in the preovulatory follicle.

Single daily dosing of aminoglycosides.

To evaluate the rationale behind dosing aminoglycosides as a single daily dose versus traditional dosing approaches, we conducted a MEDLINE search to identify all pertinent articles, and also reviewed the references of all articles. Single daily dosing of aminoglycosides is not a new concept, having been examined since 1974. The advantages of this regimen include optimum concentration-dependent bactericidal activity, longer dosing intervals due to the postantibiotic effect (PAE), and prevention of bacterial adaptive resistance. Because of longer dosing intervals, toxicity may also be delayed or reduced. Costs may be reduced due to decreased monitoring and administration. Clinically, the regimen has been implemented in various patient populations with reported success. Questions remain, however, about optimum dose, peak and trough serum concentrations, and dose adjustment in patients with renal impairment or neutropenia. More clinical experience with this method in large numbers of patients has to be published. Pharmacists can be instrumental in monitoring patients receiving once-daily therapy and by educating health care professionals as to the rationale behind the therapy.

Oxidative stress and the ovary.

Superoxide (O(2)(-)), hydrogen peroxide (H(2)O(2)), and lipid peroxides are generated in luteal tissue during natural and prostaglandin-induced regression in the rat, and this response is associated with reversible depletion of ascorbic acid. Reactive oxygen species immediately uncouple the luteinizing hormone receptor from adenylate cyclase and inhibit steroidogenesis by interrupting transmitochondrial cholesterol transport. The cellular origin of oxygen radicals in regressing corpora lutea is predominantly from resident and infiltrated leukocytes, notably neutrophils. Reactive oxygen species are also produced within the follicle at ovulation and, like the corpus luteum, leukocytes are the major source of these products. Antioxidants block the resumption of meiosis, whereas the generation of reactive oxygen induces oocyte maturation in the follicle. Although oxygen radicals may serve important physiologic roles within the ovary, the cyclic production of these damaging agents over years may lead to an increased cumulative risk of ovarian pathology that would probably be exacerbated under conditions of reduced antioxidant status.

Fluconazole for antifungal prophylaxis in chemotherapy-induced neutropenia.

Fluconazole is compared with other agents for antifungal prophylaxis in patients with chemotherapy-induced neutropenia. Fluconazole is an attractive alternative for antifungal prophylaxis because of its activity against many Candida species, long half-life, good patient tolerability, and minimal associated toxicity. The results of clinical trials suggest that fluconazole is superior to placebo and oral polyenes in preventing superficial fungal infection in neutropenic patients; however, its efficacy against systemic infection is not as strongly supported. Fluconazole use may increase emergence of resistant yeasts, particularly Candida krusei and Torulopsis glabrata. The cost of fluconazole 50 mg/day is similar to the costs of other antifungals used for prophylaxis; however, fluconazole 400 mg/day (the most frequently studied dose in neutropenic patients) is considerably more expensive. Comparative clinical trials between fluconazole and other antifungals are needed to determine which is superior for prophylaxis. Fluconazole is effective for prophylaxis against superficial fungal infection and may be an attractive alternative therapeutic regimen in patients undergoing bone marrow transplantation. In other neutropenic patients, such as those with leukemia, the superiority of fluconazole has not been substantiated; therefore, it is not recommended over other agents, such as clotrimazole and ketoconazole, at this time.

The fate of diphenyl sulphide, diphenyl sulphoxide and diphenyl sulphone in the rat.

Radiolabelled [UL-14C]-diphenyl sulphide, [UL-14C]-diphenyl sulphoxide and [UL-14C]-diphenyl sulphone were administered by gavage (1.0 mmol/kg body weight) to adult male Wistar rats following an overnight fast. For all compounds, faeces were the major route of excretion of radioactivity (50%). Urinary elimination (40%) was similar during the first (19%) and second (16%) days and a small amount of radioactivity (6%) was found within the carcass after four days. From urinary and faecal data, metabolism occurred via ring hydroxylation with subsequent conjugate formation. Oxidation of the sulphur to form the sulphoxide and sulphone also took place; a small amount of sulphoxide reduction was apparent but no sulphone reduction was found. No evidence for exclusion of the sulphur was obtained, and it appeared unlikely that extensive cleavage of the ring structures occurred.

An unusual cause of gastrointestinal bleeding: duodenal lipoma.

Common causes of chronic upper gastrointestinal bleeding include oesophageal varices, gastroduodenal ulcers and malignancy, and patients mostly present with iron deficiency type anaemia. We present the case of a 60-year-old lady who presented with iron deficiency anaemia and on investigation was found to have a large duodenal polyp requiring surgical excision. On histological examination, the polyp was revealed to be a lipoma. We review the recent literature and formulate a management plan for this rare entity.

Bowel preparation affects the amplitude and spatiotemporal organization of colonic propagating sequences.

BACKGROUND: Colonic manometry is performed using either colonoscopically assisted catheter placement, after bowel preparation, or nasocolonic intubation of the unprepared bowel. There has been little systematic evaluation of the effects of bowel cleansing upon colonic propagating pressure wave sequences. METHODS: Eight healthy volunteers underwent nasocolonic placement of a water-perfused silicone catheter which recorded pressures at 16 recording sites each spaced 7.5 cm apart in the unprepared colon for 24 h. These measures were compared with those obtained in another eight healthy volunteers in whom the catheter was placed to the caecum at colonoscopy in the prepared colon. KEY RESULTS: The colonic motor responses to meals and morning waking, and the normal nocturnal suppression did not differ between the two groups, nor were the overall frequency, regional dependence nor extent of propagating sequences (PS) influenced by bowel preparation. Bowel preparation did result in a significant increase in the frequency of high amplitude PS (22 +/- 7 vs 8 +/- 4 HAPS/24 h; P = 0.003). Additionally, a number of the measures of spatiotemporal organization among consecutive PS (linkage among sequences and predefecatory stereotypical patterning) were significantly altered by bowel preparation. CONCLUSIONS & INFERENCES: The overall frequency of PSs, the colonic responses to physiological stimuli such a meal and morning waking and nocturnal suppression, are not influenced by prior bowel preparation. However, investigators wishing to study HAPS frequency, or the more complex spatiotemporal relationships among consecutive PSs, should control for bowel preparation when making comparisons among study groups.