Risk of gastric cancer, gastrointestinal cancers and other cancers: a comparison of treatment with pantoprazole and other proton pump inhibitors.

BACKGROUND: Proton pump inhibitors (PPIs) have been shown to be carcinogenic in rodent studies. AIM: As part of a long-term post-marketing surveillance study requested by the US Food and Drug Administration, to compare incidence rates of gastric and other cancers after sustained exposures to pantoprazole, a long-acting PPI, compared with other shorter acting PPIs. METHODS: We conducted a cohort study within the membership of the Kaiser Permanente Northern California healthcare system and compared rates of gastric and other cancers among pantoprazole users and users of other PPI medications. The Cox proportional hazards model was used to adjust for potential confounders such as sex, age, receipt of treatment for Helicobacter pylori, cumulative PPI dose, total years PPI treatment and year of index date. The study was developed in consultation with, and approved by, the FDA. RESULTS: A total of 61 684 persons with at least a 240-day supply of medication (34 178 pantoprazole and 27 686 other PPIs) were followed up for a total of 547 020 person-years (274 700 vs. 272 321 person-years, respectively). The primary analyses demonstrated comparable risks between the pantoprazole and other PPI groups for gastric cancer [hazard ratio (HR) = 0.68, 95% CI 0.24-1.93); colorectal, liver, pancreatic, or small bowel cancers (HR = 0.95, 95% CI 0.65-1.40) or any cancer (HR = 1.06, 95% CI 0.93-1.21). CONCLUSIONS: We found no evidence that pantoprazole, a longer acting PPI, compared with shorter-acting agents, conferred an excess risk of gastric cancer, other gastrointestinal cancers or all cancers for pantoprazole compared with other shorter-acting PPIs.

Thermal inactivation of foot and mouth disease virus in extruded pet food.

The risk of importing foot and mouth disease, a highly contagious viral disease of livestock, severely restricts trade and investment opportunities in many developing countries where the virus is present. This study was designed to investigate the inactivation of foot and mouth disease virus (FMDV) by heat treatments used in extruded commercial pet food manufacture. If extrusion could be shown to reliably inactivate the virus, this could potentially facilitate trade for FMDV-endemic countries. The authors found that there was no detectable virus following: i) treatment of FMDVspiked meat slurry at 68°C for 300 s; ii) treatment of FMDV-spiked slurry and meal mix at 79°C for 10 or 30 s, or iii) treatment of homogenised bovine tongue epithelium, taken from an FMDV-infected animal, at 79°C for 10 s. This corresponds to an estimated 8 log10 reduction in titre (95% credible interval: 6 log10 -13 log10). Furthermore, the authors found that the pH of the slurry and meal mix was sufficient to inactivate FMDV in the absence of heat treatment. This demonstrates that heat treatments used in commercial pet food manufacture are able to substantially reduce the titre of FMDV in infected raw materials.

En raison du risque d'introduction de la fièvre aphteuse, une maladie virale très contagieuse affectant le bétail, les échanges internationaux et les possibilités d'investissement de nombreux pays en développement sont soumis à des restrictions majeures. La présente étude vise à déterminer si les traitements thermiques appliqués lors de la fabrication industrielle d'aliments extrudés destinés aux animaux de compagnie sont efficaces pour inactiver le virus de la fièvre aphteuse dans ces produits. Si la procédure d'extrusion avait pour propriété démontrée d'inactiver le virus de manière fiable, les pays où le virus de la fièvre aphteuse est présent à l'état endémique pourraient accéder plus facilement aux échanges internationaux. Les auteurs n'ont pas trouvé de virus détectable à l'issue des opérations suivantes : i) traitement à 68 °C pendant 300 s d'une bouillie de viandes à laquelle avait été ajoutée une quantité connue de virus de la fièvre aphteuse ; ii) traitement à 79 °C pendant 10 ou 30 s d'un mélange de bouillie et de pâté auquel avait été ajoutée une quantité connue de virus de la fièvre aphteuse ; iii) traitement à 79 °C pendant 10 s d'un échantillon homogénéisé d'épithélium lingual prélevé d'un bovin atteint de fièvre aphteuse. Ces résultats correspondent à une réduction estimée du titre de 8 log10 (intervalle de confiance à 95 % : 6 log10 ­13 log10). En outre, les auteurs ont constaté que le pH du mélange de bouillie et de pâté était de nature à inactiver le virus de la fièvre aphteuse, en l'absence de traitement thermique. Ces résultats démontrent que les traitements thermiques utilisés lors de la fabrication industrielle d'aliments pour animaux de compagnie permettent de réduire de manière importante les titres du virus de la fièvre aphteuse dans les matières premières infectées.

El riesgo de importar fiebre aftosa, enfermedad vírica muy contagiosa que afecta al ganado vacuno, restringe sobremanera el comercio y las oportunidades de inversión en muchos países en desarrollo en los que el virus está presente. Los autores describen un estudio encaminado a analizar el método de inactivación del virus por calor que se emplea en la fabricación industrial de piensos extrusionados para animales de compañía. Si quedaba demostrado que la extrusión es un método fiable para inactivar el virus de la fiebre aftosa, ello podría abrir perspectivas comerciales a todos aquellos países donde dicho virus es endémico. Los autores observaron que no había presencia detectable de virus después de: i) mantener a 68°C durante 300 segundos una emulsión cárnica enriquecida con virus de la fiebre aftosa; ii) mantener a 79°C durante 10 o 30 segundos una emulsión y una mezcla de harinas enriquecidas con el virus; o iii) mantener a 79°C durante 10 segundos un homogenado de epitelio lingual bovino procedente de un animal infectado por el virus. Ello corresponde a una reducción estimada de la titulación de log10 8 (intervalo de confianza al 95%: log10 6 ­ log10 13). Además, los autores observaron que, en ausencia de tratamiento térmico, el pH de la emulsión y la mezcla de harinas bastaba para inactivar el virus de la fiebre aftosa, lo que demuestra que los tratamientos térmicos utilizados en la fabricación industrial de piensos pueden reducir sustancialmente el título de virus de la fiebre aftosa en materias primas infectadas.

The effect of conventional vs. mild ovarian hyperstimulation on the total number of live babies born from a given oocyte retrieval.

PURPOSE: To compare pregnancy outcome in women with normal oocyte reserve according to whether they received conventional or mild follicle stimulating hormone (FSH) controlled ovarian hyperstimulation (COH) further stratified by age. MATERIALS AND METHODS: A ten-year retrospective study including all cycles (even multiple in given patients) was performed. Mild stimulation including all cycles initiated and continued with 150 IU FSH or less from early follicular phase. Everything else was considered conventional stimulation. Mild stimulation included natural cycles or those with just a boost of 75 IU FSH from the mid to late follicular phase. Only women with normal oocyte reserve were selected--serum FSH < 12 mIU/mL and serum E2 < 50 pg/mL. Live delivered pregnancy rates within three age groups (≤ 35, 36-39, and 40-42 years) were compared per embryo transfer and per embryo retrieval, i.e., the percentage of women having a live baby without proceeding to another IVF-ET cycle. Also compared were the average number of babies born from one retrieval. RESULTS: For aged ≤ 35 there were no differences in pregnancy rates per transfer but a trend for higher pregnancy rates per retrieval with conventional stimulation. For all other age groups both pregnancy rates per transfer and retrieval were significantly higher with conventional stimulation. This was reflected with a higher average number of babies born per retrieval with conventional. CONCLUSIONS: For women with normal oocyte reserve in general, there is no advantage of mild vs. conventional COH other than cost saving. Of course there are exceptions, e.g., ovarian hyperstimulation with conventional COH.

Mid-luteal phase injection of subcutaneous leuprolide acetate improves live delivered pregnancy and implantation rates in younger women undergoing in vitro fertilization-embryo transfer (IVF-ET).

PURPOSE: To see if the single injection of one mg of the gonadotropin releasing hormone agonist (GnRHa) leuprolide acetate given in the mid-luteal phase can increase live delivered pregnancy and implantation rates. Furthermore the purpose was to determine if improvement was found, did the mechanism involve increased secretion of human chorionic gonadotropin (hCG). MATERIALS AND METHODS: A prospective study was conducted in women aged 35 who were undergoing in vitro fertilization-embryo transfer (IVF-ET). They were advised of data from Tesarik et al. and a previous pilot study conducted in the present IVF center showing improved pregnancy rates with the injection of a GnRHa three days after embryo transfer. They were offered the option of returning for a one-mg injection s.c. of leuprolide acetate or not. Clinical and live delivered pregnancy rates were compared according to those taking or not the leuprolide acetate one-mg injection. Chi-square analysis was used for statistical comparisons. Serum beta-hCG levels were compared between those conceiving with or without the extra injection of leuprolide. RESULTS: There was a non-significant trend for higher live delivered pregnancy rates in those taking leuprolide (47.8%, 64/134) vs. those not taking it (38.6%, 76/197). For those pregnant there was no difference in hCG levels according to taking the GnRHa or not. CONCLUSIONS: The 25% increased live delivered pregnancy rate per transfer was insufficiently powered to detect a significant difference. The results do justify continuing the study. Perhaps the difference could be wider using a slightly older age group whose embryos are frequently less hearty.

Improved implantation and live delivered pregnancy rates following transfer of embryos derived from donor oocytes by single injection of leuprolide in mid-luteal phase.

PURPOSE: To determine if the use of a single injection of one-mg leuprolide acetate in mid-luteal phase can increase pregnancy rates in donor oocyte recipients. MATERIALS AND METHODS: Prospective study where couples were made aware of a study using the gonadotropin releasing hormone agonist (GnRHa) triptorelin that in the mid-luteal phase found improved pregnancy rates following embryo transfer in donor oocyte recipients. They were given the option of a single one-mg injection of the GnRHa leuprolide acetate. Pregnancy outcome was compared according to whether leuprolide was given or not. Also compared were the average first serum beta-hCG level in those who conceived according to taking leuprolide or not. RESULTS: Chi-square analysis showed a significantly higher clinical and live delivered pregnancy rate (63.9% and 52.8%) in those supplementing with leuprolide than those who did not (39.5% and 32.9%). Similarly implantation rates were significantly higher (44.2% vs. 25.2%). The average first serum beta-hCG level for those conceiving and taking leuprolide was 294 mIU/mL vs. 325 mIU/mL for those who did not. CONCLUSIONS: Similar to triptorelin the mid-luteal injection of leuprolide acetate improves pregnancy outcome in donor oocyte recipients.

Thermal Inactivation of Feline Calicivirus in Pet Food Processing.

Extrusion is the most common manufacturing process used to produce heat-treated dry dog and cat food (pet food) for domestic use and international trade. Due to reoccurring outbreaks of notifiable terrestrial animal diseases and their impact on international trade, experiments were undertaken to demonstrate the effectiveness of heat-treated extruded pet food on virus inactivation. The impact of extrusion processing in a pet food matrix on virus inactivation has not been previously reported and very few inactivation studies have examined the thermal inactivation of viruses in complex food matrices. The feline calicivirus vaccine strain FCV F-9 was used as a surrogate model RNA virus pathogen. Small-scale heat inactivation experiments using animal-derived pet food raw materials showed that a > 4 log10 reduction (log10 R) in infectivity occurred at 70 °C prior to reaching the minimum extrusion manufacturing operating temperature of 100 °C. As anticipated, small-scale pressure studies at extrusion pressure (1.6 MPa) showed no apparent effect on FCV F-9 inactivation. Additionally, FCV F-9 was shown not to survive the acidic conditions used to produce pet food palatants of animal origin that are typically used as a coating after the extrusion process.

Meta-analysis: the risk of venous thromboembolism in patients with inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a systemic disorder that predominantly affects the bowels but is also associated with venous thromboembolism (VTE). AIM: To provide a quantitative assessment of the association of IBD with venous thromboembolism risk and to explore the possible sources of heterogeneity in the current literature, a meta-analysis of case-control and cohort studies was conducted. METHODS: Studies were identified by a literature search of the PubMed and Scopus databases (from inception inclusive 31 December 2012) for English language studies. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias. RESULTS: Eleven studies met our inclusion criteria. The summary RR for deep venous thromboembolism (DVT) and pulmonary embolism (PE) comparing subjects both with and without IBD was 2.20 (95% CI 1.83-2.65). After adjusting for obesity and smoking, summary relative risks near 2.0 were seen for venous thromboembolism in both UC and CD patients. CONCLUSION: This meta-analysis showed that inflammatory bowel disease is associated with an approximately two-fold increase in the risk of venous thromboembolism.

Diabetes, hypertension and hyperlipidemia: prevalence over time and impact on long-term survival after liver transplantation.

With increasing short-term survival, the transplant community has turned its focus to delineating the impact of medical comorbidities on long-term outcomes. Unfortunately, conditions such as diabetes, hypertension and hyperlipidemia are difficult to track and often managed outside of the transplant center by primary care providers. We collaborated with Kaiser Permanente Northern California to create a database of 598 liver transplant recipients, which incorporates diagnostic codes along with laboratory and pharmacy data. Specifically, we determined the prevalence of diabetes, hypertension and hyperlipidemia both before and after transplant and evaluated the influence of disease duration as a time-dependent covariate on posttransplant survival. The prevalence of these comorbidities increased steadily from the time of transplant to 7 years after transplant. The estimated risk for all-cause mortality (hazard ratio = 1.07 per year increment, 95% CI 1.01-1.13, p < 0.02) and mortality secondary to cardiovascular events, infection/multisystem organ failure and allograft failure (hazard ratio = 1.08 per year increment, 95% CI 1.00-1.16, p = 0.05) increased for each additional year of diabetes. No associations were found for duration of hypertension and hyperlipidemia. Greater attention to management of diabetes may mitigate its negative impact on long-term survival in liver transplant recipients.

Race, ethnicity, sex and temporal differences in Barrett's oesophagus diagnosis: a large community-based study, 1994-2006.

OBJECTIVE: To evaluate the demographics and incidence of Barrett's oesophagus diagnosis using community-based data. DESIGN: Observational study. SETTING: Kaiser Permanente, Northern California healthcare membership, 1994-2006. PATIENTS: Members with an electronic diagnosis of Barrett's oesophagus. MAIN OUTCOME MEASURES: Incidence and prevalence of a new Barrett's oesophagus diagnosis by race, sex, age and calendar year. RESULTS: 4205 persons met the study definition for a diagnosis of Barrett's oesophagus. The annual incidence in 2006 was highest among non-Hispanic whites (39/100,000 race-specific member-years, 95% confidence interval (95% CI) 35 to 43), with lower rates among Hispanics (22/100,000, 95% CI 16 to 29), Asians (16/100,000, 95% CI 11 to 22), and blacks (6/100,000, 95% CI 2 to 12). The annual incidence was higher among men than women (31 vs 17/100,000, respectively, year 2006; p<0.01). The incidence increased with age from 2 per 100,000 for persons aged 21-30 years, to a peak of 31 per 100,000 member-years for persons aged 61-70 years (year 2006). There was no increase in the incidence of new diagnoses until the last two observation years, which coincided with changes in data collection methods and may be due to bias. The overall prevalence among active members increased almost linearly to 131/100,000 member-years by 2006. CONCLUSIONS: The demographic distributions of Barrett's oesophagus differ markedly by race, age and sex and were comparable to those for oesophageal adenocarcinoma. Thus, demographic disparities in oesophageal adenocarcinoma risk may arise partly from the risk of having Barrett's oesophagus, rather than from differing risks of progression from Barrett's oesophagus to cancer. There has been an almost linear increase in the prevalence of diagnosed disease.

Helicobacter pylori infection and the risk of Barrett's oesophagus: a community-based study.

OBJECTIVE: Gastric colonisation with the Helicobacter pylori bacterium is a proposed protective factor against oesophageal adenocarcinoma, but its point of action is unknown. Its associations with Barrett's oesophagus, a metaplastic change that is a probable early event in the carcinogenesis of oesophageal adenocarcinoma, were evaluated METHODS: A case-control study was carried out in the Kaiser Permanente Northern California population, a large health services delivery organisation. Persons with a new Barrett's oesophagus diagnosis (cases) were matched to subjects with gastro-oesophageal reflux disease (GORD) without Barrett's oesophagus and to population controls. Subjects completed direct in-person interviews and antibody testing for H pylori and its CagA (cytotoxin-associated gene product A) protein. RESULTS: Serological data were available on 318 Barrett's oesophagus cases, 312 GORD patients and 299 population controls. Patients with Barrett's oesophagus were substantially less likely to have antibodies for H pylori (OR = 0.42, 95% CI 0.26 to 0.70) than population controls; this inverse association was stronger among those with lower body mass indexes (BMIs < 25, OR = 0.03, 95% CI 0.00 to 0.20) and those with CagA+ strains (OR = 0.08, 95% CI 0.02 to 0.35). The associations were diminished after adjustment for GORD symptoms. The H pylori status was not an independent risk factor for Barrett's oesophagus compared with the GORD controls. CONCLUSIONS: Helicobacter pylori infection and CagA+ status were inversely associated with a new diagnosis of Barrett's oesophagus. The findings are consistent with the hypothesis that H pylori colonisation protects against Barrett's oesophagus and that the association may be at least partially mediated through GORD.

Controlling charge injection in organic field-effect transistors using self-assembled monolayers.

We have studied charge injection across the metal/organic semiconductor interface in bottom-contact poly(3-hexylthiophene) (P3HT) field-effect transistors, with Au source and drain electrodes modified by self-assembled monolayers (SAMs) prior to active polymer deposition. By using the SAM to engineer the effective Au work function, we markedly affect the charge injection process. We systematically examine the contact resistivity and intrinsic channel mobility and show that chemically increasing the injecting electrode work function significantly improves hole injection relative to untreated Au electrodes.

Octreotide for acute esophageal variceal bleeding: a meta-analysis.

BACKGROUND & AIMS: Studies of octreotide have not demonstrated a consistent benefit in efficacy or safety compared with conventional therapies. This study statistically pooled existing trials to evaluate the safety and efficacy of octreotide for esophageal variceal hemorrhage. METHODS: We identified randomized trials of octreotide for variceal hemorrhage from computerized databases, scientific meeting abstracts, and the manufacturer of octreotide. Blinded reviewers abstracted the data, and a meta-analysis was performed. RESULTS: Octreotide improved control of esophageal variceal hemorrhage compared with all alternative therapies combined (relative risk [RR], 0.63; 95% confidence interval [CI], 0.51-0.77); vasopressin/terlipressin (RR, 0.58; 95% CI, 0.42-0.81); or no additional intervention/placebo (among patients that received initial sclerotherapy/banding before randomization) (RR, 0.46; 95% CI, 0.32-0.67). Octreotide had comparable efficacy to immediate sclerotherapy for control of bleeding (RR, 0.94; 95% CI, 0.55-1.62), fewer major complications than vasopressin/terlipessin (RR, 0.31; 95% CI, 0.11-0.87), and a complication profile comparable to no intervention/placebo (RR, 1.06; 95% CI, 0.72-1.55). No specific alternative therapy demonstrated a mortality benefit. CONCLUSIONS: These results favor octreotide over vasopressin/terlipressin in the control of esophageal variceal bleeding and suggest it is a safe and effective adjunctive therapy after variceal obliteration techniques. Trials are needed to determine the optimal dose, route, and duration of octreotide treatment.

Oesophageal and gastric cardia adenocarcinomas: analysis of regional variation using the Cancer Incidence in Five Continents database.

BACKGROUND: Adenocarcinomas of the oesophagus and proximal stomach are the most rapidly increasing malignancies in some countries; however, there are no comparative studies on global disease incidence, and the relationships between these two malignancies are undefined. METHODS: We evaluated the cumulative rates and age-specific incidence rates per 100 000 population for adenocarcinomas of the oesophagus and proximal stomach for all countries in the Cancer Incidence in Five Continents database, and compared them with rates for oesophageal squamous cell carcinoma. RESULTS: Substantial variations in cumulative cancer rates were found between genders, between countries, between different ethnicities within the same country, and within the same ethnicity residing in different countries. Cumulative rates (ages 0-74 years) for oesophageal adenocarcinoma varied from 0 (e.g. Thailand) to 0.6 (Scotland, males, 95% CI : 0.56, 0.64); for proximal stomach cancer from 0 (Singapore, Malay females, 95% CI : -0.01, 0.11) to 0.52 (The Netherlands, males, 95% CI : 0.49, 0.55); and for oesophageal squamous cell carcinomas from 0 (non-Jews in Israel, females) to 1.84 (Brazil, Porto Alegre, males, 95% CI : 1.42, 2.26). There was a continuous increase in age-specific incidence rates with advancing age for oesophageal/proximal stomach adenocarcinomas, but a decrease in age-specific incidence rates for oesophageal squamous cell carcinoma after age 75 years. The cumulative rate trends for adenocarcinomas of the oesophagus and proximal stomach were often dissimilar, and varied by country, gender, and ethnicity. CONCLUSIONS: These results suggest that different risk factors may be associated with adenocarcinomas of the oesophagus versus the proximal stomach; the marked rate variation implies a substantial environmental component to the recent incidence changes.

Evaluation of cyclooxygenase-2 inhibitors using pulsed ultrafiltration mass spectrometry.

Since selective inhibition of the inducible form of cyclooxygenase (COX-2) might retain all the benefits of classical nonsteroidal antiinflammatory agents while avoiding the major side effects associated with inhibition of the constitutive isoform COX-1, COX-2 has become an important target for the discovery and development of new antiinflammatory drugs. To aid in the discovery and characterization of such selective inhibitors, we have applied a mass spectrometry-based screening technique, pulsed ultrafiltration mass spectrometry, using COX-2 as the target. In a blind study, 18 samples enriched with one or more inhibitors of COX-2 were evaluated. The matrixes for the test samples consisted of DMSO, r DMSO solutions of a plant extract, or a bacterial fermentation broth extract. The composition of the samples was unknown during the assays, as were the concentrations of the COX-2 inhibitors. A soluble recombinant form of human COX-2 was incubated with each sample, and then an aliquot of each mixture was injected into the stirred ultrafiltration chamber fitted with a 30000 MW cutoff ultrafiltration membrane. After the unbound and weakly bound compounds were washed away, the ligand-receptor complexes were disrupted using an acidified 10% methanol solution. The released ligands were trapped on a C18 cartridge and then identified using liquid chromatography-negative ion electrospray mass spectrometry with the trapping cartridge as the HPLC column. Neither the plant matrix nor the fermentation broth extract were found to interfere with the assay. Two or three ligands for COX-2 were identified in each sample, which included polar and nonpolar compounds and inhibitors with IC50 values ranging from 100 microM to 10 nM.

Potential regulation of GnRH gene by a steroidogenic factor-1-like protein.

Steroidogenic factor-1 (SF-1) is a member of an orphan nuclear hormone receptor superfamily. It plays a critical role in the development and function of the hypothalamic-pituitary-gonadal and adrenal axis. However, whether SF-1 can regulate transcription of gonadotrophin-releasing hormone (GnRH) gene is not known. To examine this possibility, we first over-expressed SF-1 and found that it not only decreased steady state GnRH messenger ribonucleic acid (mRNA) levels but also reduced its promoter activity in GT1-7 neurons. The inhibitory effect of SF-1 was lost when the 5'-flanking region of GnRH gene containing two distal (-1479 to -1474 bp and -1059 to -1054 bp) hexamers was deleted. Gel mobility shift assays showed that GT1-7 cell nuclear extracts contained a protein that formed a specific complex with synthetic oligonucleotides containing the two distal hexamers or a consensus SF-1 binding sequence. The migration of this complex was, however, slower than the complex formed with MA-10 cell nuclear extracts which were shown to contain a 53 kDa SF-1 protein. The addition of anti-SF-1 antibody supershifted the complex formed with MA-10, but not with GT1-7 cell nuclear extracts. The same antibody, however, detected a 60 kDa protein and immunostained nuclei of GT1-7 neurons. These results are consistent with GT1-7 neurons containing an SF-1-like protein that can bind to the distal hexamer sequences in the 5'-flanking region of rat GnRH gene to inhibit its transcription.

Kindergarten children's knowledge and perceptions of alcohol, tobacco, and other drugs.

Kindergarten children's knowledge and perceptions of alcohol, tobacco, and other drugs (ATODs) were assessed and the congruence between parent ATOD use and children's knowledge of ATODs was examined. Data were collected during the pre-intervention phase of an ATOD prevention trial with 5- and 6-year-old children and their parents. Three elementary schools were randomly selected from a population of 15 high-risk elementary schools in Lexington, Ky., (n = 126 parent-child dyads). Children were interviewed about their knowledge, feelings, and attitudes toward ATODs using the Child Drug Awareness Inventory. Parents self-reported ATOD use. Almost all (95%) kindergarten children recognized cigarettes; 56% correctly identified alcoholic beverages; and 17% recognized at least one illicit drug. Minority children were almost four times more likely to recognize illicit drugs than were non-minority children. Children's knowledge of ATODs was not correlated with the parents' reported drug use. ATOD prevention programs for young children merit greater emphasis.

Structure-activity relationship studies on 1-[2-(4-Phenylphenoxy)ethyl]pyrrolidine (SC-22716), a potent inhibitor of leukotriene A(4) (LTA(4)) hydrolase.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory mediator that has been implicated in the pathogenesis of a number of diseases including inflammatory bowel disease (IBD) and psoriasis. Since the action of LTA(4) hydrolase is the rate-limiting step for LTB(4) production, this enzyme represents an attractive pharmacological target for the suppression of LTB(4) production. From an in-house screening program, SC-22716 (1, 1-[2-(4-phenylphenoxy)ethyl]pyrrolidine) was identified as a potent inhibitor of LTA(4) hydrolase. Structure-activity relationship (SAR) studies around this structural class resulted in the identification of a number of novel, potent inhibitors of LTA(4) hydrolase, several of which demonstrated good oral activity in a mouse ex vivo whole blood assay.

Accuracy of endoscopic databases for assessing patient symptoms: comparison with self-reported questionnaires in patients infected with the human immunodeficiency virus.

BACKGROUND: Endoscopic databases are increasingly used for clinical research, but their validity as research instruments has not been assessed. We compared the accuracy of endoscopic indications recorded in an endoscopic database with patient symptom questionnaires. METHODS: All patients infected with the human immunodeficiency virus referred to the outpatient gastroenterology practice were prospectively evaluated using recognized symptom questionnaires. For patients undergoing esophagogastroduodenoscopy, the procedure indications recorded in the endoscopic database and the patient's self-reported symptom scores were compared. RESULTS: Ninety-three patients were evaluated. The symptoms of nausea/vomiting, diarrhea, and anorexia were highly predictive for the presence of these symptoms on the patient questionnaires. The symptoms of dyspepsia/abdominal pain did not predict well the presence of these symptoms on the questionnaire. Patients reported frequent and severe symptoms that were not recorded as indications for the procedures. The overall agreement (kappa statistic) was highly variable, from slight (kappa = 0.07 for anorexia) to moderate (kappa = 0.44 for diarrhea). CONCLUSIONS: Endoscopic indications are variably associated with self-reported symptom scores. These findings raise concerns about using some endoscopic database indications as accurate representations of patients' symptoms. Until performance characteristics of a given database are known, symptom-oriented research should use validated questionnaires whenever possible.

O- and N-methylation in the biosynthesis of staurosporine.

The feeding of (13)C- and (2)H-enriched methionine to Streptomyces staurosporeus established that the methyl carbon and proton source of both the 3'-O- and 4'-N-methyl groups of staurosporine (1) was methionine and that all three methyl protons from methionine were retained on 1. In the presence of the methyltransferase inhibitor, sinefungin, the biosynthesis of staurosporine was blocked at the last step, O-methylation. An intermediate, 3'-demethoxy-3'-hydroxystaurosporine (2), was efficiently accumulated in the medium. Other general methyltransferase inhibitors failed to produce any other staurosporine intermediates or analogues.

Evaluation of upper gastrointestinal tract symptoms in patients infected with HIV.

OBJECTIVE: Upper gastrointestinal tract (UGI) symptoms are frequent in patients infected with the human immunodeficiency virus (HIV), but little published information exists about their characteristics or methods of evaluation. We evaluated the prevalence of nonesophageal UGI symptoms in a referral population, the utility of esophagogastroduodenoscopy (EGD) for diagnosis, and clinical predictors of abnormal endoscopic findings in patients infected with HIV. METHODS: All HIV-infected patients referred to.the outpatient gastroenterology clinics were prospectively evaluated using recognized symptom questionnaires. EGD indications, results, and the patients' self-reported symptom scores were compared. HIV-infected patients undergoing EGD were compared with HIV-infected patients not receiving an EGD and with symptomatic non-HIV-infected patients undergoing EGD. RESULTS: A total of 201 patients completed 280 questionnaires. Among 93 patients who underwent endoscopy, severe symptoms occurring at least several times per week included: anorexia (70%), upper abdominal pain (34%), vomiting (32%), or a recent weight loss of approximately 15 lb (31%). Patients undergoing EGD had more frequent/severe symptoms, but did not have differences in overall well-being or mean GI symptom score. The frequency of substantial and treatable endoscopic findings among patients infected with HIV was comparable to that found in the non-HIV-infected control group. There were no independent symptoms predicting substantial or treatable disease on EGD. CONCLUSIONS: We conclude that: 1) upper gastrointestinal symptoms are common in HIV-infected patients referred for GI consultation; 2) symptomatic HIV patients have a high prevalence of both treatable and untreatable upper GI pathologies; 3) and physicians use symptom frequency and severity to select patients for EGD, but these factors correlate poorly with abnormalities on EGD. Given this discrepancy, longitudinal study is needed to determine whether treating endoscopic abnormalities improves UGI symptoms.