Effect of CYP2C19*17 gene variant on Helicobacter pylori eradication in peptic ulcer patients

Objective Eradication of Helicobacter pylori is an important treatment strategy in peptic ulcer patients. Current regimens of eradication consist of proton pump inhibitor (PPI) and two antibiotics. The principal enzyme involved in PPIs metabolism is CYP2C19, which exhibits an interindividual variability of activity, mainly due to genetic polymorphism. Two alleles (CYP2C19*2 and CYP2C19*3), responsible for slow PPIs metabolism, were previously associated with higher efficacy of eradication. Recently, a novel CYP2C19 gene variant (CYP2C19*17), associated with faster metabolism of CYP2C19 substrates, was described. In the present study, a potential association between CYP2C19*17 allele and lower H. pylori eradication efficacy was tested in a group of peptic ulcer patients.Methods A total of 125 peptic ulcer patients, positive for H. pylori infection, were treated with triple therapy (pantoprazole+amoxicillin+metronidazole). Subsequently, the patients were divided into two groups (group 1 – success, and group 2 – failure of eradication after therapy) and genotyped for the presence of CYP2C19 variant alleles (*2, *3, and *17).Results Frequency of CYP2C19 alleles in two groups of patients were: 56.4 versus 65 (p=0.060) for *1, 15.4 versus 5.3 (p=0.015) for *2, and 28.2 versus 25.5 (p=0.663) for *17 allele, respectively. CYP2C19*3 was not detected in the evaluated population. No significant differences in frequency nor distribution of *17 allele were found between two groups of patients. CYP2C19*2 allele was associated with successful H. pylori eradication (p<0.02), *2 allele carriers were found to be over 4-times more prone to the treatment compared to *1/*1 homozygotes (OR=4.2, p=0.015).Conclusion Our results suggest that, contrary to CYP2C19*2, CYP2C19*17 allele has no impact on efficacy of H. pylori eradication in peptic ulcer patients treated with pantoprazole.     

Chronic 5-HT6 receptor modulation by E-6837 induces hypophagia and sustained weight loss in diet-induced obese rats

E-6837 is a novel, selective and high-affinity 5-HT(6) receptor ligand (pK(i): 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5-HT(6) receptor and full agonism at a constitutively active human 5-HT(6) receptor by monitoring the cAMP signaling pathway.The effects of chronic treatment with E-6837 were determined in diet-induced obese (DIO)-rats on changes in body weight, food and water intake, plasma indices of comorbid risk factors, and weight regain on compound withdrawal. The centrally acting antiobesity drug, sibutramine, was used as the reference comparator.Sustained body weight loss and decreased cumulative food intake of DIO-rats was observed with E-6837 (30 mg kg(-1), p.o., twice a day) during the 4-week treatment period. The onset of the E-6837 effect on body weight was slower than that of sibutramine (5 mg kg(-1), p.o.), while its maximal effect was greater, that is -15.7 versus -11.0%.E-6837-induced weight loss was exclusively mediated by a decrease (31.7%) in fat mass, with a concomitant reduction (49.6%) in plasma leptin. Reduced obesity was also reflected in improved glycemic control.Although weight regain occurred after withdrawal from either compound, the body weights after E-6837 (-6.6%) remained lower than after sibutramine (-3.8%) indicating that the greater efficacy of the former did not result in profound rebound hyperphagia/weight gain.These results show that the 5-HT(6) receptor partial agonist, E-6837, is a promising new approach to the management of obesity with the potential to produce greater sustained weight loss than sibutramine.     

A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts

Interaction of insulin-like growth factor receptor I (IGF-IR) with its ligands has been reported to induce cell proliferation, transformation and blockade of cell apoptotic functions. IGF-IR is overexpressed on numerous tumor cell types and its blockade could be of importance for anti-cancer therapy. We have generated a humanized anti-IGF-IR antibody h7C10 that blocks in vitro IGF-I and IGF-II-induced cell proliferation of MCF-7 breast cancer cells. Analysis of the IGF-I transduction cascade demonstrated that the humanized anti-IGF-IR antibody and its murine parental form block IGF-I-induced tyrosine phosphorylation, both its beta-chain and IRS-1 tyrosine phosphorylation. This presumably leads to cell cycle arrest and, consequently, growth inhibition. Treatment of nude mice bearing either human breast cancer cells (MCF-7) or non small lung cancer cells (A549) with h7C10, or its murine parental form 7C10, inhibited significantly tumor growth. An almost complete inhibition of A549 tumor growth was observed when mice were treated with the anti-IGF-IR antibody combined with either a chemotherapeutic agent, Vinorelbine or an anti-epidermal growth factor receptor (EGFR) antibody, 225. Combined therapy prolonged significantly the life span of mice in an orthotopic in vivo model of A549; the combination of the anti-IGF-IR antibody with an anti-EGFR antibody was superior to the Vinorelbine combination. The present results indicate that the humanized anti-IGF-IR antibody h7C10 has a great potential for cancer therapy when combined with either a chemotherapeutic agent or an antibody that targets other growth factor receptors, such as the epidermal growth factor receptor.     

Ultrastructural localization of Tartrate-resistant acid phosphatase (purple acid phosphatase) activity in chicken cartilage and bone

Tartrate-resistant acid adenosine triphosphatase activity at pH 6.5, using a lead-salt method, was localized at light and electron microscopic levels in cartilage and bone matrices, osteocalsts, and chondrocalsts. Cartilage matrix staining occurred after vascular invasion of the growth plate. In osteoclasts, activity was present in lysosomes, extracellular ruffled border channels, and the underlying cartilage and bone matrices. Staining artifacts occurred at lower pH levels (pH 5.4, 5.0). Adenosine diphosphate, p-nitrophenylphosphate, thiamine pyrophosphate, and α-naphthylphosphate also acted as substrates; but no activity was observed when adenosine monophosphate, adenylate-(β,γ-methylene) diphosphate, and β-glycerophosphate were used. The activity was inhibited by NaF, dithionite, and a high concentration of p-chloromercuribenzoic acid, and activated by simultaneous addition of FeCl₂ and ascorbic acid, as has been shown in biochemical studies. These histochemical results support the view that the adenosine triphosphate hydrolyzing activity at pH 6.5 is due to tartrate-resistant acid phosphatase (TRAP). There were some differences in ultrastructural localization between TRAP and tartrate-sensitive acid phosphatase (TSAP) activities in osteoclasts: TSAP activity was more intense in lysosomes and Golgi complexes and TRAP was stronger in the cartilage and bone matrices. It is suggested, therefore, that most of TRAP is in an inactive form in cells and is activated when secreted.     

Pulmonary edema and fluid mobilization as determinants of the duration of ECMO support

The physiological variables that govern recovery of pulmonary function during neonatal extracorporeal membrane oxygenation (ECMO) remain poorly understood. We hypothesized that pulmonary hypertension (PHN) resolves soon after starting ECMO and that neonatal weight gain, pulmonary edema, and fluid mobilization are major determinants of recovery of pulmonary function and the ability to decrease ECMO support. To evaluate this, 17 consecutive neonates requiring ECMO for severe respiratory failure were reviewed. PHN was studied by daily echocardiography to assess the direction of ductal shunting. To evaluate fluid flux, pulmonary function, and edema during ECMO, we measured body weight, urine output, and ECMO flow every 12 hours. To evaluate pulmonary edema, serial chest radiographs obtained every 12 hours were randomly reviewed and scored by two radiologists with a semiquantitative chest radiograph index score (CRIS). By 25% of bypass time, PHN had resolved in all patients. However, at that time, weight had increased to 9.16% +/- 1.78% above birth weight, and the CRIS was 44% worse than the value just prior to ECMO. From 25% time on bypass, as urine output increased, patient weight and CRIS progressively decreased, allowing ECMO support to be weaned. At the time of discontinuation of ECMO support, weight had decreased to 2.0% +/- 1.3% above birth weight, and urine output remained steady at 3.0 +/- 0.3 mL/kg/h. Within 24 hours of stopping ECMO, the CRIS showed a 58% improvement compared to maximal scores during ECMO. We conclude that PHN decreases early in ECMO and that edema and its mobilization are important determinants of the improvement in pulmonary function and duration of ECMO.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impact of resistance to anti-tuberculosis drugs on treatment outcome using World Health Organization standard regimens

We compared treatment outcome in 410 patients with drug-susceptible tuberculosis (DS-TB) and 150 patients with drug-resistant tuberculosis (DR-TB) among 560 adult patients (> or = 15 years old) notified with smear-positive pulmonary tuberculosis between July 1997 and June 1998 in the West Province of Cameroon and treated with World Health Organization (WHO) standard regimens under field conditions. Information on treatment outcome was collected for all smear-positive TB patients having a positive culture with drug susceptibility tests performed for isoniazid, rifampicin, ethambutol and streptomycin. Treatment outcome was recorded as cured, completed treatment, failed, defaulted, died or transferred out, 332 of the 410 patients (81%) with DS-TB were cured, compared to 109/150 (72.7%) patients with DR-TB (odds ratio [OR] = 0.62, 95% confidence interval [CI] 0.40-0.99). Seven patients (1.7%) failed treatment in the DS-TB group vs. 9 (6.0%) in the DR-TB group (OR = 3.67, 95% CI 1.23-11.18). No significant difference was found in rates of death, default or transfer. Sputum smear conversion at the end of the intensive treatment phase was observed in 78.8% of the cases, drug resistance having no effect on the conversion rate. After adjusting for age, sex and resistance, the death rate was higher in patients also infected with human immunodeficiency virus (HIV). In TB cases with multidrug resistance, standard regimens result in unacceptably high failure rates (26.1%). For all other drug-resistant forms of TB, rifampicin-based short-course chemotherapy gave satisfactory results. The death toll in the West Province seems due to HIV co-infection rather than to TB alone. To prevent development of drug-resistance, the proportion of defaulters must be decreased and prevention and control strategies endorsed by the WHO and the International Union Against Tuberculosis and Lung Disease must be implemented nation-wide.     

Spontaneous CSF otorrhea caused by abnormal development of the facial nerve canal

In two patients with surgically proved CSF fistula through the facial nerve canal, MR and CT examinations showed smooth enlargement of the geniculate fossa with CSF signal. In the clinical setting of CSF otorrhea or rhinorrhea, the presence of an enlarged labyrinthine facial nerve canal and enlarged geniculate fossa on CT scans and CSF intensity on MR images strongly suggests a CSF fistula through the facial nerve canal.     

Therapeutic methods of gut microbiota modification in colorectal cancer management – fecal microbiota transplantation,prebiotics, probiotics,and synbiotics

ABSTRACT

The link between gut microbiota and the development of colorectal cancer has been investigated. An imbalance in the gut microbiota promotes the progress of colorectal carcinogenesis via multiple mechanisms, including inflammation, activation of carcinogens, and tumorigenic pathways as well as damaging host DNA. Several therapeutic methods are available with which to alter the composition and the activity of gut microbiota, such as administration of prebiotics, probiotics, and synbiotics; these can confer various benefits for colorectal cancer patients. Nowadays, fecal microbiota transplantation is the most modern way of modulating the gut microbiota. Even though data regarding fecal microbiota transplantation in colorectal cancer patients are still rather limited, it has been approved as a clinical method of treatment-recurrent Clostridium difficile infection, which may also occur in these patients. The major benefits of fecal microbiota transplantation include modulation of immunotherapy efficacy, amelioration of bile acid metabolism, and restoration of intestinal microbial diversity. Nonetheless, more studies are needed to assess the long-term effects of fecal microbiota transplantation. In this review, the impact of gut microbiota on the efficiency of anti-cancer therapy and colorectal cancer patients’ overall survival is also discussed.     

Adolescents’ and Adults’ Experiences of Being Surveyed About Violence and Abuse: A Systematic Review of Harms,Benefits, and Regrets

The neuroscience and psychological literatures suggest that talking about previous violence and abuse may not only be beneficial, as previously believed, but may also be associated with risks. Thus, studies on such topics introduce ethical questions regarding the risk–benefit ratio of sensitive research. We performed a systematic review of participants’ experiences related to sensitive research and compared consequent harms, benefits, and regrets among victims and nonvictims of abuse. Thirty studies were included (4 adolescent and 26 adult studies). In adolescent studies, 3% to 37% of participants (median: 6%) reported harms, but none of these studies measured benefits or regrets. Among adults, 4% to 50% (median: 25%) reported harms, 23% to 100% (median: 92%) reported benefits, and 1% to 6% (median: 2%) reported regrets. Our results suggest that the risk–benefit ratio related to sensitive research is not unfavorable, but there are gaps in the evidence among adolescents.Sensitive research topics include those that are highly private and potentially psychologically traumatic. Substance use, sexual practices, violence and abuse, death, accidents, combat (including war), and natural disasters might all be considered sensitive research topics. Since the 1930s and 1940s, research has increasingly focused on sensitive topics, predominantly owing to the epidemics of illicit drug use, AIDS, and teenage pregnancies.1,2 There is a clear scientific rationale for research on sensitive topics to generate accurate information about prevalence, risk and protective factors, and intervention strategies. The self-reports of research participants are one of the most efficient data collection methods to gather such information.In the clinical arena of trauma-related disorders, including posttraumatic stress disorder (PTSD), earlier approaches of debriefing and “talking through” traumatic experiences were thought to be helpful intervention strategies to manage trauma and reduce risk. More recent evidence, however, suggests that such approaches may be harmful and may lead to retraumatization.3 The past decade has also seen an emerging neuroscience literature focusing on memory consolidation and reconsolidation; this literature suggests that reliving a memory might strengthen the memory trace.4 Taken together, psychological and neuroscience evidence suggests that there may be both risks and benefits of trauma-based clinical work.There has also been a debate in research settings as to whether recalling and answering questions about past trauma or abuse has negative or positive consequences for study participants.5–10 Some argue that asking about abuse might be upsetting, harmful, and stigmatizing and may lead to retraumatization; that survivors might not be emotionally stable enough to assess risk or seek help; and that researchers have an obligation to protect survivors from questions about their experiences. In contrast, others suggest that disclosure in the context of research participation may be followed by emotional relief, that participants identify such disclosure as beneficial, and that most participants do not regret or negatively appraise their research experience.11–18 Furthermore, it has been suggested that the emotional distress experienced by participants involved in sensitive research is an indicator of emotional engagement with a research project rather than an indicator of harm.5Given this debate, it is important to examine the literature regarding harms, benefits, and regrets in the context of sensitive research. A key consideration is differences between those with previous exposure to violence and abuse (victimization or perpetration) and those who have not been exposed. Another consideration is whether responses to research differ by gender. Females might be more vulnerable to the harms of research participation because prevailing norms supporting gender power inequities and male violence against women and girls may limit the accessibility of support during and after participation. Responses to participation may also be age dependent. In particular, adolescents who are exposed to abuse might be particularly vulnerable because they may need more support than adults during and after the research, and such support may be less accessible to them.Given the uncertainty regarding the risks, benefits, and risk-to-benefit ratio of participating in sensitive research, we conducted a systematic review of quantitative and qualitative studies investigating adolescents’ and adults’ experiences of participating in studies that included sensitive questions regarding violence and abuse (including intimate partner violence [IPV]) victimization and perpetration. We compared the consequent harms, benefits, and regrets among individuals who had been victims and perpetrators of violence or abuse with those of individuals who had not been victims or perpetrators. Furthermore, we investigated whether there were gender and age differences in the reporting of harms and benefits of research experience. Our goal was to produce evidence to guide researchers and ethics committees in avoiding underprotection or overprotection of human participants in research on violence and abuse.