Effect of CYP2C19 and MDR1 polymorphisms on cure rate in patients with acid-related disorders with Helicobacter pylori infection

A proton pump inhibitor (PPI) plus two antibiotics (amoxicillin and either clarithromycin or metronidazole) are recommended for treatment of acid-related disorders with Helicobacter pylori (H. pylori) infection. The aim of this pharmacogenetic study was to evaluate the efficacy of triple therapy with PPIs on eradication of H. pylori infection in relation to cytochrome P₄₅₀ 2C19 (CYP2C19) and P-glycoprotein (MDR1) gene polymorphisms. The retrospective study involved 70 Polish Caucasian patients with H. pylori infection, diagnosed and treated with one of the two different triple therapy regimens [omeprazole, amoxicillin, and clarithromycin (OAC) or pantoprazole, amoxicillin, and metronidazole (PAM)]. Using genomic DNA, CYP2C19 (*2 and *3) and C3435T MDR1 alleles were determined by means of polymerase chain reaction-restriction fragment length polymorphism assays. A significantly higher prevalence (P<0.05) of heterozygous extensive metabolizers (hetEM) with CYP2C19*1/*2 genotype (32.4% versus 8.3%) and homozygous with 3435TT MDR1 genotype (38.2% versus 13.9%) was found in patients cured after the first cycle of triple therapy than in patients with failure of eradication after the first cycle. CYP2C19*1/*2 and 3435TT MDR1 genotypes as well as PAM regimen of treatment were also predictive of successful eradication of H. pylori infection after the first cycle of triple therapy at univariate/multivariate logistic regression analysis. This pharmacogenetic study on the influence of different CYP2C19 and C3435T MDR1 genotypes on H. pylori eradication suggests that CYP2C19 and MDR1 polymorphisms may be independent predictable determinants of the efficacy of triple therapy including PPI. The PAM regimen of treatment seems to be more effective after the first cycle of the therapy than the OAC regimen.     

The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers

Rationale N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have been reported to induce schizophrenia-like symptoms in humans, including memory impairments. Although the NMDA receptor has been shown to impair memory acquisition by disrupting long-term potentiation (LTP), limited research has been done on studying the effects of NMDA antagonists on the post-LTP cascade of events implicated in consolidation as measured by administering the drug after the initial learning experience.Objective The purpose of this experiment was to examine the effect of ketamine on mental status and to identify NMDA antagonist-induced memory deficits by comparing the recall performance of items presented both immediately before and during ketamine infusion.Methods Thirteen normal controls received a 60-min infusion of ketamine in a randomized double-blind, cross-over design. Mental status was evaluated with the Brief Psychiatric Rating Scale and the Clinician-Administered Dissociative States Scale. The first 12-item word list was presented immediately before infusion, and two lists were subsequently presented during the infusion. Verbal memory performance was assessed by measuring the delayed cued recall of each list 30 min after its presentation.Results At the beginning, subjects experienced perceptual and reality distortion symptoms, followed later by mild subjective effects. Ketamine significantly reduced the delayed recall of words presented immediately before, but not during, drug infusion. Ketamine-induced decrements in verbal recall correlated significantly with plasma ketamine levels.Conclusion This study characterizes the behavioral effects associated with ketamine and suggests that ketamine decreases verbal memory performance by interfering with early consolidation processes.     

Immunomodulatory effects of the fungicide Mancozeb in agricultural workers

Available data suggest that ethylenebisdithiocarbamates (EBDCs) may have immunomodulatory effects. This study aimed to investigate the immunological profile of farmers exposed to Mancozeb, an EBDC fungicide, through the determination of several serum, cellular, and functional immune parameters. Twenty-six healthy subjects entered the study, 13 vineyards exposed to Mancozeb and 13 unexposed controls. Exposure was assessed through the determination of ethylentiourea (ETU) in urine. Complete and differential blood count, serum immunoglobulins, complement fractions, autoantibodies, lymphocyte subpopulations, proliferative response to mitogens, natural killer (NK) activity, and cytokine production were measured. Post-exposure samples showed ETU urine concentration significantly higher than pre-exposure and control groups. A significant increase in CD19+ cells, both percentage and absolute number, and a significant decrease in the percentage of CD25+ cells were found in post-exposure samples compared to controls. A statistically significant increase in the proliferative response to phorbol myristate acetate plus ionomycin (PMA + ionomycin) was observed in the post-exposure group compared to controls and baseline, while a significant reduction in LPS-induced TNF-alpha release in post-exposure samples was observed. Overall, our results suggest that low-level exposure to Mancozeb has slight immunomodulatory effects, and point out a method adequate to reveal immune-modifications in workers occupationally exposed to potential immunotoxic compounds, based on a whole blood assay.     

Cytotoxic activity and effect on nitric oxide production of tirucallane-type triterpenes

Hexane extract from the bark of Amphipterygium adstringens, as well as its principal constituents, masticadienonic acid and 3alpha-hydroxymasticadienolic acid, inhibited the growth of five human cancer cell lines. Derivatives of, namely 24,25 S-dihydromasticadienonic acid and masticadienolic acid, were also evaluated. The results showed that both and had greater activity than on colon cancer cell lines. The effects of on the production of nitric oxide (NO) from both resting and lipopolysaccharide-activated macrophages were determined. It was found that and caused an increase in NO release from resting macrophages; in lipopolysaccharide-activated macrophages, only and caused an increase in NO production.     

Treatment of 72 newly diagnosed Waldenstrom macroglobulinemia cases with oral melphalan, cyclophosphamide, and prednisone: results and cost analysis

BACKGROUND: Current treatment regimens for Waldenstrom macroglobulinemia (WM) are based on the use of oral alkylating agents. Recently, however, other more costly agents have been proposed for the treatment of WM. In the current study, the authors report on results obtained using oral melphalan, cyclophosphamide, and prednisone (MCP) to treat 72 patients with WM, and they compare these results (and the associated costs) with those observed using more aggressive protocols. METHODS: Between July 1973 and April 2002, the authors documented overexpression of the immunoglobulin M paraprotein in 317 consecutive patients. Of these, 100 had newly diagnosed WM, and the 72 who were symptomatic were treated using the MCP protocol. Response rate, overall survival (OS), response duration, freedom from progression (FFP), event-free survival (EFS) duration, toxicity, and cost per course in Euro and U.S. dollars were evaluated for patients receiving this regimen. RESULTS: Seventy-one of 72 patients (99%) were evaluable. Of these patients, 55 (77%) achieved a response; 7 others (10%) experienced disease stabilization, and the remaining 9 (13%) experienced disease progression. After a median follow-up of 72 months (range, 3-195 months), the median durations of EFS, FFP, response, and OS were 47, 55, 64, and 66 months, respectively. No World Health Organization Grade III or IV toxicities were observed, and side effects were limited to transient nausea, emesis, and mild neutropenia. The cost per course of the MCP regimen was $16, similar to that of standard protocols involving chlorambucil and much less than that of more aggressive protocols (price range, $91-11091) proposed for the treatment of WM. CONCLUSIONS: Like chlorambucil-based protocols, the MCP regimen is a cost-effective and safe option for the treatment of patients with WM. Furthermore, the results obtained do not appear to be inferior to those yielded by more expensive, aggressive, and toxic intravenous protocols.     

Risk factors for the development of second primary tumors among men after laryngeal and hypopharyngeal carcinoma

BACKGROUND: Second primary tumors (SPT) constitute a major threat to the survival of patients with laryngeal carcinoma. However, to the authors' knowledge little is known regarding the risk factors for developing SPTs or about the strategy to be followed to avoid them. METHODS: Eight hundred seventy-six male patients with laryngeal/hypopharyngeal carcinoma enrolled in a population-based, case-control study in 5 centers from South Europe during 1979-1982 were followed up to ascertain the occurrence of SPTs. Standardized incidence ratios were calculated to estimate the risk of SPT occurring in the cohort. Cox proportional hazard models were fitted to estimate the hazard ratio for development of SPTs in relation to use of tobacco smoking, alcohol consumption, and dietary habits before the first primary tumor. RESULTS: One hundred forty-five patients developed an SPT with an annual average rate of 2.1%. An excess risk of developing an SPT of the tongue, mouth, esophagus, and lung was observed. No elevated risks of SPTs were observed in other organs. Alcohol consumption strongly increased the risk of developing an SPT of the upper aerodigestive tract (UADT). Heavy cumulative cigarette smoking increased the risk of developing a lung SPT. A protective effect of high intake of citrus fruit was noticed for SPT in the lung, whereas high butter intake was associated with an increased risk for SPT of the UADT. CONCLUSIONS: Continuous medical surveillance was essential in the UADT and lung to reduce the risk from an SPT after initial laryngeal/hypopahryngeal carcinoma. Alcohol consumption before the first primary tumor was a risk factor for SPT of the UADT. The study suggested a protective role of citrus fruits in the development of a lung SPT.     

Validation of commonly used immunostains on cell-transferred cytologic specimens

BACKGROUND: Immunocytochemical staining (ICC) is often limited by the lack of cell blocks that contain diagnostic cells or by the unavailability of smear materials. The cell-transfer technique, in which original smear material is divided into several pieces and then transferred to multiple slides, can facilitate multiple ICC on limited materials. However the reliability of the staining results has not been systematically evaluated. METHODS: The authors validated 21 commonly used antibodies (cytokeratin [CK] 7, CK 20, TTF-1, panCK, vimentin, HMB-45, Mart-1, leukocyte common antigen, chromogranin, synaptophysin, estrogen receptor, progesterone receptor, prostate-specific antigen, prostatic acid phosphatase, calretinin, CK5/6, WT-1, BerEP4, MOC-31, p63, and thyroglobulin) on the cell-transferred materials of various tumor samples (n = 20) and reactive effusion samples (n = 2). The staining results were compared with the previously available ICC results (performed either on cell block sections or on smears) of the same specimens. RESULTS: One hundred pieces of transferred materials were immunostained, of which 5 (5%) were lost during the staining procedure. Of the remaining 95 pieces, 92 (97%) showed staining results that agreed with those of the previous ICC, whereas 3 (3%) showed results that disagreed. The original ICC in the latter three specimens was performed on cell block sections and showed focally positive synaptophysin staining in a sample with a neuroendocrine tumor, focally positive CK5/6 staining in a pleural effusion sample with mesothelioma, and positive TTF-1 staining in a lymph node sample with metastatic lung carcinoma. Their corresponding ICC of cell-transferred materials showed negative results. An increase in background staining was observed in 1 of the 95 tissue pieces, but no false-positive results were observed. CONCLUSIONS: In general, ICC can be reliably performed on cell-transferred tissue specimens for markers tested. However, caution should be taken when interpreting ICC results in tissue specimens with limited cellularity and heavy background staining.     

The predictive value of CD8, CD4, CD68, and human leukocyte antigen-D-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase

BACKGROUND: To establish the prognostic value of immune system cells that infiltrate melanoma, the authors evaluated the distribution and density of T lymphocyte subsets, macrophages, and dendritic cells in samples of primary cutaneous melanoma from 47 patients with Stage I and II melanoma according to the American Joint Committee on Cancer staging system. METHODS: Immunohistochemical demonstrations of CD8 and CD4 lymphocytes, CD68 macrophages, human leukocyte antigen-D-related (HLA-DR) cells, S-100 protein, and melanoma-associated antigens Melan A and HMB-45 were performed. The results were derived from independent histopathologic reviews by two pathologists. The low-density, moderate-density, and high-density groups of cells that infiltrated the base of the tumor during the vertical growth phase were compared with the overall survival rate using the Kaplan-Meier method and the log-rank test. Clinical variables (gender, age, tumor location, Clark level, vascular/lymphatic invasion, and thickness) also were analyzed. RESULTS: The CD8 lymphocytes exhibited independent statistically positive significance in survival (log-rank test, 8.49; P = 0.01) between patients in different lymphocyte density groups. There was a difference in 5-year survival among patients in the high-density group (78.8%), the moderate-density group (44.4%), and the low-density group (25.0%). The CD4 lymphocytes, which were less numerous than CD8 cells, had similar distribution. There also was a correlation of HLA-DR cells with overall survival (log-rank test, 5.29; P = 0.02). CD68 cell density was not found to be correlated with survival. CONCLUSIONS: The presence and number of infiltrating CD8 lymphocytes as well as the overall occurrence of HLA-DR cells may be considered independent, favorable prognostic factors in melanoma. The current results may be important for identifying other prognostic factors with which to evaluate disease progression and develop immune therapies for patients with melanoma.     

The parent's perspective

The present paper gives an insight from a parent's perspective into the roles of health professionals and service providers in the daily management of a child with complex needs that include enteral feeding. It focuses on the case of a 9-year-old boy and discusses some aspects of his diagnosis and treatment, and the support received. It highlights the need for a multi-agency approach based around the child, in which parents are consulted, the opinions of professionals from the different disciplines are valued by other professionals and professionals do not issue conflicting advice but share knowledge before giving advice. There should be national accessibility to support services and a standardised training programme for carers. Better communication between parents, carers, health professionals and service providers and working together can reduce the stress for the patient and carer, and put less strain on much-needed resources.