A Facile and Practical One-Pot Synthesis of beta-Oxo Thioamides from beta-Oxo Amides and Isothiocyanates

A facile and practical one-pot synthesis of beta-oxo thioamides from beta-oxo amides has been developed. By treatment with isothiocyanates in ethanol in the presence of potassium carbonate, a series of beta-oxo amides was converted, under reflux, in high yields into the corresponding beta-oxo thioamides.

Effects of ultrahigh pressure extraction conditions on yields and antioxidant activity of ginsenoside from ginseng

Ultrahigh pressure technique was employed to extract ginsenosides from roots of ginseng (Panax ginseng C.A. Meyer). The optimal conditions for ultrahigh pressure extraction (UPE) of total ginsenosides were quantified by UV-vis spectrophotometry with the ginsenoside Re as standard, the signal ginsenosides were quantified by HPLC and ELSD with ginsenosides Re, Rg(1), Rb-1, Rc and Rb-2 as standards. Orthogonal design was applied to evaluate the effects of four independent factors (extraction pressure, extraction temperature, extraction time and ethanol concentration) on the yield and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity of ginsenoside, which are based on microwave extraction (ME), ultrasound extraction (UE), soxhlet extraction (SE) and heat reflux extraction (HRE) method. The results showed that UPE method can produce ginsenoside with the highest yield and the best radical scavenging activity compared to other used ones. Scanning electron microscopic (SEM) images of the plant cells after ultrahigh pressure treatment was obtained to provide visual evidence of the disruption effect.

塔里木盆地塔北、塔中地区早古生代白云岩形成机理

In Tarim Basin, extensive carbonates of Lower Paleozoic occur, in which thick Cambrian and Lower Ordovician dolostones are widespread and show a potential perspective in hydrocarbon exploration. So they are viewed as an important target for exploration. Tarim Basin is a poly phase composite basin, which underwent multiphase tectonic modification and volcanic activities; these exerted significant influences on the basin-fills and basin fluid evolution, thereby the diagenetic history, particularly on the deep-buried Lower Paleozoic dolostones. Referring to the classification of dolomite texture proposed by Gregg & Sibley (1984) and Sibley & Gregg (1987). In view of crystal size, crystal shape, crystal surface and contact relation, eight genetic textures of dolomite crystals are identified, based on careful petrographic examinatoins. These textures include: 1) micritic dolomite; 2) relict mimetic dolomite; 3)finely crystalline, planar-e(s), floating dolomite; 4)finely crystalline, planar-e(s) dolomite; 5) finely-coarse crystalline, nonplanar-a dolomite; 6)coarse crystalline, nonplanar saddle dolomite; 7) finely-medium crystalline, planar-e(s) dolomite cement; 8) coarse crystalline, nonplanar saddle dolomite cement, in which the former six textures occurs as in matrix, the latter two in the cements. Detailed geochemistry analysis is carried out on the basis of genetic textures of dolomite and related minerals such as quartz and calcite. The result showed that the calcite has the highest average content in Sr, which can be sorted into two groups; micritic dolomite has the highest average content in Sr among all kinds of dolomites; the REE patterns of all kinds of dolomites is similar to those of marine limestone samples. Saddle dolomite cement has δ13C values from -2.44‰ to 1.27‰ PDB, and δ18O values from -13.01‰ to -5.12‰ PDB, which partially overlap with those of matrix dolomite (δ13C values from -2.83‰ to 2.01‰ PDB, δ18O values from -10.63‰ to -0.85‰ PDB). Saddle dolomite cement has 87Sr/86Sr ratios from 0.7086 to 0.7104, which totally overlap with those of matrix dolomite (0.7084 ~ 0.7116). Compared with saddle dolomite derived from other basins all over the world, the saddle dolomites of Tarim Basin have similar δ13C, δ18O and 87Sr/86Sr ratios values with those of matrix dolomite. This scenario reflects the unusual geological setting and special dolomitizing liquid of Tarim Basin. The values of δ18O, δ13C and 87Sr/86Sr ratios of calcite also can be sorted out two groups, which may been resulted from the one stage of extensive uplift of Tarim Basin from Mesozoic to Cenozoic. Fluid inclusion microthermometry data of the diagenetic mineral indicates that matrix dolomite has relatively low homogenization temperatures (Th) of 80～105oC and salinities of 12.3％ (wt% NaCl equivalent); saddle dolomite has highest Th values, which concentrate in 120～160oC and salinities of 13.5～23.7％ (wt% NaCl equivalent); quartz has relatively low Th of 135～155oC and salinities of 17.8～22.5％ (wt% NaCl equivalent); calcite has relatively low Th of 121～159.5oC and salinities of 1.4～17.5％ (wt% NaCl equivalent). These data suggest that the saddle dolomites could have formed in thermal brine fluids. Based on comprehensive petrographical study, detailed geochemistry and fluid inclusion microthermometry analysis on Lower Paleozoic dolomite of Tarim Basin, three types of dolomitisation mechanism are proposed: Penecontemporaneous dolomitisation (Sabkha dolomitisation & Reflux dolomitisation); Burial dolomitisation (shallow-intermediate burial dolomitisation & Deep burial dolomitisation ); Hydrothermal cannibalized dolomitisation. In view of host-specified occurrences of hydrothermal dolomite, the low abundance of saddle dolomite and high geochemical similarities between saddle dolomite and host dolomite, as well as highest Th and high salinities , the hydrothermal dolomite in Tarim Basin is thus unique, which could have been precipitated in modified fluid in the host dolomite through intraformational thermal fluid cannibalization of Mg ions from the host. This scenario is different from the cases that large scale dolomitizing fluid migration took place along the fluid pathways where abundant saddle dolomite precipitated. Detailed observations on 180 petrographic and 60 casting thin sections show original pores in Lower Paleozoic dolomite were almost died out by complicated diagenetic process after a long time geologic evolution. On the other hand, deep-buried dolomite reservoirs is formed by tectonic and hydrothermal reforming on initial dolomites. Therefore, the distribution of structure-controlled hydrothermal dolomite reservoirs is predicted in Tabei and Tazhong Area of Tarim Basin based on the geophysical data.

A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir.

This study has investigated the effects of herpes simplex thymidine kinase gene (HSV-tk) transfer followed by ganciclovir treatment as adjuvant gene therapy to surgical resection in patients with recurrent glioblastoma multiforme (GBM). The study was open and single-arm, and aimed at assessing the feasibility and safety of the technique and indications of antitumor activity. In 48 patients a suspension of retroviral vector-producing cells (VPCs) was administered by intracerebral injection immediately after tumor resection. Intravenous ganciclovir was infused daily 14 to 27 days after surgery. Patients were monitored for adverse events and for life by regular biosafety assaying. Tumor changes were monitored by magnetic resonance imaging (MRI). Reflux during injection was a frequent occurrence but serious adverse events during the treatment period (days 1-27) were few and of a nature not unexpected in this population. One patient experienced transient neurological disorders associated with postganciclovir MRI enhancement. There was no evidence of replication-competent retrovirus in peripheral blood leukocytes or in tissue samples of reresection or autopsy. Vector DNA was shown in the leukocytes of some patients but not in autopsy gonadal samples. The median survival time was 8.6 months, and the 12-month survival rate was 13 of 48 (27%). On MRI studies, tumor recurrence was absent in seven patients for at least 6 months and for at least 12 months in two patients, one of whom remains recurrence free at more than 24 months. Treatment-characteristic images of injection tracks and intracavity hemoglobin were apparent. In conclusion, the gene therapy is feasible and appears to be satisfactorily safe as an adjuvant to the surgical resection of recurrent GBM, but any benefit appears to be marginal. Investigation of the precise effectiveness of this gene therapy requires prospective, controlled studies.

Predictors of therapy resistant asthma: outcome of a systematic evaluation protocol

Background: It has been suggested that asthmatic subjects with persisting symptoms despite adequate maintenance therapy should be systematically evaluated to identify factors contributing to poor control. The aims of this study were to examine the prevalence of these factors in a cohort of sequentially referred poorly controlled asthmatics, and to determine if any factor or combination of factors predicted true therapy resistant asthma (TRA).

Methods: Patients were evaluated using a systematic evaluation protocol including induced sputum analysis, psychiatric assessment, ear, nose and throat examination, pulmonary function testing, high resolution CT scan of the thorax, and 24 hour dual probe ambulatory oesophageal pH monitoring; any identified provoking factor was treated. Asthma was managed according to BTS guidelines.

Results: Of 73 subjects who completed the assessment, 39 responded to intervention and 34 had TRA. Subjects with TRA had a greater period of instability, a higher dose of inhaled steroids at referral, more rescue steroid use, and a lower best percentage forced expiratory volume in 1 second (FEV1%). Oesophageal reflux, upper airway disease, and psychiatric morbidity were common (57%, 95%, 49%, respectively) but were not more prevalent in either group. Using multivariate logistic regression analysis, inhaled steroid dose >2000 µg BDP, previous assessment by a respiratory specialist, and initial FEV1% of <70% at referral predicted a final diagnosis of TRA.

Conclusions: In poorly controlled asthmatics there is a high prevalence of co-morbidity, identified by detailed systematic assessment, but no difference in prevalence between those who respond to intervention and those with TRA. Targeted treatment of identified co-morbidities has minimal impact on asthma related quality of life in those with therapy resistant disease.

Relationship between Helicobacter pylori infection and gastric atrophy and the stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence: Results from the FINBAR case-control study.

Objective: A number of studies have shown an inverse association between infection with Helicobacter pylori and oesophageal adenocarcinoma (OAC). The mechanism of the apparent protection against OAC by H pylori infection and, in particular, the role of gastric atrophy is disputed. The relationship between all stages of the oesophageal inflammation, metaplasia, adenocarcinoma sequence and H pylori infection and gastric atrophy was explored. Methods: A case-control study involving 260 population controls, 227 OAC, 224 Barrett's oesophagus (BO) and 230 reflux oesophagitis (RO) patients recruited within Ireland was carried out. H pylori and CagA (cytotoxin-associated gene product A) infection was diagnosed serologically by western blot, and pepsinogen I and II levels were measured by enzyme immunoassay. Gastric atrophy was defined as a pepsinogen I/II ratio of <3. Results: H pylori seropositive was inversely associated with OAC, BO and RO; adjusted ORs (95% CIs), 0.49 (0.31 to 0.76), 0.35 (0.22 to 0.56) and 0.42 (0.27 to 0.65), respectively. Gastric atrophy was uncommon (5.3% of all subjects), but was inversely associated with non-junctional OAC, BO and RO; adjusted ORs (95% CIs), 0.34 (0.10 to 1.24), 0.23 (0.05 to 0.96) and 0.27 (0.08 to 0.88), respectively. Inverse associations between H pylori and the disease states remained in gastric atrophy-negative patients. Conclusion: H pylori infection and gastric atrophy are associated with a reduced risk of OAC, BO and RO. While use of the pepsinogen I/II ratio as a marker for gastric atrophy has limitations, these data suggest that although gastric atrophy is involved it may not fully explain the inverse associations observed with H pylori infection.

Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol

Background-Asthma, post-nasal drip syndrome (PNDS), and gastrooesophageal reflux (GOR) account for many cases of chronic non-productive cough (CNPC). Each may simultaneously contribute to cough even when clinically silent, and failure to recognise their contribution may lead to unsuccessful treatment.

Methods—Patients (all lifetime non-smokers with normal chest radiographs and spirometric measurements) referred with CNPC persisting for more than three weeks as their sole respiratory symptom underwent histamine challenge, home peak flow measurements, ear, nose and throat (ENT) examination, sinus CT scanning, and 24 hour oesophageal pH monitoring. Treatment was prescribed on the basis of diagnoses informed by investigation results.

RESULTS—Forty three patients (29 women) of mean age 47.5 years (range 18-77) and mean cough duration 67 months (range 2-240) were evaluated. On the basis of a successful response to treatment, a cause for the cough was identified in 35 patients (82%) as follows: cough variant asthma (CVA) (10 cases), PNDS (9 cases), GOR (8cases), and dual aetiologies (8 cases). Histamine challenge correctly predicted CVA in 15 of 17 (88%) positive tests. ENT examination and sinus CT scans each had low positive predictive values for PNDS (10 of 16 (63%) and 12 of 18 (67%) positive cases, respectively), suggesting that upper airways disease frequently co-exists but does not always contribute to cough. When negative, histamine challenge and 24 hour oesophageal pH monitoring effectively ruled out CVA and GOR, respectively, as a cause for cough.

CONCLUSION—This comprehensive approach aids the accurate direction of treatment and, while CVA, PNDS and GOR remain the most important causes of CNPC to consider, a group with no identifiable aetiology remains.

A Population-Based Study of IGF Axis Polymorphisms and the Esophageal Inflammation, Metaplasia, Adenocarcinoma Sequence

BACKGROUND & AIMS: Insulin-like growth factor (IGF) axis plays a key role in cell development, proliferation, and survival and is implicated in the etiology of several cancers. Few studies have examined the relationship between genetic variation of this axis and esophageal adenocarcinoma (EAC) or its precursors. METHODS: In a population-based case-control study, we investigated the association of common polymorphisms of IGF-1, IGF-2, IGF-1 receptor, IGF binding protein -3, growth hormones (GH) 1 and GH2, and GH receptor with reflux esophagitis (RE), Barrett esophagus (BE), and EAC. Two hundred and thirty RE, 224 BE, 227 EAC cases, and 260 controls were studied. Gene polymorphisms were identified using publicly available online resources; 102 IGF axis tag and putatively functional single-nucleotide polymorphisms (SNPs) were analyzed using MassARRAY iPLEX and Taqman assays. Results were analyzed using Haploview.
RESULTS: Three polymorphisms were disease-associated. IGF1 SNP rs6214 was associated with BE (adjusted P = .039). Using GG genotype as reference, odds ratio for BE in AA (wild-type) was 0.43 (95% confidence interval [CI], 0.24-0.75). GH receptor SNP rs6898743 was associated with EAC (adjusted P = .0112). With GG as reference, odds ratio for EAC in CC (wildtype) genotype was 0.42 (95% CI, 0.23-0.76). IGF1 (CA)(17) 185-bp allele was associated with RE (adjusted P = .0116). Using IGF1(non17) as reference, odds ratio for RE in IGF1(17) carriers was 7.29 (95% CI, 1.57-46.7).
CONCLUSIONS: In this study, 3 polymorphisms of IGF genes were associated with EAC or its precursors. These polymorphisms may be markers of disease risk; independent validation of our findings is required. These results suggest the IGF pathway is involved in EAC development.

High concentrations of pepsin in bronchoalveolar lavage from children with cystic fibrosis are associated with high interleukin-8

Background Gastro-oesophageal reflux is common in children with cystic fibrosis (CF) and is thought to be associated with pulmonary aspiration of gastric contents. The measurement of pepsin in bronchoalveolar lavage (BAL) fluid has recently been suggested to be a reliable indicator of aspiration. The prevalence of pulmonary aspiration in a group of children with CF was assessed and its association with lung inflammation investigated. Methods This was a cross-sectional case–control study. BAL fluid was collected from individuals with CF (n=31) and healthy controls (n=7). Interleukin-8 (IL-8), pepsin, neutrophil numbers and neutrophil elastase activity levels were measured in all samples. Clinical, microbiological and lung function data were collected from medical notes. Results The pepsin concentration in BAL fluid was higher in the CF group than in controls (mean (SD) 24.4 (27.4) ng/ml vs 4.3 (4.0) ng/ml, p=0.03). Those with CF who had raised pepsin concentrations had higher levels of IL-8 in the BAL fluid than those with a concentration comparable to controls (3.7 (2.7) ng/ml vs 1.4 (0.9) ng/ml, p=0.004). Within the CF group there was a moderate positive correlation between pepsin concentration and IL-8 in BAL fluid (r=0.48, p=0.04). There was no association between BAL fluid pepsin concentrations and age, sex, body mass index z score, forced expiratory volume in 1 s or Pseudomonas aeruginosa colonisation status. Conclusions Many children with CF have increased levels of pepsin in the BAL fluid compared with normal controls. Increased pepsin levels were associated with higher IL-8 concentrations in BAL fluid. These data suggest that aspiration of gastric contents occurs in a subset of patients with CF and is associated with more pronounced lung inflammation.

Toenail trace element status and risk of Barrett's oesophagus and oesophageal adenocarcinoma. Results from the FINBAR study

Trace elements have been cited as both inhibitory and causative agents of cancer but importantly exposure to them is potentially modifiable. Our study aimed to examine toenail trace element status and risk of Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Toenail clippings from each hallux were obtained from 638 participants of the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study comprising 221 healthy controls, 98 reflux oesophagitis, 182 BO and 137 OAC cases. The concentrations of eight toenail trace elements were determined using instrumental neutron activation analysis. Using multivariable adjusted logistic regression analysis, odds ratios (OR) and 95% confidence intervals (CIs) were calculated within tertiles of trace element concentrations. A twofold increased risk of BO was observed, but not OAC, among individuals in the highest tertile of toenail zinc status OR 2.21 (95% CI, 1.11-4.40). A higher toenail selenium status was not associated with risk of OAC OR 0.94 (95% CI, 0.44-2.04) or BO OR 0.89 (95% CI, 0.37-2.12). A borderline significant increased risk of BO was detected with a higher toenail cobalt concentration, OR 1.97 (95% CI, 1.01-3.85). No association was found between toenail levels of chromium, cerium, mercury and OAC or BO risk. This is the first case-control study to investigate a variety of trace elements in relation to OAC and BO risk. Despite antioxidant and proapoptotic properties, no associations were found with selenium. Higher concentrations of toenail zinc and cobalt were associated with an increased BO risk, but not OAC. These findings need confirmation in prospective analysis.

Vitamin D, calcium and dairy intake, and risk of oesophageal adenocarcinoma and its precursor conditions

Evidence is accumulating that vitamin D may be protective against carcinogenesis, although exceptions have been observed for some digestive tract neoplasms. The aim of the present study was to explore the association between dietary vitamin D and related nutrients and the risk of oesophageal adenocarcinoma and its precursor conditions, Barrett's oesophagus and reflux oesophagitis. In an all-Ireland case-control study conducted between March 2002 and July 2005, 218 oesophageal adenocarcinoma patients, 212 Barrett's oesophagus patients, 208 reflux oesophagitis patients and 252 population-based controls completed a 101-item FFQ, and provided lifestyle and demographic information. Multiple logistic regression analysis was applied to examine the association between dietary intake and disease risk. Oesophageal adenocarcinoma risk was significantly greater for individuals with the highest compared with the lowest tertile of vitamin D intake (OR 1·99, 95 % CI 1·03, 3·86; P for trend = 0·02). The direct association could not be attributed to a particular vitamin D food source. Vitamin D intake was unrelated to Barrett's oesophagus and reflux oesophagitis risk. No significant associations were observed for Ca or dairy intake and oesophageal adenocarcinoma, Barrett's oesophagus or reflux oesophagitis development. High vitamin D intake may increase oesophageal adenocarcinoma risk but is not related to reflux oesophagitis and Barrett's oesophagus. Ca and dairy product intake did not influence the development of these oesophageal lesions. These findings suggest that there may be population subgroups at an increased risk of oesophageal adenocarcinoma if advice to improve vitamin D intake from foods is implemented. Limited work has been conducted in this area, and further research is required.

Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.

The effect of lifestyle changes on results of 24-h ambulatory oesophageal pH monitoring

Twenty-four-hour pH monitoring is the 'gold standard' investigation of gastro-oesophageal reflux disease. It has been suggested that results may be influenced by lifestyle alteration during the study. The aim of this study was to determine the influence of lifestyle alteration and anxiety on outcome in pH monitoring.

Open access gastroscopy--3 year experience of a new service

We have audited the first 3 yr of a new open access gastroscopy service in the Royal Victoria Hospital, Belfast to assess service demands, patient demography and diagnostic trends. Over 3 yr there were 1872 referrals (800 from fundholding general practitioners), 8.8 per cent were non attenders and 5.4 per cent cancelled appointments. Endoscopic diagnostic categories showed no significant change over the 3 yr, 39 per cent non ulcer dyspepsia, 35 per cent gastro-oesophageal reflux disease (GORD), 17 per cent peptic ulcer disease (PUD), 6 per cent GORD and PUD, 1 per cent gastric erosions and 0.8 per cent carcinoma.

Maintenance therapy with cisapride after healing of erosive oesophagitis:a double-blind placebo-controlled trial

There are few data on the role of prokinetic agents as maintenance therapy in moderately severe reflux oesophagitis despite the high relapse rate of this condition after healing.