The role of acid in the pathogenesis of indomethacin-induced gastric antral ulcers in the rat.

BACKGROUND: The role of acid in the pathogenesis of indomethacin- induced ulcers of the rat gastric antrum was studied by comparing the effects of pretreating animals with both long-acting (loxtidine, AH22216) and short-acting (ranitidine and cimetidine) inhibitors of acid secretion. RESULTS: Ranitidine and cimetidine were much weaker at inhibiting antral damage when compared to their reported potencies as antisecretory agents. In marked contrast, loxtidine and AH22216 inhibited indomethacin-induced antral ulcers at doses similar to their reported potencies as inhibitors of acid secretion. Histological analysis at doses causing near maximal inhibition of macroscopic damage revealed an almost complete absence of ulcers but a large and significant increase in mucosal damage due to superficial erosions. Hourly dosing with hydrochloric acid reversed the protective effect of ranitidine, cimetidine and loxtidine on macroscopic damage and, histologically, this was associated with the widespread appearance of antral ulcers and a reduction in the proportion of mucosal damage caused by superficial erosions. CONCLUSIONS: The results of this study suggest that the pathogenesis of nonsteroidal anti-inflammatory drug (NSAID)-induced antral ulcers involves at least two stages: (1) an initial acid-independent formation of mucosal erosions followed by (2) an acid-dependent conversion of erosions to frank ulcers. Clinically, drugs that suppress acid completely for long periods may be very effective in preventing NSAID-induced gastric antral ulcers.     

Elderly suicide: an analysis of coroner's inquests into two hundred cases in Cheshire 1989 - 2001

Elderly suicide is an index of more widespread disorder and discontent among the elderly, and furthermore is a potentially preventable cause of death. This study used coroner's inquest records of 200 elderly in Cheshire who killed themselves, and in which their unexpected deaths attracted a verdict of suicide. Sociodemographic characteristics, clinical aspects of the suicidal process and health care contact before death are reviewed. Unlike most available studies, cases of unexpected death in which an open verdict was given were not included in this study, which covered a 13 year period. The findings are interpreted and compared to the currently available literature on suicide in the elderly. Late life suicide is characterised by less warning, higher lethality and greater prevalence of depression and physical illness. However, suicide risk often remains undetected. All suicidal behaviour in the elderly should be taken seriously by psychiatric and primary care services, in order to reduce suicide rates in the elderly.     

Design, synthesis, and biological evaluation of 6-substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors

A group of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyran-2-ones (14a-v), possessing either a H or F substituent at the para-position of the C-4 phenyl ring, were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo antiinflammatory-analgesic activities. Although 6-ethylthio-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14s) exhibited a very high in vitro COX-2 inhibitory potency (IC(50) = 0.0032 muM) and COX-2 selectivity (SI > 120 000), 14s exhibited moderate antiinflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay. In contrast, the less potent (IC(50) = 0.10 muM), and less selective (SI = 2880) COX-2 inhibitor 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14i) exhibited good antiinflammatory activity where a 1 mg/kg oral dose reduced inflammation 32 and 67% at 3 and 5 h postdrug administration relative to the reference drug celecoxib where a 50 mg/kg oral dose reduced inflammation by 79 and 58% at the respective 3 and 5 h time periods. Molecular modeling studies, where 14i was docked in the active site of both COX-1 and COX-2, reveals that the C-6 ethoxy substituent orients the pyran-2-one ring to position the SO(2)Me pharmacophore in the vicinity of the secondary pocket in COX-2. The absence of this COX-2 secondary pocket in the COX-1 binding site is due to the presence of the bulky Ile(523) in COX-1 such that access to the amino acid residues (Ile(517), Phe(518), Gln(192), and His(90)), which line the COX-2 secondary pocket with which the SO(2)Me pharmacophore could interact, is hindered. The six-membered pyran-2-one ring system is a suitable central template to design selective COX-2 inhibitors.     

Validation and reproducibility of computerised cell-viability analysis of tissue slices

Background

The identification of live cells using membrane integrity dyes has become a frequently used technique, especially with articular cartilage and chondrocytes in situ where tissue slices are used to assess cell recovery as a function of location. The development of a reproducible computerised method of cell evaluation would eliminate many variables associated with manual counting and significantly reduce the amount of time required to evaluate experimental results.

Methods

To validate a custom computerised counting program, intra-person and inter-person cell counts of nine human evaluators (three groups – unskilled, novice, and experienced) were compared with repeated pixel counts of the custom program on 15 digitised images (in triplicate) of chondrocytes in situ stained with fluorescent dyes.

Results

Results indicated increased reproducibility with increased experience within evaluators [Intraclass Correlation Coefficient (ICC) range = 0.67 (unskilled) to 0.99 (experienced)] and between evaluators [ICC = 0.47 (unskilled), 0.85 (novice), 0.93 (experienced)]. The computer program had perfect reproducibility (ICC = 1.0). There was a significant relationship between the average of the experienced evaluators results and the custom program results (ICC = 0.77).

Conclusions

This study demonstrated that increased experience in cell counting resulted in increased reproducibility both within and between human evaluators but confirmed that the computer program was the most reproducible. There was a good correlation between the intact cell recovery determined by the computer program and the experienced human evaluators. The results of this study showed that the computer counting program was a reproducible tool to evaluate intact cell recovery after use of membrane integrity dyes on chondrocytes in situ. This and the significant decrease in the time used to count the cells by the computer program advocate its use in future studies because it has significant advantages.

     

Iron, ascorbate and copper status of Sowetan Blacks with calcific chronic pancreatitis

Vitamin C can be used to overcome oxidative stress and ease pain in chronic pancreatitis. But its use is deprecated in conditions of tissue iron overload, because its bioactive form, ascorbate, can accelerate free-radical reactions that are driven by transition metals. We measured iron, ascorbate and copper in Sowetan Blacks (RSA) with chronic pancreatitis, obtaining serum/plasma from 14 consecutive patients and 15 controls. Compared with data from corresponding groups in Manchester, African samples had less ascorbate (p < 0.0001), but more caeruloplasmin (p < 0.0001). African and British controls had comparable iron and iron-binding capacity. Plasma from African patients had less ascorbate than that from African controls (p < 0.005) and in six samples, ferritin exceeded 300 micrograms/l (677 pmol/l). Low- molecular-mass iron or copper, capable of participating in free radical reactions, was not detected. British patients, had similar caeruloplasmin levels to African patients but higher ascorbate levels. There is no evidence of iron overload in our African samples. Outwardly healthy controls from Soweto have elevated levels of caeruloplasmin, possibly to compensate for dietary deficiency of ascorbate. Persistent oxidative stress is a unifying feature of chronic pancreatitis, but its degree is higher in African than British patients. Supplements of vitamin C should be safe in Blacks of southern Africa.      

Hypergammaglobulinemia can be associated with a positive direct antiglobulin test, a nonreactive eluate, and no evidence of hemolysis

To determine the cause of a positive direct antiglobulin test (DAT), blood banks routinely perform serologic tests on eluates prepared from DAT-positive red cells. Negative eluates traditionally have been suspected to be associated with drug reactions. This report confirms that the most frequent cause of a positive DAT and a nonreactive eluate is hypergammaglobulinemia. The results of 74 patient samples with positive DATs were analyzed retrospectively. Eluates prepared from the red cells of 54 patients (72.9%) reacted; eluates from 20 patients (27.1%) did not react. This latter group had identical serologic and clinical findings, suggesting that they made up a homogeneous group. In particular, the patients had a positive DAT, a negative indirect antiglobulin test, and a negative eluate; an increased serum concentration of IgG; and no evidence of hemolysis. In a subsequent study, DATs were performed prospectively on red cells from 44 consecutive patients with elevated serum IgG levels. The serum IgG concentration was highest in the three patients whose red cells had a positive DAT. The DAT also became positive in two patients treated with high-dose intravenous gammaglobulin (IV IgG). These studies indicate that a negative eluate from red cells with a positive DAT, a common serologic finding, is often caused by hypergammaglobulinemia. The authors postulate that IgG binds nonspecifically to the red cells because of the hypergammaglobulinemia.     

QUADAS评价:一种用于诊断性研究的质量评价工具(修订版)

背景 QUADAS是一种新近发展起来的诊断性研究的质量评价工具。虽然已有系统评价采用了QUADAS,但尚未得以正式确证。本研究的目的是评价QUADAS的有效性和实用性。方法3位评价者采用QUADAS独立评价30项研究的质量。比较每位评价者的评分与最终结论之间的意见一致度。这主要是通过比较所有QUADAS条目的总分和每个单项的得分来实现的。20位曾在其系统评价中使用过QUADAS的评价者就其使用经验完成一份简短的问卷。结果就所有条目而言,每位评价者的评分与最终结论之间的意见一致度分别达到了91%、90%和85%。就单项QUADAS条目而言,一致度在50%至100%之间,中位值是90%。与难以解释的试验结果和退出病例相关的条目,评分结果差异最大。有关QUADAS内容的反馈意见普遍较好,仅少数评价者提出了有关QUADAS涵盖面、使用便利性、评分说明的清晰度及有效性方面的问题。结论QUADAS内容本身无需作大的修改。评价过程的主要困难出现在难以解释的试验结果和退出病例这2个条目的评分上。对这些条目的评分指南提出了修改意见。评价者必需根据其系统评价制定相应的评分指南,并确保所有评价者都清楚如何评分。评价者还应考虑是否所有的QUADAS条目都与其系统评价相关,以及其他质量条目是否应作为其系统评价的评价部分。