Development of an E-learning System for the Endoscopic Diagnosis of Early Gastric Cancer: An International Multicenter Randomized Controlled Trial.

BACKGROUND: In many countries, gastric cancer is not diagnosed until an advanced stage. An Internet-based e-learning system to improve the ability of endoscopists to diagnose gastric cancer at an early stage was developed and was evaluated for its effectiveness. METHODS: The study was designed as a randomized controlled trial. After receiving a pre-test, participants were randomly allocated to either an e-learning or non-e-learning group. Only those in the e-learning group gained access to the e-learning system. Two months after the pre-test, both groups received a post-test. The primary endpoint was the difference between the two groups regarding the rate of improvement of their test results. FINDINGS: 515 endoscopists from 35 countries were assessed for eligibility, and 332 were enrolled in the study, with 166 allocated to each group. Of these, 151 participants in the e-learning group and 144 in the non-e-learning group were included in the analysis. The mean improvement rate (standard deviation) in the e-learning and non-e-learning groups was 1·24 (0·26) and 1·00 (0·16), respectively (P<0·001). INTERPRETATION: This global study clearly demonstrated the efficacy of an e-learning system to expand knowledge and provide invaluable experience regarding the endoscopic detection of early gastric cancer (R000012039).

Azathioprine dose escalation in inflammatory bowel disease.

BACKGROUND: Forty per cent of patients with inflammatory bowel disease fail to respond to standard dose azathioprine (2 mg/kg/day). AIMS: To evaluate the efficacy and safety of increasing the azathioprine dose according to a fixed schedule and guided by clinical response and adverse effects. METHODS: We reviewed the records of all patients with inflammatory bowel disease treated by a single clinician over 6 years, unresponsive to at least 3 months treatment with standard dose azathioprine, and whose dose was subsequently increased. RESULTS: Forty patients (27 male; 24 Crohn's, 16 ulcerative colitis) with chronic active disease or recurrent flares despite standard dose azathioprine for a median 8 months (range 3-114) increased their dose from a median 2.02 (1.61-3.19) mg/kg/day to 2.72 (2.37-3.99) mg/kg/day in one to four increments of 0.5 mg/kg/day, and were followed over a median 6 (0.5-54) months. Eleven of the 40 patients (seven Crohn's, four ulcerative colitis) responded or had reduced frequency of flare-ups at the end of follow-up, while 17 of the 40 patients had no benefit. Response was more likely for maximum doses < or =2.5 mg/kg/day (six of 11 patients) than for doses >2.5 mg/kg/day (five of 29 patients) (P = 0.042). Twelve patients (11 of whom received maximum doses >2.5 mg/kg/day) were unable to maintain an increased azathioprine dose because of leukopenia in eight, nausea in three, and raised liver enzymes in one (all transient and reversible). CONCLUSIONS: Increasing the azathioprine dose up to 2.5 mg/kg/day appears beneficial in patients who have not responded to 2 mg/kg/day. Further increase above 2.5 mg/kg/day is less likely to be efficacious, and is associated with a substantial risk of adverse reactions.

Crystal structure of human squalene synthase. A key enzyme in cholesterol biosynthesis.

Squalene synthase catalyzes the biosynthesis of squalene, a key cholesterol precursor, through a reductive dimerization of two farnesyl diphosphate (FPP) molecules. The reaction is unique when compared with those of other FPP-utilizing enzymes and proceeds in two distinct steps, both of which involve the formation of carbocationic reaction intermediates. Because FPP is located at the final branch point in the isoprenoid biosynthesis pathway, its conversion to squalene through the action of squalene synthase represents the first committed step in the formation of cholesterol, making it an attractive target for therapeutic intervention. We have determined, for the first time, the crystal structures of recombinant human squalene synthase complexed with several different inhibitors. The structure shows that SQS is folded as a single domain, with a large channel in the middle of one face. The active sites of the two half-reactions catalyzed by the enzyme are located in the central channel, which is lined on both sides by conserved aspartate and arginine residues, which are known from mutagenesis experiments to be involved in FPP binding. One end of this channel is exposed to solvent, whereas the other end leads to a completely enclosed pocket surrounded by conserved hydrophobic residues. These observations, along with mutagenesis data identifying residues that affect substrate binding and activity, suggest that two molecules of FPP bind at one end of the channel, where the active center of the first half-reaction is located, and then the stable reaction intermediate moves into the deep pocket, where it is sequestered from solvent and the second half-reaction occurs. Five alpha helices surrounding the active center are structurally homologous to the active core in the three other isoprenoid biosynthetic enzymes whose crystal structures are known, even though there is no detectable sequence homology.

Construction and murine immunogenicity of recombinant Bacille Calmette Guérin vaccines expressing the B subunit of Escherichia coli heat labile enterotoxin.

Three recombinant strains of Mycobacterium bovis Bacille Calmette Guerin (rBCG) were prepared in which the immunogenic B subunit of human Escherichia coli heat labile enterotoxin (LT-Bh) was expressed either as a cytoplasm protein, a cell wall associated lipoprotein or a secreted protein. Intraperitoneal immunisation of mice with these rBCG induced IgG and IgA antibodies to LT-Bh and shifted the serum IgG subclass response to subsequent challenge with purified LT-Bh from IgG1 to an IgG2a. Oral administration of recombinant BCG induced mucosal and serum IgA antibodies to LT-Bh which peaked four months after immunisation. Antibody responses were greater when LT-Bh was expressed as a secreted protein or lipoprotein rather than in the cytoplasm. Oral vaccination with recombinant BCG may be an effective approach, particularly to induce mucosal IgA and prime for a serum TH1 recall response.

Stimulation of mucosal immunity.

The mucosal immune system is composed of distinct regional immune tissue (e.g., "GALT," gut-associated lymphoid tissue; "BALT," bronchus-associated lymphoid tissue; reproductive tract and breast tissue, and so forth) interconnected by trafficking of primed lymphocytes as a common "mucosa-associated lymphoid tissue," "MALT" (1). In addition, immune responses within MALT may occur independently of systemic immunity, with distinctive regulatory mechanisms and the induction of dimeric secretory IgA (SIgA) at the mucosal surface. As a result traditional methods for inducing systemic immunity may not induce significant SIgA, and techniques have been developed to deliver antigen directly to a mucosal surface in such a way as to induce immunity rather than immunological tolerance. The trafficking of primed B- and T-cells between mucosal sites, probably regulated by specific adhesion molecules, such as α4ß7 integrin on lymphocytes and MAdCAM- on mucosal blood vessels (2), leads to dissemination of the mucosal immune response. One benefit of this, therefore, is that immunization of an accessible mucosal surface may induce an immune response at less accessible mucosal sites (such as the genital tract). Furthermore, by characterizing mucosa homing lymphocytes trafficking in the blood, it may be possible to indirectly study mucosal responses.

Drug-resistant tuberculosis: mechanisms and management.

Infection with Mycobacterium tuberculosis remains a major global health problem and the recent outbreaks of multidrug resistant (MDR) tuberculosis have been a major cause for concern. An accurate picture of the extent of this problem is not possible because only a limited number of countries have reliable surveillance programmes. However, the experience in the USA reinforces the need for strict adherence to standard public health measures and good clinical practices to minimise the impact of MDR tuberculosis in the human immunodeficiency virus era.

Antibiotic resistance: the current position and the molecular mechanisms involved.

The introduction of antibiotics heralded a new era in the chemotherapy of infectious diseases, but over the ensuing years bacterial evolutionary responses to the selective pressure of antibiotics have resulted in microorganisms resistant to virtually every known antibiotic. The consequences have been very important in clinical practice, as patients infected with a multi-resistant organism suffer increased morbidity and mortality and often require the use of expensive and potentially toxic antibiotic regimens in order to achieve effective, specific treatment.

Isometric training in human elbow flexor muscles. The effects on voluntary and electrically evoked forces.

The elbow flexor muscles of four men were trained using maximal voluntary isometric contractions. Thirty contractions a day were performed for five weeks. The four men and four control subjects were tested once a week: measurements of the supramaximally stimulated isometric twitch force, the time taken for the twitch force to peak and the tetanic force were carried out; simultaneously, measurements of the force of maximal voluntary isometric contraction and resistance to fatigue were made. The testing sessions produced no training effect on control subjects. Training produced a 20 per cent increase in the force of maximal voluntary isometric contraction after five weeks, but the forces of electrically evoked twitch and tetanus showed no increase. It was concluded that the increase in the force of maximal voluntary isometric contraction must be related to factors other than the force-generating capacity of the muscle fibres themselves.

[The role of public relations in medical practice. With special reference to medical research]. / Die rol van openbare betrekkinge in geneeskundige praktyk. Met spesifieke verwysing na mediese navorsing.

Because medical practice and especially medical research depend on the goodwill of others, increased emphasis should be placed on the role of public relations, especially in the complex area of communication between medical scientists and the man in the street. The nature of these communication problems is described, and suggestions are made as to how public relations, if properly managed, can give substance to an otherwise ill-defined concept. Opportunities and problems in the marketing of medical research are briefly described.