A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency.

Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced HIV-1 transmission at very high rates. However, certain individuals who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due to adverse effects and the emergence of drug-resistant HIV-1 variants. Here, we report GRL-142, a novel HIV-1 protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which has extremely potent activity against all HIV-1 strains examined with IC50 values of attomolar-to-picomolar concentrations, virtually no effects on cellular growth, extremely high genetic barrier against the emergence of drug-resistant variants, and favorable intracellular and central nervous system penetration. GRL-142 forms optimum polar, van der Waals, and halogen bond interactions with HIV-1 protease and strongly blocks protease dimerization, demonstrating that combined multiple optimizing elements significantly enhance molecular and atomic interactions with a target protein and generate unprecedentedly potent and practically favorable agents.

Obesity and gastrointestinal diseases.

The prevalence of obesity in the Japanese population has been increasing dramatically in step with the Westernization of lifestyles and food ways. Our study demonstrated significant associations between obesity and a number of gastrointestinal disorders in a large sample population in Japan. We demonstrated that reflux esophagitis and hiatal hernia were strongly related to obesity (BMI > 25) in the Japanese. In particular, obesity with young male was a high risk for these diseases. On the other hand, it has been reported that obesity is also associated with Barrett's esophagus and colorectal adenoma; however, obesity was not a risk factor for these diseases in our study. The difference of ethnicity of our subjects may partly explain why we found no data to implicate obesity as a risk factor for Barrett's esophagus. Arterial sclerosis associated with advanced age and hyperglycemia was accompanied by an increased risk of colorectal adenoma.

Endoscopic submucosal dissection for submucosal invasive gastric cancer and curability criteria.

AIMS: The aims of the present study were to evaluate the feasibility of endoscopic submucosal dissection (ESD) as curative treatment for node-negative submucosal invasive early gastric cancer (EGC) and to consider further expansion of the curability criteria for submucosal invasive EGC. METHODS: A total of 977 EGC in 855 patients treated by ESD were enrolled. They were divided into intramucosal cancer (M); minimally submucosal invasive cancer (<500µm from the muscularis mucosa) (SM1); and deeper submucosal invasive cancer (>500µm from the muscularis mucosa) (SM2). The technical feasibility of ESD for SM1 and M were compared, and the clinical prognosis of SM1 was evaluated. Furthermore, the volume of carcinoma invading to the submucosal layer, which we called the SM volume index, was calculated virtually to analyze its correlation with lymphatic-vascular invasion. RESULTS: There were no statistical differences in technical outcomes and complications between M and SM1. Curative resection rates were significantly better in M than in SM1 (M, 92.6%; SM1, 63.8%). No local recurrences and distant metastases were found in 48 SM1 patients declared to have undergone curative resections. Most cases (72.0%) with successful ESD but non-curative resection exceeded 30mm in maximum size, and no local recurrences and metastases were found in these patients. The SM volume index of these cases was comparatively small. CONCLUSION: The technical and theoretical validity of ESD for SM1 was validated. The possibility of further expansion of the curability criteria for submucosal invasive cancers was suggested by the evaluation of the SM volume index.

Usefulness of endoscopic ultrasound for the prediction of intraoperative bleeding of endoscopic submucosal dissection for gastric neoplasms.

BACKGROUND AND AIM: Intraoperative bleeding is an important determining factor for the technical difficulty and safety of endoscopic submucosal dissection (ESD) for gastric neoplasms, which was previously difficult to predict before ESD. In the present study, we investigated whether endoscopic ultrasound (EUS) could be used to preoperatively predict intraoperative bleeding. METHODS: The study included 106 patients who underwent EUS before ESD. EUS was used to evaluate the submucosal vascular structure. Patients who had at least 10 vascular structures per field of view or a vessel at least 500 µm in diameter were classified into the rich group (Group R), and others were classified into the non-rich group (Group N). The two groups were compared retrospectively with respect to procedure time, degree of anemia, frequency of clip use, and others. RESULTS: There were 24 patients in Group R and 82 patients in Group N. Submucosal caner was found in 54.2% of patients in Group R and 18.3% in Group N. The reduction in hemoglobin was 5.8% in Group R and 3.45% in Group N. The procedure time was 151 min in Group R and 100 min in Group N. The frequency of clip use was 79.2% in Group R and 31.7% in Group N. A multivariate analysis revealed a significant difference in the depth of invasion and frequency of clip use between the two groups. CONCLUSIONS: The results suggest that identification of submucosal vascular structure by EUS might allow prediction of intraoperative bleeding during ESD.

Endoscopic submucosal dissection for residual/locally recurrent lesions after endoscopic therapy for colorectal tumors.

BACKGROUND AND STUDY AIM: Residual or locally recurrent lesions may occur after endoscopic therapy for epithelial colorectal tumors. Additional endoscopic mucosal resection is difficult for large lesions. Endoscopic submucosal dissection may be useful for such lesions, but may be more technically difficult for residual/locally recurrent lesions than for primary lesions. This study evaluated the efficacy of endoscopic submucosal dissection for residual/locally recurrent lesions in comparison with primary lesions. METHOD: This retrospective case-control investigated 34 residual/locally recurrent lesions and 384 primary lesions treated using endoscopic submucosal dissection. Tumor size, resected specimen size, procedure duration, en bloc resection rate, curative resection rate, histology, associated complications, and recurrence rate were compared between groups. RESULTS: Procedure duration tended to be longer (85 ± 53 min vs 73 ± 55 min) and tumors were significantly smaller (20 ± 13 mm vs 33 ± 20 mm; P < 0.001) in the residual/locally recurrent group, compared with primary lesions. Both groups showed similar percentages of en bloc (100% vs 97.4%) and curative resection (88.4% vs. 83.6%). Perforation rate was significantly higher in the residual/locally recurrent group (14.7% vs 4.4%, P < 0.05). However, emergency surgery was only needed in 1 of 5 cases in the residual/locally recurrent group, with the remaining 4 cases conservatively managed using endoclips. CONCLUSIONS: Endoscopic submucosal dissection for residual/locally recurrent lesions was curative and efficacy. This procedure could help to avoid surgical resection and frequent follow-up examinations in many patients.

The relationship between three types of aggression and peer relations in elementary school children.

Previous studies have repeatedly found that aggression causes various internalizing and externalizing problems. Despite the robust relationship, exactly how aggression causes these problems remains unclear, although it is plausible to postulate that this occurs both directly and indirectly (via other behavioural factors). One possible indirect factor might be the aggravation of peer relations. The poor peer relations of aggressive children could make them isolated psychologically or physically from peers, which in turn might result in depressive or disruptive problems. This study examined the relationships between three types of aggression and peer relations in Japanese elementary school children. The three aggression types comprised reactive-expressive (i.e., verbal and physical aggression), reactive-inexpressive (e.g., hostility), and proactive-relational aggression (i.e., aggression that can break human relationships, for instance, by circulating malicious rumours). Participants were 1581 children in grades 4 to 6 (752 boys and 829 girls), all of whom completed the Proactive-Reactive Aggression Questionnaire for Children to measure three types of aggression and the Peer Relation Questionnaire to measure peer relations (mutual understanding, self-disclosure, and similarity of taste) and number of friends. Hierarchical regression analyses of the data showed that higher scores of relational aggression were significantly associated with higher scores of all of the peer relations and the number of friends, and that higher scores of inexpressive aggression were significantly associated with lower scores of all except for self-disclosure in the peer relations. These findings suggest that among the three types of aggression, relational aggression leads to the best friendship in both dyadic relations and the number of friends, whereas inexpressive aggression to the poorest friendship. The implications of these findings with respect to internalizing and externalizing problem behaviours for aggressive children are discussed.

[Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine].

The effect of the intake of 200 g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0-24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0-24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0-24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p < 0.05). The finding that the ratios of Cmax and AUC0-24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0-24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.