Conjugation of weak ligands with weak antigens to activate TLR-7: A step toward better vaccine adjuvants.

To study the structure-activity relationship (SAR) of Toll-like receptor 7 (TLR-7) agonists based on 8-oxoadenines, a novel subset of C9-substituted 8-hydroxy-2-(2-methoxyethoxy)-adenines and their antigen conjugates were synthesized. In vitro, the ability of cytokines (IL-12p70 and IFN-γ) induction of ligands with alkyl acid at C9-position were very weak compared with benzoic acid counter parts. Unexpectedly, its antigen conjugates that conjugated with proteins or peptides with weak immunogenicity, showed enhanced activity of cytokines induction. After administered systemically in mice in vivo, all conjugates induced prolonged increase in pro-inflammatory cytokines and antigen-specific IgG levels in serum compared with free compounds. Results from molecular dynamics (MD) simulations further confirmed the conclusion and provided the details of interaction to explain the phenomenon of experiment. In conclusion, we discovered that TLR-7 could be activated via some conjugates of weak ligand and weak antigen, which could be safer adjuvant candidates for vaccines in the future.

Biofeedback-guided pelvic floor exercise therapy for obstructive defecation: an effective alternative.

AIM: To compare biofeedback-guided pelvic floor exercise therapy (BFT) with the use of oral polyethylene glycol (PEG) for the treatment of obstructive defecation. METHODS: A total of 88 subjects were assigned to treatment with either BFT (n = 44) or oral PEG (n = 44). Constipation symptoms (including difficult evacuation, hard stool, digitation necessity, incomplete emptying sensation, laxative dependence, perianal pain at defecation, and constipation satisfaction), Wexner Scores, and quality of life scores were assessed after 1, 3, and 6 mo. RESULTS: At the 6 mo follow-up, the symptoms of the BFT group patients showed significantly greater improvements compared with the PEG group regarding difficult evacuation, hard stools, digitation necessity, laxative dependence, perianal pain at defecation, constipation satisfaction, Wexner Constipation Score, and quality of life score (P < 0.05). The quality of life score of the BFT group at the final follow-up time (6 mo) was 80 ± 2.2. After a complete course of training, improvements in the clinical symptoms of the BFT group were markedly improved (P < 0.05), and the Wexner Constipation Scores were greatly decreased compared with the oral PEG group (P < 0.05). CONCLUSION: We concluded that manometric biofeedback-guided pelvic floor exercise training is superior to oral polyethylene glycol therapy for obstructive defecation.

Effect of acetazolamide and gingko biloba on the human pulmonary vascular response to an acute altitude ascent.

Acetazolamide and gingko biloba are the two most investigated drugs for the prevention of acute mountain sickness (AMS). Evidence suggests that they may also reduce pulmonary artery systolic pressure (PASP). To investigate whether these two drugs for AMS prevention also reduce PASP with rapid airlift ascent to high altitude, a randomized controlled trial was conducted on 28 healthy young men with acetazolamide (125 mg bid), gingko biloba (120 mg bid), or placebo for 3 days prior to airlift ascent (397 m) and for the first 3 days at high altitude (3658 m). PASP, AMS, arterial oxygen saturation (Sao2), mean arterial pressure (MAP), heart rate (HR), forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow (PEF) were assessed both at 397 m and 3658 m. HR, PEF, and PASP increased with altitude exposure (p<0.05), and SaO2 decreased (p<0.05). PASP with acetazolamide (mean at 3658 m, 26.2 mm Hg; incremental change, 4.7 mm Hg, 95% CI., 2.6-6.9 mm Hg) was lower than that with ginkgo biloba (mean at 3658 m, 33.7 mm Hg, p=0.001; incremental change, 13.1 mm Hg, 95%CI., 9.6-16.5 mm Hg, p=0.002), and with placebo (mean at 3658 m, 34.7 mm Hg, p<0.001; 14.4 mm Hg, 95% CI., 8.8-20.0 mm Hg, p=0.001). The data show that a low prophylactic dosage of acetazolamide, but not gingko biloba, mitigates the early increase of PASP in a quick ascent profile.