Identification of N,N-disubstituted phenylalanines as a novel class of inhibitors of hepatitis C NS5B polymerase

The HCV NS5B RNA dependent RNA polymerase plays an essential role in viral replication. The discovery of a novel class of inhibitors based on an N,N-disubstituted phenylalanine scaffold and structure-activity relationships studies to improve potency are described.     

多种信号途径介导花生四烯酸与5-羟色胺在促人类血小板凝集中的协同作用

AIM: To examine the signalling mechanisms involved in the synergistic interaction of 5-hydroxytryptamine (5-HT) and arachidonic acid (AA) in human platelet aggregation. METHODS: Blood was obtained from healthy human subjects, mixed with 3.8 % sodium citrate (9:1), and centrifuged to prepare platelet rich plasma (PRP). Aggregation was monitored using a Dual-channel Lumi-aggregometer. The agonist-induced influx of Ca^2 was measured using Fura-2 AM. TXA2 formation was studied using radiochemical method. RESULTS: Subthreshold concentration of 5-HT (2μmol/L) potentiated the effect of low dose of AA (0.2 mmol/L) in human platelets. This synergistic effect was blocked by 5-HT2 receptor antagonist (methysergide IC50=5.2 nmol/L; cyproheptadine IC50=0.6 nmol/L), and thromboxane A2 receptor antagonist (SQ 29 548; IC5o=30 nmol/L), showing that the effect is receptor-mediated.To examine the down-stream signalling pathways, we found that such an interaction was inhibited by calcium channel blockers (diltiazem; IC50=3 μmol/L and verapamil; IC50=5 μmol/L), phospholipase C (PLC) inhibitor (U73122;IC50=4 μmol/L), cyclooxygenase inhibitor, (indomethacin; IC50=0.2 μmol/L) and mitogen-activated protein (MAP) kinase inhibitor (PD98059; IC5o=3 ktmol/L). The effect was also inhibited by a specific tyrosine light chain kinase(TLCK) inhibitor, herbimycin A with IC50 value of 5 μmol/L. Pretreatment of platelet with 5-HT and AA induced rise in intracellular calcium and this effect was blocked by verapamil. CONCLUSION: The synergism between 5-HT and AA in platelet aggregation involves activation of PLC/Ca^2 , COX, and MAP kinase pathways.     

Effect of the foot on the mechanical alignment of the lower limbs

The authors evaluated the effect of the foot on the loading axis of the lower limb measured from radiographs in 30 pediatric patients. Deviation at the knee was calculated for the hip-ankle (traditional) and the hip-foot lines (heel lined up with a metal wire). A trigonometric model of the limb loading axis was developed with predicted mechanical axis deviations at the knee. Statistics were based on the methods of Bland and Altman. Mechanical axis deviation at the knee in the frontal plane varies with foot height, foot-tibial angle, and genu valgum. The predicted trigonometric model was found to be in agreement with measured radiographic values. Including the foot in the radiographic measurement of limb alignment may increase validity of surgical planning for correction of malalignment and for evaluation of degenerative arthritis risk at the knee level.     

Kimura's disease of parotid gland presenting as solitary parotid swelling

BACKGROUND: Kimura's disease is a chronic inflammatory disorder of unknown etiology commonly seen among orientals and characterized histologically by lymphatic follicles, vascular proliferation, and marked eosinophilic infiltration. It has a predilection for the head and neck region. The lesion is benign but can be mistaken to be a malignant lesion. METHODS: Between January 1987 and December 1999, eight cases of Kimura's disease were treated at the Department of Plastic Surgery, Hospital Kuala Lumpur. All the patients underwent surgical excision followed by initial high-dose steroid therapy and low-dose maintenance. RESULTS: All the patients are men, seven belong to the Malay race and one is Chinese. The patients' ages at diagnosis are 18 to 46 years. All were initially seen with swelling in the parotid gland, ranging from 1 year to 20 years' duration. Pruritus of the overlying skin was seen in seven patients. Treatment by surgical excision and steroid therapy has led to no recurrences. CONCLUSION: Kimura's disease of parotid gland is rare. It is a chronic inflammatory condition also called eosinophilic hyperplastic lymphogranuloma. Treatment by surgical excision and steroid therapy has led to no recurrences.     

Dietary prevention of allergic diseases in infants and small children.

Because of scientific fraud four trials have been excluded from the original Cochrane meta-analysis on formulas containing hydrolyzed protein for prevention of allergy and food intolerance in infants. Unlike the conclusions of the revised Cochrane review the export group set up by the Section on Paediatrics, European Academy of Allergology and Clinical Immunology (SP-EAACI) do not find that the exclusion of the four trials demands a change of the previous recommendations regarding primary dietary prevention of allergic diseases. Ideally, recommendations on primary dietary prevention should be based only on the results of randomized and quasi-randomized trials (selection criteria in the Cochrane review). However, regarding breastfeeding randomization is unethical, Therefore, in the development of recommendations on dietary primary prevention, high-quality systematic reviews of high-quality cohort studies should be included in the evidence base. The study type combined with assessment of the methodological quality determines the level of evidence. In view of some methodological concerns in the Cochrane meta-analysis, particularly regarding definitions and diagnostic criteria for outcome measures and inclusion of non peer-reviewed studies/reports, a revision of the Cochrane analysis may seem warranted. Based on analysis of published peer-reviewed observational and interventional studies the results still indicate that breastfeeding is highly recommended for all infants irrespective of atopic heredity. A dietary regimen is effective in the prevention of allergic diseases in high-risk infants, particularly in early infancy regarding food allergy and eczema. The most effective dietary regimen is exclusively breastfeeding for at least 4-6 months or, in absence of breast milk, formulas with documented reduced allergenicity for at least the first 4 months, combined with avoidance of solid food and cow's milk for the first 4 months.     

Study of serum lipid and lipoprotein in pre-eclampsia with special reference to parity

A cross sectional study was done to determine serum lipid and lipoprotein cholesterol in pre-eclamptic women in their third trimester, taking normal pregnant women in third trimester as controls. The values were compared in patients of different parity. It was observed that serum triglycerides (TG), cholesterol (Chol), LDL-c, VLDL-c, phospholipids (PL) and total lipids (TL) were significantly raised, while HDL-c, was significantly lower in pre-eclampsia compared to normal pregnancy. TG and VLDL-c were found to be increased significantly with parity.     

Erratum to: Engineering cotton (Gossypium hirsutum L.) for resistance to cotton leaf curl disease using viral truncated AC1 DNA sequences

Virus Genes - An error notified in the labelling of Fig.&;nbsp;1b, 3′tAC1 has been erroneously published as 5′tAC1.