Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b.

Rosmarinic acid has been reported to inhibit complement activation in vivo as well as in vitro. Previous studies suggested that the inhibitory effect was due to inhibition of C3/C5 convertases, but inhibition of C3b attachment would yield the same results. Recent work in our laboratory demonstrated that compounds with polyhydroxylated phenyl rings are highly reactive with the thioester bond in nascent C3b. These compounds block complement activation by preventing attachment of C3b to the activating surface. Because rosmarinic acid contains two 3,4-dihydroxyphenyl groups, the current study was undertaken to re-examine the mechanism of inhibition by analyzing the effect of rosmarinic acid on C3b attachment. In assays using purified complement proteins, rosmarinic acid inhibited covalent attachment of C3b to cells with an 1C50 = 34 microM. Inhibition of C5 convertase activity required 1500 microM rosmarinic acid, and no significant inhibition of the C3 convertase enzyme, which produces C3b from C3, was observed at 10,000 microM. In hemolytic assays using human serum, rosmarinic acid was shown to inhibit activation of both the classical (IC50 = 180 microM) and the alternative (IC50 = 160 microM) pathways of complement. Rosmarinic acid concentrations up to 10,000 microM did not cause direct inactivation of C3. Radioiodination of rosmarinic acid was used to demonstrate covalent activation-dependent incorporation of rosmarinic acid specifically into the thioester-containing alpha'-chain of nascent C3b. These findings indicate that inhibition of complement activation by rosmarinic acid is due to the reaction of rosmarinic acid with the activated thioester of metastable C3b, resulting in covalent attachment of the inhibitor to the protein.     

Why immunization coverage fails to catch up in India? A community‐based analysis

Background An effort has been made in this paper to examine the impact of community and household vis‐à‐vis individual‐level variables on immunization coverage among Indian children. Methods National Family Health Survey‐2 data set has been used for the analysis. Multilevel regression analyses have been used to explore the relative effects of community‐, household‐ and individual‐level factors on immunization coverage. Three community‐level variables, i.e. availability of health facilities, availability of all‐weather roads and information, education and communication (IEC) activities conducted during last year, are included in this analysis. Results Availability of health facility and information, education and communication activities plays a significant role in determining the level of immunization coverage among children. Even with community‐level variables in the model, individual‐level variables, i.e. parent's education, birth order of child and number of antenatal care visits, retain their predictive role for the potential immunization coverage. Conclusions Universal immunization can be achieved by providing services at community level and information about the available services and their benefits to the community. There is a considerable, unexplained variation in the immunization coverage between different communities, even in the most complex model used in this study, which could explain the entire heterogeneity of immunization coverage among Indian states.     

Advances in the management of gastric cancer

Gastric cancer is a common malignancy in our country and patients continue to present at an advanced stage. Following confirmation of diagnosis, CT scan, endoscopic ultrasound and laparoscopy are the essential staging modalities. Radical gastrectomy remains the initial treatment of choice. Although controversy persists about the extent of lymph node dissection, there is a general consensus in performing D2 dissection but with preservation of pancreas and spleen. Patients who have high risk of relapse are treated with postoperative chemoradiotherapy. The regimen of preoperative chemotherapy followed by gastrectomy and postoperative chemotherapy has also become important in recent years. Both these chemotherapeutic options confer survival advantage and patients need to be appraised about various treatment strategies at the very outset.     

Nutritional and Antioxidant Potential of <Emphasis Type="Italic">Aegle marmelos</Emphasis> Fermented Fruit Juice

Aegle marmelos fruit, leaf and bark, are traditionally used for treatment of diabetes, liver toxicity, fungal infection, microbial infection, inflammation and pyrexia. In the present study, an attempt has been made to ferment the A. marmelos fruit juice and evaluate its nutritional and antioxidant potential as well as its sensory attributes. The nutritional potential of the fermented fruit juice showed an increased level of titratable acidity and lactic acid content of 1.7 g tartaric acid/L and 7.2 mg/L respectively. The 2, 2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid (ABTS) and Hydrogen peroxide (H₂O₂) scavenging activity of the fermented fruit juice was found out to be 81.10, 34.44 and 33.33 % respectively at 15 µl/mL concentration. Principal component analysis (PCA) reduced five sensory attributes (aroma, color, flavor, taste and aftertaste) to three independent components, which accounted for a 79.265 % variance (PC1, 31.278 %; PC2, 27.288 %; PC3, 20.699 %). It is concluded that the fermented fruit juice is rich in antioxidants and can be potentially used as a medicinal drink with higher nutritional potential.     

Panel 2.10: reproductive, mental, and child health

This is a summary of the presentations and discussion of Panel 2.10, Reproductive, Mental, and Child Health of the Conference, Health Aspects of the Tsunami Disaster in Asia, convened by the World Health Organization (WHO) in Phuket, Thailand, 04-06 May 2005. The topics discussed included issues related to reproductive, mental, and child health as pertain to the responses to the damage created by the Tsunami. It is presented in the following major sections: (1) background; (2) key issues; (3) discussion; and (4) recommendations. Key issues discussed included: (1) coordination/collaboration; (2) provision of services; and (3) raising awareness and advocacy.     

Pentamidine is an inhibitor of PRL phosphatases with anticancer activity

The PRL family oncogenic phosphatases are attractive targets for developing inhibitors as anticancer therapeutics given their potentially pathogenic role in human malignancies. Herein we demonstrate that pentamidine, an anti-protozoa drug with an unknown mechanism of action, is an inhibitor of PRLs with anticancer potential. Pentamidine at its therapeutic doses inhibited recombinant PRL phosphatases in vitro and inactivated ectopically expressed PRLs in NIH3T3 transfectants with an effective duration more than 24 h after a pulse cell treatment. The drug had in vitro growth-inhibitory activity against human cancer cell lines that express the endogenous PRLs. Pentamidine at a tolerable dose markedly inhibited the growth of WM9 human melanoma tumors in nude mice coincident with the induction of tumor cell necrosis and is capable of inactivating ectopically expressed PRL-2 in the cancer cells. These observations suggest the potential of pentamidine in anticancer therapies and may provide a basis for developing novel PTPase-targeted therapeutics.     

Argininosuccinate Synthetase-1 (ASS1) Loss in High-Grade Neuroendocrine Carcinomas of the Urinary Bladder: Implications for Targeted Therapy with ADI-PEG 20

High-grade neuroendocrine carcinomas (HGNECs) of the urinary bladder encompass small cell (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). Currently, recommended initial management is with systemic chemotherapy, followed by consolidative therapy with either radical cystectomy or radiotherapy in patients with localized disease. Nevertheless, survival in this setting remains poor. We therefore evaluated the potential to modify arginine metabolism as an alternative, targeted therapy approach in these carcinomas. In humans, arginine is a semi-essential amino acid and its synthesis enzyme argininosuccinate synthetase (ASS1) represents the rate-limiting step in arginine biosynthesis. Neoplasms that show low to absent ASS1 expression require extracellular arginine for cancer cell survival, and thus can be targeted using arginine-degrading enzymes such as pegylated arginine deiminase (ADI-PEG 20). An initial study by our group of 19 patients demonstrated that a high percentage of SCNEC lack ASS1 expression. Herein, we evaluated an expanded cohort of 74 radical cystectomy patients with HGNEC, including 63 SCNEC, 5 LCNEC, and 6 mixed morphology HGNEC patients. ASS1 expression was assessed through immunohistochemistry. Fifty-eight (of 74, 78%) patients with HGNEC showed absent ASS1 expression, including all patients with LCNEC and mixed morphology (11 of 11, 100%). Ten-year survival from disease-specific death was not statistically significant between ASS1-expressing and ASS1-deficient cases (p?=?0.75). Our results show that HGNEC of the bladder may be candidates for arginine deprivation therapy using drugs such as ADI-PEG 20. Further studies are needed to validate these findings and to determine the therapeutic efficacy of such agents.     

Preoperative portal vein embolisation for primary and metastatic liver tumours: volume effects, efficacy, complications and short-term outcome

BackgroundThe aim of portal vein embolisation is to induce hyperplasia of normal tissue when resection of a cancerous portion of the liver is contraindicated only by the volume of liver that would remain following operation.MethodsEight patients with inoperable liver tumours (3 women and 5 men, median age 69.5 years, 3 colorectal hepatic metastasts,2 choloangiocarcinomas and 3 hepatocellular cancers) were selected for portal vein embolisation. Selected portal branches were occluded with microparticles and coils. Liver volumes were determined by magnetic resonance imaging (MRI) before embolisation and again before operation.ResultsEmbolisation was successfully performed in all 8 patients, 7 by the percutaneous-transhepatic route, while one patient required open cannulation of a mesenteric vein. Management was altered in 6 patients who proceded to ‘curative’ resection; projected remaining liver volumes increased (Wilcoxon''s matched pairs test p=0.02) from a median of 361 cc to a median of 550 cc; two patients had disease progression such that operation was no longer indicated. In one patient a misplaced coil unintentionally occluded a portal branch to normal liver.ConclusionsPortal vein embolisation produced appreciable hyperplasia of the normal liver and extended the option of ‘curative’ operation to 6 out of the 8 cases attempted. Complications can occur. The long-term results following operation are unknown.     

Determination of hand and palm area as a ratio of body surface area in Indian population

Background:

Accurate estimation of body surface area (BSA) burn is important. In small and patchy burns, the patient''s hand is used to estimate percentage of burn which is traditionally considered as 1%. There is discrepancy about what percentage of TBSA is constituted by the palm and hand. Therefore, this study was designed to determine correctly the TBSA represented by the palmar surface of the entire hand and palm in the Indian population.

Material and Methods:

300 healthy adult (male and female) and 300 healthy children (male and female) were included in the study. TBSA was calculated using DuBois formula and hand and palm surface area was calculated using hand tracing on plain paper. The hand/palm percentage of BSA (ratio) was determined by dividing hand/palm surface area by total BSA.

Results:

The mean hand and palm ratio for adults was 0.92% and 0.50%, respectively. The mean hand and palm ratio in children was 1.06% and 0.632%, respectively.

Conclusion:

The hand area (palm plus digits) is more closely represented to 1% of TBSA in Indian population.