5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1)receptor antagonists: structure-activity relationship studies on the substituent at N2-position

To establish structure-activity relationships a new series of analogues of the highly potent and selective CCK(1) receptor antagonist (4aS,5R)-2-benzyl-5-(N-Boc-tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]-pyrimidine (1a) modified at N2-position of the central scaffold has been prepared and evaluated as CCK receptor ligands. With this aim the N2-benzyl group has been replaced by methyl, cyclohexyl, aromatic groups, 1-phenylethyl, and 1-carboxy-2-phenylethyl group. Then, substituents with different electronic and steric properties were introduced into different positions of the phenyl group of analogues 19a and 19b. The results of the CCK receptor binding and in vitro functional activity evaluation suggest the importance of the lipophilic character and an appropriate spatial orientation of the moiety linked at the N2-position of the 1,3-dioxoperhydropyrido[1,2-c]pyrimidine template for potent and selective binding and antagonist activity at CCK(1) receptor subtype. The 2-cyclohexyl and (2S)-1-naphthyl derivatives 18a and (2S)-20a have emerged as more potent and selective CCK(1) receptor antagonists than the lead compound 1a. Additionally, the results confirm the (4aS,5R)-stereochemistry at the central bicyclic skeleton as an essential structural requirement for potent binding to this receptor subtype.     

Magnesium level of serum and cerebrospinal fluid in cases of protein calorie malnutrition

Summary One hundred cases of PCM comprising 44 cases of marasmus, 26 cases of oedematous malnutrition and 30 cases of kwashiorkor were taken up for this study along with fifty normal children as controls. There was a definite fall of serum protein, albumin, A/G ratio along with serum and C.S.F. magnesium in cases of PCM, specially in oedematous malnutrition and kwashiorkor compared with the control group. Hypomagnesemia had a direct relation with serum protein and albumin level. Magnesium therapy along with nutritional therapy resulted in early improvement of clinical features and rise in biochemical values compared with the group not given in magnesium therapy. From the Department of Paediatrics, V.S.S. Medical College, Burla, Sambalpur, Orissa.     

Emblica officinalis exerts wound healing action through up-regulation of collagen and extracellular signal-regulated kinases (ERK1/2)

During wound healing, the wound site is rich in oxidants, such as hydrogen peroxide, mostly contributed by neutrophils and macrophages. Ascorbic acid and tannins of low molecular weight, namely emblicanin A (2,3-di- O -galloyl-4,6-( S )-hexahydroxydiphenoyl-2-keto-glucono-δ-lactone) and emblicanin B (2,3,4,6-bis-( S )-hexahydroxydiphenoyl-2-keto-glucono-δ-lactone) present in Emblica officinalis (emblica), have been shown to exhibit a very strong antioxidant action. We proposed that addition of these antioxidants to the wound microenvironment would support the repair process. The present investigation was undertaken to determine the efficacy of emblica on dermal wound healing in vivo. Full-thickness excision wounds were made on the back of the rat and topical application of emblica accelerated wound contraction and closure. Emblica increased cellular proliferation and cross-linking of collagen at the wound site, as evidenced by an increase in the activity of extracellular signal-regulated kinase 1/2, along with an increase in DNA, type III collagen, acid-soluble collagen, aldehyde content, shrinkage temperature and tensile strength. Higher levels of tissue ascorbic acid, α-tocopherol, reduced glutathione, superoxide dismutase, catalase, and glutathione peroxidase support the fact that emblica application promotes antioxidant activity at the wound site. In summary, this study provides firm evidence to support that topical application of emblica represents a feasible and productive approach to support dermal wound healing.     

Calibration of force extension and force degradation characteristics of orthodontic latex elastics.

The force-extension characteristics of orthodontic elastics made of natural rubber latex by 4 manufacturers were subjected to static testing under dry and wet conditions. The elastics consisted of 3 sizes: 3/16, 1/4, and 5/16 inch lumen sizes, each with forces specified according to the standard extension index of three times the lumen diameter. Most of the elastics did not match the specified index using the dry tests, but this should not be a serious clinical concern as all elastics showed acceptable regularity of force-extension characteristics. There was notable force degradation of all elastics when subject to water immersion, approximating 30% during the hour, but with an average less than 7% further loss up to 3 days. There were significant differences in force extension and force degradation characteristics between different extensions and force magnitudes for the elastics of the different manufacturers. It is suggested that the clinician could use the table of force degradation values for different extensions to select an appropriate elastic.     

Interaction among smoking status,single nucleotide polymorphisms and markers of systemic inflammation in healthy individuals

Cigarette smoke contains toxic and carcinogenic substances that contribute to the development of cancer and various diseases. Genetic variation might be important, because not all smokers develop smoking‐related disease. The current study addressed the possible interactions among selected single nucleotide polymorphisms (SNPs) in genes related to systemic inflammation, smoking status, the levels of circulating immune response cells and plasma biomarkers of systemic inflammation. Sixty‐four healthy blood donors were recruited, 31 of whom were current smokers and 33 were never‐users of tobacco products, references. Compared to references, the smokers showed significantly increased levels of circulating total white blood cells, lymphocytes, monocytes, neutrophils, basophils and C‐reactive protein (CRP). Smokers also more frequently exhibited circulating cell phenotypes that are associated with an immunocompromised state: CD8^dim cells in the lymphocyte group, CD13⁺ CD11⁺, CD13⁺ CD14⁺, CD13⁺ CD56⁺ cells in the monocyte group and CD13⁺ CD11⁺, CD13⁺ CD56⁺ cells in the neutrophil group. We observed an interaction among SNPs, smoking status and some of the studied biomarkers. The average plasma CRP level was significantly higher among the smokers, with the highest level found among those with the CRP rs1800947 CC genotype. Additionally, an increased CD8⁺ GZB⁺ cells in the CD8^dim group were found among smokers with the GZB rs8192917 AA genotype. Thus, smoking appears to be associated with systemic inflammation and increased levels of circulating immunosuppressive cells. The extent of these effects was associated with SNPs among the smokers. This observation may contribute to a better understanding of the genetic susceptibility of smoking‐related disease and the variations observed in clinical outcomes.