cAMP-dependent protein kinase involves calcium tolerance through the regulation of Prz1 in Schizosaccharomyces pombe.

The cAMP-dependent protein kinase Pka1 is known as a regulator of glycogenesis, meiosis, and stress responses in Schizosaccharomyces pombe. We demonstrated that Pka1 is responsible for calcium tolerance. Loss of functional components of the PKA pathway such as Git3, Gpa2, Cyr1, and Pka1 yields a CaCl2-sensitive phenotype, while loss of Cgs1, a regulatory subunit of PKA, results in CaCl2 tolerance. Cytoplasmic distribution of Cgs1 and Pka1 is increased by the addition of CaCl2, suggesting that CaCl2 induces dissociation of Cgs1 and Pka1. The expression of Prz1, a transcriptional regulator in calcium homeostasis, is elevated in a pka1∆ strain and in a wild type strain under glucose-limited conditions. Accordingly, higher expression of Prz1 in the wild type strain results in a CaCl2-sensitive phenotype. These findings suggest that Pka1 is essential for tolerance to exogenous CaCl2, probably because the expression level of Prz1 needs to be properly regulated by Pka1.

Ion-paired pirenzepine-loaded micelles as an ophthalmic delivery system for the treatment of myopia.

Myopia is one of the most common ocular disorders for which standard treatments, such as refractive surgery, often involve invasive procedures. Pirenzepine (PRZ), a muscarinic receptor antagonist, has been recognized as a promising candidate for the treatment of myopia, but possesses poor ocular bioavailability. The overall objective of this study was to prepare PRZ-sorbic acid complexes suitable to be encapsulated into micelles with high efficiency for optimal ophthalmic delivery. The results demonstrated that sorbic acid, used as the counter ion, had the most significant effects in increasing the octanol-water distribution coefficient of PRZ as well as improving its corneal permeability in vitro among various counter ions tested. In vivo absorption results showed that a 1.5 times higher bioavailability was achieved by the addition of sorbic acid at a 1:1 ratio. Cytotoxicity studies in vitro and biocompatibility studies in vivo indicated that the micelles did not cause significant toxicities to the eyes.

Pediatrician's cough and cold medication prescription for hypothetical cases - A cross-sectional multi-centric study.

BACKGROUND: Concerns over inappropriate use of cough and cold medication (CCM) in children have been raised. In addition to being ineffective, these are now considered toxic for young children. Despite this fact studies from some regions have shown high use of these medications by physicians. However data on pediatricians and from India are negligible. AIM: To study the burden and patterns of cough and cold medications use by pediatricians for hypothetical cases. METHODS: In this cross-sectional study; 172 pediatricians of various hospitals of Delhi and Haryana were enrolled from February 15 to March 15, 2012. They were contacted personally by authors and asked to write their prescriptions for two hypothetical case scenarios [having cough and cold] of two different age groups; (1) less than 2 years and (2) 2-5 years. We made two categories as recommendations exist for children less than 2 years while recommendations for the second category are underway. RESULTS were summarized as percentages, counts and; presented in tables and figures. Chi square test was used to establish association between categorical variables of subgroups. RESULTS: Response rate was 93%. The most used CCM was antihistaminics (82%) and systemic sympathomimetics (48%). The use of CCM was significantly less in teaching hospitals as compared to non-teaching (77% vs. 95%; p-value - 0.025). However there was no statistical difference in the practice of post graduates and more senior pediatricians (p value-0.895). No difference in CCM use in two age groups {(82% (less than 2 years) vs. 85% (2-5 years); p-value - 0.531} was observed. CONCLUSION: Overall use of CCM is still high irrespective of patient age, pediatrician's seniority or hospital setting. Efforts should be made to create awareness among the pediatricians regarding cautious use of these medications.

Propranolol, a ß-adrenoceptor antagonist, worsens liver injury in a model of non-alcoholic steatohepatitis.

Prazosin an α1-adrenoceptor (AR) antagonist has been shown to reduce liver injury in a mouse model of non-alcoholic steatohepatitis (NASH) and is suggested as a potential treatment of NASH especially given its concomitant anti-fibrotic properties. The effect however, of ß-AR blockade in non-cirrhotic NASH is unknown and is as such investigated here. In the presence of the ß-blocker propranolol (PRL), mice fed normal chow or a half methionine and choline deficient diet, supplemented with ethionine (HMCDE), to induce NASH, showed significantly enhanced liver injury, as evidenced by higher hepatic necrosis scores and elevated serum aminotransferases (ALT). Mechanistically, we showed that murine hepatocytes express α and ß adrenoceptors; that PRL directly induces hepatocyte injury and death as evidenced by increased release of lactate dehydrogenase, FASL and TNF-α from hepatocytes in the presence of PRL; and that PRL activated the apoptotic pathway in primary hepatocyte cultures, as indicated by upregulation of Fas receptor and caspase-8 proteins. The ß-AR antagonist PRL therefore appears to enhance liver injury through induction of hepatocyte death via the death pathway. Further studies are now required to extrapolate these findings to humans but meanwhile, ß-AR antagonists should be avoided or used with caution in patients with non-cirrhotic NASH as they may worsen liver injury.