Arrhythmogenic Calmodulin Mutations Disrupt Intracellular Cardiomyocyte Ca\u3csup\u3e2+\u3c/sup\u3e Regulation by Distinct Mechanisms

BACKGROUND: Calmodulin (CaM) mutations have been identified recently in subjects with congenital long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT), but the mechanisms responsible for these divergent arrhythmia-susceptibility syndromes in this context are unknown. We tested the hypothesis that LQTS-associated CaM mutants disrupt Ca2+ homeostasis in developing cardiomyocytes possibly by affecting either late Na current or Ca2+-dependent inactivation of L-type Ca2+ current. METHODS AND RESULTS: We coexpressed CaM mutants with the human cardiac Na channel (NaV1.5) in tsA201 cells, and we used mammalian fetal ventricular cardiomyocytes to investigate LQTS- and CPVT-associated CaM mutations (LQTS- and CPVT-CaM). LQTS-CaM mutants do not consistently affect L-type Na current in heterologous cells or native cardiomyocytes, suggesting that the Na channel does not contribute to LQTS pathogenesis in the context of CaM mutations. LQTS-CaM mutants (D96V, D130G, F142L) impaired Ca2+-dependent inactivation, whereas the CPVT-CaM mutant N54I had no effect on Ca2+-dependent inactivation. LQTS-CaM mutants led to loss of Ca2+-transient entrainment with the rank order from greatest to least effect: CaM-D130G~CaM-D96V\u3e\u3eCaM-F142L. This rank order follows measured Ca2+-CaM affinities for wild-type and mutant CaM. Acute isoproterenol restored entrainment for CaM-130G and CaM-D96V but caused irreversible cytosolic Ca2+ overload for cells expressing a CPVT-CaM mutant. CONCLUSIONS: CaM mutations associated with LQTS may not affect L-type Na+ current but may evoke defective Ca2+-dependent inactivation of L-type Ca2+ current

Can Dietary Phytogenic Mixture Improve Performance for Growth, Digestive Enzyme Activity, Blood Parameters, and Antioxidant and Related Gene Expressions of Nile Tilapia, Oreochromis niloticus?

The form of dietary phytogenic inclusion and its physiological causal mechanisms for growth promotion and immune stimulation in fish remain unknown. The study examined the effects of dietary phytogenic mixture extracted from lemon (Citrus limon), onion (Allium cepa), and garlic (Allium sativum) (LOG) on Nile tilapia performance, digestive enzymes, haemato-biochemical indices, oxidative stress, and associated gene expression for 70 days. In this experiment, diets were supplemented with 0, 10, 20, and 30 ml LOG kg−1 in isonitrogenous and isoenergetic diets and fed to tilapia with an average initial body weight (4.23 ± 0.09 g). Compared to the control diet, the dietary LOG at 20 ml kg−1 elicited the highest final body weight (FBW, 35.50 g fish−1), weight gain (WG, 31.2 g fish−1), specific growth rate (SGR, 3.02%, day fish−1), and survival rate (99.33%). Significant quadratic differences in chymotrypsin, trypsin, amylase, and lipase were shown with increasing LOG supplementation. There was a quadratic response in hematology parameters of fish with increasing LOG levels. Significant linear decreases in ALT, AST, cholesterol, and triglyceride were shown with the increased LOG inclusion in the diets. A polynomial correlation in total protein, albumin, and globulin was found under different inclusion levels of LOG while significant quadratic increases in SOD, CAT, and Gpx and significant quadratic decrease in MDA was found with increasing LOG supplementation. The IGM-2, SOD, and CAT gene expressions were quadratically improved; the highest relative expression was obtained by fish received 20 ml LOG kg−1 diet. Growth hormone gene expression was quadratically modulated in the liver and pituitary of fish fed diverse doses of dietary LOG compared with the control. The phytogenic of LOG at 20 ml kg−1 elicited the best tilapia performance and hematological indices, increased antioxidant and digestive enzyme activities, and gene expressions of growth, immunoglobulin and superoxide dismutase

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially