Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling

BACKGROUND: In the nematode, Caenorhabditis elegans, a conserved insulin-like signaling pathway controls larval development, stress resistance and adult lifespan. AGE-1, a homolog of the p110 catalytic subunit of phosphoinositide 3-kinases (PI3K) comprises the major known effector pathway downstream of the insulin receptor, DAF-2. Phospholipid products of AGE-1/PI3K activate AKT/PKB kinase signaling via PDK-1. AKT/PKB signaling antagonizes nuclear translocation of the DAF-16/FOXO transcription factor. Reduced AGE-1/PI3K signaling permits DAF-16 to direct dauer larval arrest and promote long lifespan in adult animals. In order to study the downstream effectors of AGE-1/PI3K signaling in C. elegans, we conducted a genetic screen for mutations that suppress the constitutive dauer arrest phenotype of age-1(mg109) animals. RESULTS: This report describes mutations recovered in a screen for suppressors of the constitutive dauer arrest (daf-C) phenotype of age-1(mg109). Two mutations corresponded to alleles of daf-16. Two mutations were gain-of-function alleles in the genes, akt-1 and pdk-1, encoding phosphoinositide-dependent serine/threonine kinases. A fifth mutation, mg227, located on chromosome X, did not correspond to any known dauer genes, suggesting that mg227 may represent a new component of the insulin pathway. Genetic epistasis analysis by RNAi showed that reproductive development in age-1(mg109);akt-1(mg247) animals was dependent on the presence of pdk-1. Similarly, reproductive development in age-1(mg109);pdk-1(mg261) animals was dependent on akt-1. However, reproductive development in age-1(mg109); mg227 animals required only akt-1, and pdk-1 activity was dispensable in this background. Interestingly, while mg227 suppressed dauer arrest in age-1(mg109) animals, it enhanced the long lifespan phenotype. In contrast, akt-1(mg247) and pdk-1(mg261) did not affect lifespan or stress resistance, while both daf-16 alleles fully suppressed these phenotypes. CONCLUSION: A screen for suppressors of PI3K mutant phenotypes identified activating mutations in two known pathway components, providing insights into their regulation. In particular, the interdependence of akt-1 and pdk-1, even in activated forms, supports the existence of AGE-1-independent pathways for these phospholipid-dependent kinases. Phenotypic analysis of these alleles shows that the larval and adult outputs of AGE-1/PI3K are fully separable in these mutants

Effects of a four-year health systems intervention on the use of maternal and infant health services: results from a programme evaluation in two districts of rural Chad

BACKGROUND: Attendance of maternal and infant care services in rural Chad are consistently low. Our study aimed to assess the use of antenatal (ANC) and postnatal care (PNC) services, health facility delivery and infant health services after 4 years of a health systems intervention for improving the infrastructure, supplies, training and sensitization for maternal and infant health in two districts of rural Chad. METHODS: Data from a repeated cross-sectional household survey conducted in Yao and Danamadji in 2015 and in 2018 were analyzed. A stratified two-stage cluster sampling methodology was applied to achieve a representative sample of the rural settled and mobile population groups in the study area. A generalized linear model was applied to determine the health care utilization rates. Multivariate regression models were used to assess the association between the programme intervention and utilization outcomes of selected maternal and infant health services. RESULTS: Complete datasets were available for 1284 households at baseline. The endline analysis included 1175 households with complete survey data. The use of at least one ANC amongst pregnant women increased in both settled communities (from 80% in 2015 to 90% in 2018) and amongst mobile pastoralist communities (from 48% in 2015 to 56% in 2018). The rate of home delivery among settled communities and mobile pastoralists changed little between baseline and endline and remained high for both population groups. Individuals that were covered by the health systems intervention were however significantly more likely to attend ANC and less likely to give birth at home. PNC services only showed improvements amongst the settled communities (of 30%). Infants' reported health outcomes and vaccination coverage considerably improved; the latter especially among mobile pastoralist (from 15% in 2015 to 84% in 2018). CONCLUSION: A combination of health systems strengthening interventions was associated with an increased use of certain maternal and infant health services. However, to facilitate equitable access to and use of health care services in particular in times of increased vulnerability and by certain population groups in hard-to-reach areas, reinforced health education and culturally adapted communication strategies, including gender-specific messaging will be needed over a sustained period

Studies of Caenorhabditis elegans DAF-2/insulin signaling reveal targets for pharmacological manipulation of lifespan

Much excitement has arisen from the observation that decrements in insulin-like signaling can dramatically extend lifespan in the nematode, Caenorhabditis elegans, and fruitfly, Drosophila melanogaster. In addition, there are tantalizing hints that the IGF-I pathway in mice may have similar effects. In addition to dramatic effects on lifespan, invertebrate insulin-like signaling also promotes changes in stress resistance, metabolism and development. Which, if any, of the various phenotypes of insulin pathway mutants are relevant to longevity? What are the genes that function in collaboration with insulin to prolong lifespan? These questions are at the heart of current research in C. elegans longevity. Two main theories exist as to the mechanism behind insulin's effects on invertebrate longevity. One theory is that insulin programs metabolic parameters that prolong or reduce lifespan. The other theory is that insulin determines the cell's ability to endure oxidative stress from respiration, thereby determining the rate of aging. However, these mechanisms are not mutually exclusive and several studies seem to support a role for both. Here, we review recently published reports investigating the mechanisms behind insulin's dramatic effect on longevity. We also spotlight several C. elegans genes that are now known to interact with insulin signaling to determine lifespan. These insights into pathways affecting invertebrate lifespan may provide a basis for developing strategies for pharmacological manipulation of human lifespan

Učinak ricinoleične kiseline iz ricinusova ulja na proizvodna svojstva i hemato-biokemijski profil krava pasmine Kankrej u laktaciji

The aim of the present study was to evaluate the effects of dietary ricinoleic acid from castor oil on the milk yield, composition, fatty acid profile and haemato-biochemical profile in lactating Kankrej cows. Twenty lactating Kankrej cows were assigned to the following groups: control (CON), basal diet without any additive and treatment (RAS), basal diet with 2 g/animal/day of ricinoleic acid from castor oil. Dietary ricinoleic acid had no (P>0.05) effect on dry matter intake and feed efficiency. Milk yield (milk, 4% fat corrected milk and energy corrected milk) were not affected (P>0.05) by the feeding of ricinoleic acid. The milk composition showed no significant differences between the groups. A significantly (P0.05) in haemato-biochemical profile between the CON and RAS groups. It was concluded that supplementation of 2 g/animal/day ricinoleic acid from castor oil had no effect on milk yield, milk composition and haemato-biochemical profile. However, it increased the milk fat percentages of unsaturated fatty acids and polyunsaturated fatty acids, and decreased milk saturated fatty acids, without any adverse effect on the health status of the cows.Cilj istraživanja bio je procijeniti učinak ricinoleične kiseline iz ricinusova ulja na prinos mlijeka, kemijski sastav mlijeka, profil masnih kiselina u mlijeku te na hemato-biokemijski profil krava pasmine Kankrej u laktaciji. Ukupno 20 krava u laktaciji podijeljeno je u: kontrolnu skupinu (CON), skupinu koja je dobivala osnovnu hranu, bez dodataka i pokusnu skupinu (RAS), koja je dobivala osnovnu hranu i 2 g po životinji dnevno ricinoleične kiseline iz ricinusova ulja. Ricinoleična kiselina nije imala učinka (P>0,05) na unos suhe tvari i iskorištavanje hrane. Dodatak ricinoleične kiseline nije utjecao (P>0,05) na prinos mlijeka (mlijeko, obogaćeno mlijeko s 4 % masnoće i energijski obogaćeno mlijeko). Sastav mlijeka nije pokazao znakovite razlike među skupinama. Uočen je znakovito veći postotak C4:0, C6:0 i C8:0 u mlijeku u skupini RAS (P0,05) u hemato-biokemijskom profilu skupina CON i RAS. Zaključeno je da dodatak 2 g ricinoleične kiseline po životinji dnevno ne utječe na prinos i sastav mlijeka te hemato- biokemijski profil, međutim povećava postotak mliječne masti, nezasićenih masnih kiselina i višestruko nezasićenih masnih kiselina, a smanjuje postotak zasićenih masnih kiselina bez posljedica za zdravlje krava

Should the appendix always be removed during surgery for mucinous ovarian tumors?

Background: Appendectomy is performed in all mucinous ovarian tumors (MOT) identified intraoperatively to ensure microscopic metastases from appendix are not missed. Several recent studies suggested that appendectomy should only be performed in cases with a grossly abnormal appendix or with evidence of pseudomyxoma peritonei. Our study aimed to determine the frequency of malignancy in a grossly normal appendix in women undergoing surgery for borderline or malignant MOT.Methods: In a single institution retrospective study, women undergoing surgery for MOT from January 1, 2008 to June 30, 2016 were included. Women with benign MOT, those with a history of either prior appendicectomy or prior gastrointestinal (GI) malignancy were excluded.Results: Of 266 women identified with MOT, 153 with borderline and malignant MOT were included in the study after application of inclusion criteria. The study population comprised of 29 (18.95%) borderline and 124 (81.05%) malignant MOT. Among the borderline MOT, 13/29 had undergone appendectomy. Five (38.46%) had grossly abnormal appendices of whom 1 had mucinous cystadenoma, 3 had borderline mucinous tumor and 1 had mucinous cystadenocarcinoma of the appendix. Histology was normal in all 8 (61.54%) grossly normal appendices. Among the malignant MOT, 80/124 (64.52%) underwent appendicectomy. Nineteen (23.46%) had grossly abnormal appendices and histology was suggestive of adenocarcinoma of appendix. Histology was normal in all 62 (76.54%) macroscopically normal appendices.Conclusions: Present results suggest that appendectomy be performed only for those appendices that are grossly abnormal or associated with pseudomyxoma peritonei at surgery for MO

Association of atrial fibrillation and obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with recurrent atrial fibrillation (AF) after electrocardioversion. OSA is highly prevalent in patients who are male, obese, and/or hypertensive, but its prevalence in patients with AF is unknown. METHODS AND RESULTS: We prospectively studied consecutive patients undergoing electrocardioversion for AF (n=151) and consecutive patients without past or current AF referred to a general cardiology practice (n=312). OSA was diagnosed with the Berlin questionnaire, which is validated to identify patients with OSA. We also assessed its accuracy compared with polysomnography in a sample of the study population. Groups were compared with the 2-tailed t, Wilcoxon, and chi2 tests. Logistic regression modeled the association of AF and OSA after adjustment for relevant covariates. Patients in each group had similar age, gender, body mass index, and rates of diabetes, hypertension, and congestive heart failure. The questionnaire performed with 0.86 sensitivity, 0.89 specificity, and 0.97 positive predictive value in our sample. The proportion of patients with OSA was significantly higher in the AF group than in the general cardiology group (49% versus 32%, P=0.0004). The adjusted odds ratio for the association between AF and OSA was 2.19 (95% CI 1.40 to 3.42, P=0.0006). CONCLUSIONS: The novel finding of this study is that a strong association exists between OSA and AF, such that OSA is strikingly more prevalent in patients with AF than in high-risk patients with multiple other cardiovascular diseases. The coinciding epidemics of obesity and AF underscore the clinical importance of these results

Day-night variation of acute myocardial infarction in obstructive sleep apnea.

OBJECTIVES: This study sought to evaluate the day-night variation of acute myocardial infarction (MI) in patients with obstructive sleep apnea (OSA). BACKGROUND: Obstructive sleep apnea has a high prevalence and is characterized by acute nocturnal hemodynamic and neurohormonal abnormalities that may increase the risk of MI during the night. METHODS: We prospectively studied 92 patients with MI for which the time of onset of chest pain was clearly identified. The presence of OSA was determined by overnight polysomnography. RESULTS: For patients with and without OSA, we compared the frequency of MI during different intervals of the day based on the onset time of chest pain. The groups had similar prevalence of comorbidities. Myocardial infarction occurred between 12 am and 6 am in 32% of OSA patients and 7% of non-OSA patients (p = 0.01). The odds of having OSA in those patients whose MI occurred between 12 am and 6 am was 6-fold higher than in the remaining 18 h of the day (95% confidence interval: 1.3 to 27.3, p = 0.01). Of all patients having an MI between 12 am and 6 am, 91% had OSA. CONCLUSIONS: The diurnal variation in the onset of MI in OSA patients is strikingly different from the diurnal variation in non-OSA patients. Patients with nocturnal onset of MI have a high likelihood of having OSA. These findings suggest that OSA may be a trigger for MI. Patients having nocturnal onset of MI should be evaluated for OSA, and future research should address the effects of OSA therapy for prevention of nocturnal cardiac events