Differential receptor occupancy requirements for muscarinic cholinergic stimulation of inositol lipid hydrolysis in brain and in neuroblastomas

The potency with which carbamoylcholine enhances phosphoinositide (PPI) hydrolysis in different brain regions (neostriatum, cerebral cortex, and hippocampus) and in two neuroblastomas (the murine N1E-115 and human SK-N-SH) differs by 10- to 20-fold. To determine whether the presence of a muscarinic receptor (mAChR) reserve might account for these differences, we have examined the effect of propylbenzilylcholine mustard (PrBCM) on mAChR number and on agonist-stimulated PPI hydrolysis. In the cerebral cortex, in hippocampus, and in N1E-115 cells, PrBCM treatment resulted in a loss of the PPI response, as measured by the release of [3H]inositol phosphates, that was equal to or greater than the reduction in receptor number, as determined by the loss of either [3H]quinuclidinylbenzilate- or [3H]N-methylscopolamine-binding sites. From dose response curves for carbamoylcholine, it was determined that alkylation of mAChRs resulted in a reduction in the maximum release of inositol phosphates but had no effect on agonist potency. The KA values for carbamoylcholine obtained following receptor inactivation were similar to those for the EC50 (120-316 microM). In contrast, in both the neostriatum and SK-N-SH cells, PrBCM treatment resulted in a greater loss of mAChR number than of stimulated inositol phosphate release, and dose response curves for carbamoylcholine were shifted to higher agonist concentrations. The KA values (34-65 microM) were 2- to 9-fold higher than the comparable EC50 values. Moreover, in both tissues the PPI response elicited by partial agonists was more susceptible to receptor alkylation than that elicited by carbamoylcholine. The two groups of tissues also differ in their sensitivity to pirenzepine, which is a markedly weaker antagonist of stimulated PPI hydrolysis in SK-N-SH cells and neostriatum (Ki 160-250 nM), than in the cerebral cortex, hippocampus, and N1E-115 cells (Ki 10-20 nM). These results suggest: 1) that a population of "spare" receptors exists for mAChR-mediated inositol lipid hydrolysis in some neuronal tissues, 2) that both M1 and M2 mAChRs may be coupled to PPI turnover, and 3) that M2 mAChRs appear to be more efficiently coupled to phosphoinositide hydrolysis than their M1 counterparts.     

Current tuberculosis screening practices.

Health department officials in all 50 states and 14 major cities responded to a survey questionnaire designed to obtain information about current tuberculosis screening practices. Persons being screened fell into the groups designated as high risk by the American Thoracic Society (ATS) and the Centers for Disease Control (CDC). The methods used for screening were generally those advocated by ATS, CDC, and the Food and Drug Administration (FDA), although chest radiographs continue to be overused. Screening in about one-half of the groups is mandated by law or regulation. There appears to be some confusion about the circumstances in which "two-step" tuberculin testing should be used. Data on the productivity and costs of screening activities were very limited. We encourage those responsible for tuberculosis screening programs to evaluate them, discontinue those which are unproductive, and intensify those which are productive.     

Impact of postanesthesia care unit delirium on self-reported cognitive function and perceived health status: a prospective observational cohort study

Quality of Life Research - The objective of this study was to determine the influence of postanesthesia care unit (PACU) delirium on self-reported cognitive function and perceived health...     

Universal School Meals and Associations with Student Participation,Attendance, Academic Performance,Diet Quality,Food Security,and Body Mass Index: A Systematic Review

The school environment plays an important role in children’s diets and overall health, and policies for universal free school meals have the potential to contribute to positive child health outcomes. This systematic review evaluates studies examining the association between universal free school meals and students’ school meal participation rates, diets, attendance, academic performance, and Body Mass Index (BMI), as well as school finances. The search was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA). A search for studies published in economically developed countries published through December 2020 was performed in PubMed, Education Resources Information Center (ERIC), Thomson Reuters’ Web of Science, and Academic Search Ultimate, followed by examining the references in the resultant literature. A total of 47 studies were identified and the Newcastle-Ottawa Scale (NOS) was applied to assess bias. Nearly all studies examining universal free school meals found positive associations with school meal participation. Most studies examining universal free school meals that included free lunch found positive associations with diet quality, food security, and academic performance; however, the findings of studies examining only universal free breakfast were mixed. Research findings were similarly mixed when examining attendance as an outcome. Concerns about adverse outcomes on student BMI were not supported by the literature; in fact, several studies detected a potentially protective effect of universal free school meals on BMI. Research examining the impact of universal free meals on school finances was limited, but suggest that lower-income school districts in the U.S. may have positive financial outcomes from participation in universal free school meal provisions. Additionally, providing free meals to students may be associated with improved household incomes, particularly among lower-income families with children. Further research is needed to examine the financial implications of universal free meals for both school districts and families. Overall, universal free school meals may have multiple benefits for students and countries should consider universal free school meal provisions with strong nutrition guidelines. (PROSPERO registration: CRD42020221782).     

Zinc Nutritional Status in a Series of Children with Chronic Diseases: A Cross-Sectional Study

Background: Zinc is an essential trace element for the normal growth and development of human beings. The main objective was to evaluate the nutritional status of zinc and its association with nutritional indicators in a series of children with chronic diseases. Methods: The prevalence of patients with dietary zinc deficiency or deficit zinc intake (<80% DRI: dietary reference intake) was analyzed through prospective 72 h dietary surveys, and serum zinc deficiency or hypozincemia (≤70 µg/dL in children under 10 years of age in both sexes and in females older than 10 years and <74 μg/dL in males older than 10 years) was measured through atomic absorption spectrophotometry. The participants were classified according to their nutritional status by body mass index (BMI). Results: Mean serum zinc level in obese (87 µg/dL), undernourished (85 µg/dL), and eutrophic children (88 µg/dL) were normal, but in the undernutrition (60% DRI) and eutrophic (67% DRI) groups the mean dietary zinc intake was low compared to that in the obesity group (81% DRI). There were different associations between nutritional parameters, dietary zinc intake, and serum zinc. All patients with hypozincemia had dietary zinc deficiency. Conclusions: In the whole series, 69% of participants showed a zinc intake lower than recommended and might be at high risk of zinc deficiency.     

Nozizeptionsmonitoring

Die Anaesthesiologie - Die intraoperative Dosierung von Opioiden stellt eine Herausforderung im anästhesiologischen Alltag dar; insbesondere, da potenzielle Effekte einer intraoperativen...     

Decision Aids for Preventive Treatment Alternatives for BRCA1/2 Mutation Carriers: a Systematic Review

Introduction Women with a pathogenic BRCA1/2 mutation have a markedly increased lifetime risk of developing breast and/or ovarian cancer. The current preventive treatment alternatives that are offered are an intensified breast cancer screening programme and risk-reducing operations. Before deciding on one option, medical and personal factors such as life situation and individual preferences must be weighed carefully. Decision aids are used internationally to support BRCA1/2 mutation carriers during their decision-making process. In this study these are analysed structurally for the first time and their applicability to the German context is examined. Material and Methods A systematic literature search in five electronic databases and a manual search were performed. The identified decision aids were evaluated with regard to formal criteria, medical content and quality. The qualitative assessment used the criteria of the International Patient Decision Aid Standards Collaboration (IPDASi v4.0), which examined various dimensions (e.g., information, probabilities, values). Results Twenty decision aids, which were published between 2003 and 2019 in Australia (n = 4), the United Kingdom (n = 3), Canada (n = 2), the Netherlands (n = 2) and the USA (n = 9), were included. Nine focus on BRCA1/2 mutation carriers and eleven include other risk groups. Eighteen include risk-reducing operations as decision options, 14 list screening methods for breast and/or ovarian cancer, and 13 describe the possibility of pharmacological prevention by means of selective oestrogen receptor modulators or aromatase inhibitors. Nine of the 20 decision aids meet fundamental quality criteria (IPDASi v4.0 qualification criteria). Conclusion International decision aids can serve formally as a basis for a German decision aid for BRCA1/2 mutation carriers. Some of them differ markedly in content from the recommendations of German guidelines. Only a few achieve a high quality. Key words: BRCA1, BRCA2, decision aid, familial breast cancer, familial ovarian cancer     

Discovery of novel non-peptide CCR1 receptor antagonists

Ligands for the CCR1 receptor (MIP-1alpha and RANTES) have been implicated in a number of chronic inflammatory diseases, most notably multiple sclerosis and rheumatoid arthritis. Because these ligands share a common receptor, CCR1, we sought to discover antagonists for this receptor as an approach to treating these disorders. A novel series of 4-hydroxypiperidines has been discovered by high throughput screening (HTS) which potently inhibits the binding of MIP-1alpha and RANTES to the recombinant human CCR1 chemokine receptor. The structure-activity relationships of various segments of this template are described as the initial HTS lead 1 was optimized synthetically to the highly potent receptor antagonist 6s. This compound has been shown to have at least 200-fold selectivity for inhibition of CCR1 over other human 7-TM receptors, including other chemokine receptors. In addition, data obtained from in vitro functional assays demonstrate the functional antagonism of compound 6s and structurally related analogues against the CCR1 receptor in a concentration dependent manner. The discovery and optimization of potent and selective CCR1 receptor antagonists represented by compound 6s potentially represent a novel approach to the treatment of chronic inflammatory diseases.