The effect of the intramolecular C–H⋯O interactions on the conformational preferences of bis-arylsulfones – 5-HT6 receptor antagonists and beyond

The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C–H⋯O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

The impact of weak intramolecular C–H⋯O interactions on the conformational stability of bis-arylsulfones is discussed, suggesting different role of sulfonyl group in the ligand – 5HT₆ receptor interaction.     

Do patients’ information requirements for choice in health care vary with their socio‐demographic characteristics?

Objectives

This study examines whether the information used to inform hospital choice, and the sources of that information, varies with patients’ socio‐demographic characteristics. It also examines whether information used by patients to inform choice is associated with attending their local hospital.

Methods

A survey of 1033 patients who were offered a choice of hospital provider for elective treatment in England. Logistic regression was used to examine associations between patient characteristics and information used to inform choice of a hospital provider and sources of information used.

Results

Factors most important to patients in choosing a hospital were quality of care, cleanliness, standard of facilities and reputation. While quality of care and related factors are important to the majority of patients, those with lower levels of education were more likely to report that location and appointment times were important. Those who thought quality important were more likely to attend their local hospital provider. The main sources of information used to inform choice of hospital were own experience, family and friends and the general practitioner (GP). Patients who sought advice from their GP or booking advisors were less likely to attend their local hospitals.

Conclusions

Differences among patients as to what factors are important when choosing a hospital provider and what information and support they access suggest there needs to be a variety of information sources and support available to promote choice. Greater shared decision making through active involvement and support by GPs or booking advisors may be required if they are to make choices in line with their preferences.     

Socioeconomic inequalities in children’s diet: the role of the home food environment

Background

It is well documented in the literature that low socioeconomic status (SES) is associated with lower consumption of healthy foods and that these differences in consumption patterns are influenced by neighborhood food environments. Less understood is the role that SES differences in physical and social aspects of the home food environment play in consumption patterns.

Methods

Using data on 4^th grade children from the 2009–2011 Texas School Physical Activity and Nutrition (SPAN) study, we used mixed-effects regression models to test the magnitude of differences in the SPAN Health Eating Index (SHEI) by parental education as an indicator of SES, and the extent to which adjusting for measures of the home food environment, and measures of the neighborhood environment accounted for these SES differences.

Results

Small but significant differences in children’s SHEI by SES strata exist (-1.33 between highest and lowest SES categories, p<0.01). However, incorporating home food environment and neighborhood environment measures in this model eliminates these differences (-0.7, p=0.145). Home food environment explains a greater portion of the difference. Both social (mealtime structure) and physical aspects (food availability) of the home food environment are strongly associated with consumption of healthy and unhealthy foods.

Conclusions

Our findings suggest that modifiable parent behaviors at home can improve children’s eating habits and that the neighborhood may impact diet in ways other than through access to healthy food.

     

17-β estradiol attenuates ovariectomy-induced changes in cardiomyocyte contractile function via activation of AMP-activated protein kinase

Menopause increases the risk of cardiometabolic diseases in women. This circumstance is usually attributed to a deficiency in circulating estrogen levels although the underlying mechanism remains elusive. Given the pivotal role of AMP-activated protein kinase (AMPK) in the regulation of energy metabolism and cardiac function, this study was designed to examine the role of AMPK in estrogen deficiency and replacement-exerted cardiomyocyte responses. Adult female WT and AMPK kinase dead (KD) mice were subjected to bilateral ovariectomy (OVX) or sham operation. A cohort of ovariectomized mice received 17β-estradiol (E2) (40 μg/kg/day, i.p.) for 6 weeks. Mechanical and intracellular Ca²⁺ properties were evaluated including peak shortening (PS), time-to-PS (TPS), time-to-90%-relengthening (TR₉₀), and maximal velocity of shortening/relengthening (±dL/dt). Levels of AMPK, Akt JNK, ACC, SERCA, membrane Glut4, AS160 and PGC-1α were assessed using Western blot. OVX significantly decreased PS, ±dL/dt and intracellular Ca²⁺ rise in responsible to electric stimulus, prolonged TR₉₀ and intracellular Ca²⁺ decay without affecting TPS and resting intracellular Ca²⁺, the effects of which were reconciled by E2 replacement. Western blot analysis depicted that OVX suppressed phosphorylation of Akt AMPK and ACC although it promoted JNK phosphorylation, the effects of which were mitigated or significantly attenuated by E2 treatment in WT but not KD mice. Moreover, OVX procedure downregulated SERCA2a and membrane Glut4 while inhibiting AS160 phosphorylation without affecting PGC-1α levels. In vitro study revealed that E2 corrected cardiomyocyte contractile dysfunction elicited by OVX in cardiomyocytes from WT but not the AMPK kinase dead mice. Taken together, these data suggest that E2 treatment ameliorates estrogen deficiency-induced changes in cardiac contractile function possibly through an AMPK-dependent mechanism.     

Punishing parents: Child removal in the context of drug use

New amendments to child welfare policy in New South Wales turn a spotlight on parents who use drugs and raise concerns about adequate provision of services for families facing issues with alcohol and other drug use. Sections of the new legislation are explicitly focused on parents who use illicit drugs, expanding the reach of child protection services over expectant parents during pregnancy. This targeting of women who are ‘addicted’ highlights the ambiguous scientific and moral attention to drug use in pregnancy. It also raises practical questions about the potential for the legislation to increase stigma towards drug use and disproportionately affect vulnerable and disadvantaged families. [Olsen A. Punishing parents: Child removal in the context of drug use. Drug Alcohol Rev 2015;34:27–30]     

Imidacloprid induces morphological and molecular damages on testis of lizard (Podarcis sicula)

Ecotoxicology - The insecticide imidacloprid was evaluated under laboratory conditions in the adult male Italian wall lizards (Podarcis sicula) to assess its potential toxicity. By an acute oral...