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Reports on the preparation of a class of low-melting N,N'-dialkylimidazolium salts with carborane counterions, some of the most inert and least nucleophilic anions. Indication of the main importance of the alkylation pattern on the imidazolium cation on the melting point; Low melting point due to packing inefficiency of the cation.

The family name of the co-author of the article mentioned above was incorrectly presented. The correct name should have been "Annett Helleskov Rasmussen" instead of "Annett Rasmussen Helleskov". [ABSTRACT FROM AUTHOR]

Depression among pregnant women living with HIV (WLWH) in sub-Saharan Africa leads to poor pregnancy and HIV outcomes. This cross-sectional analysis utilized enrollment data from a randomized trial (Mobile WAChX, NCT02400671) in six Kenyan public maternal and child health clinics. Depressive symptoms were assessed with the Patient Health Questionnaire-9 (PHQ-9), stigma with the Stigma Scale for Chronic Illness, and intimate partner violence (IPV) with the Abuse Assessment Screen. Correlates of moderate-to-severe depressive symptoms ("depression", PHQ-9 score ≥10) were assessed using generalized estimating equation models clustered by facility. Among 824 pregnant WLWH, 9% had depression; these women had more recent HIV diagnosis than those without depression (median 0.4 vs. 2.0 years since diagnosis, p =.008). Depression was associated with HIV-related stigma (adjusted Prevalence Ratio [aPR]:2.36, p =.025), IPV (aPR:2.93, p =.002), and lower social support score (aPR:0.99, p =.023). Using population-attributable risk percent to estimate contributors to maternal depression, 81% were attributable to stigma (27%), recent diagnosis (24%), and IPV (20%). Integrating depression screening and treatment in prevention of mother-to-child HIV transmission programs may be beneficial, particularly in women recently diagnosed or reporting stigma and IPV. [ABSTRACT FROM AUTHOR]

Background: Despite improved policies to prevent mother-to-child HIV transmission (MTCT), adherence to maternal antiretroviral therapy (ART) and infant Nevirapine prophylaxis (NVP) is low in South Africa. We describe ART adherence amongst a cohort of HIV-positive mothers and HIV-exposed but uninfected infants from 6 weeks until 18 months post-delivery and identify risk factors for nonadherence.Methods: Data were collected in 2012-2014 through a nationally representative survey of PMTCT effectiveness. Mother-infant pairs were enrolled during the infant's first immunization visit at 6 weeks. Mothers and HIV-exposed infants (2811 pairs) were followed to 18 months at 3-month intervals. Mothers who self-reported being on ART at 6 weeks postpartum (N = 1572 (55.9%)) and infants on NVP at 6 weeks (N = 2370 (84.3%)) were eligible for this analysis and information about their adherence was captured at each interview they attended thereafter. We defined nonadherence within each 3-month interval as self-report of missing > 5% of daily ART/NVP doses, estimated adherence using a Cox survival curve with Andersen & Gill setup for recurring events, and identified risk factors for nonadherence with an extended Cox regression model (separately for mothers and infants) in Stata 13. Results are not nationally representative as this is a subgroup analysis of the follow-up cohort.Results: Amongst mothers on ART at 6 weeks postpartum, cumulative adherence to maternal ART until 18 months was 63.4%. Among infants on NPV at 6 weeks postpartum, adherence to NVP was 74.5%.. Risk factors for nonadherence to maternal ART, controlling for other factors, included mother's age (16-24 years vs. ≥34 years, adjusted Hazard Ratio (aHR): 1.9, 95% CI: 1.4-2.5), nondisclosure of HIV status to anyone (nondisclosure vs. disclosure: aHR: 1.7, 95% CI: 1.3-2.1), and timing of ART initiation (initiated ART after delivery vs. initiated ART before delivery: aHR: 1.6, 95% CI: 1.3-2.0). Provincial variation was seen in nonadherence to infant NVP, controlling for other factors.Conclusion: Maintaining ART adherence until 18 months postpartum remains a crucial challenge, with maternal ART adherence among the six week maternal ART cohort below 65% and infant NVP adherence among breastfeeding infants in this cohort below 75%.This is gravely concerning, given the global policy shift to lifelong ART amongst pregnant and lactating women, and the need for extended infant prophylaxis amongst mothers who are not virally suppressed. Our findings suggest that young mothers and mothers who do not disclose their status should be targeted with messages to improve adherence, and that late maternal ART initiation (after delivery) increases the risk of maternal nonadherence. [ABSTRACT FROM AUTHOR]

Background: The 2016 'Start Free, Stay Free, AIDS Free' global agenda, builds on the 2011-2015 'Global Plan'. It prioritises 22 countries where 90% of the world's HIV-positive pregnant women live and aims to eliminate vertical  transmission of HIV (EMTCT) and to keep mothers alive. By 2019, no Global Plan priority country had achieved EMTCT; however, 11 non-priority countries had. This paper synthesises the characteristics of the first four countries validated for EMTCT, and of the 21 Global Plan priority countries located in Sub-Saharan Africa (SSA). We consider what drives vertical transmission of HIV (MTCT) in the 21 SSA Global Plan priority countries.Methods: A literature review, using PubMed, Science direct and the google search engine was conducted to obtain global and national-level information on current HIV-related context and health system characteristics of the first four EMTCT-validated countries and the 21 SSA Global Plan priority countries. Data representing only one clinic, hospital or region were excluded. Additionally, key global experts working on EMTCT were contacted to obtain clarification on published data. We applied three theories (the World Health Organisation's building blocks to strengthen health systems, van Olmen's Health System Dynamics framework and Baral's socio-ecological model for HIV risk) to understand and explain the differences between EMTCT-validated and non-validated countries. Additionally, structural equation modelling (SEM) and linear regression were used to explain associations between infant HIV exposure, access to antiretroviral therapy and two outcomes: (i) percent MTCT and (iii) number of new paediatric HIV infections per 100 000 live births (paediatric HIV case rate).Results: EMTCT-validated countries have lower HIV prevalence, less breastfeeding, fewer challenges around leadership, governance within the health sector or country, infrastructure and service delivery compared with Global Plan priority countries. Although by 2016 EMTCT-validated countries and Global Plan priority countries had adopted a public health approach to HIV prevention, recommending lifelong antiretroviral therapy (ART) for all HIV-positive pregnant and lactating women, EMCT-validated countries had also included contact tracing such as assisted partner notification, and had integrated maternal and child health (MCH) and sexual and reproductive health (SRH) services, with services for HIV infection, sexually transmitted infections, and viral hepatitis. Additionally, Global Plan priority countries have limited data on key SRH indicators such as unmet need for family planning, with variable coverage of antenatal care, HIV testing and triple antiretroviral therapy (ART) and very limited contact tracing. Structural equation modelling (SEM) and linear regression analysis demonstrated that ART access protects against percent MTCT (p<0.001); in simple linear regression it is 53% protective against percent MTCT. In contrast, SEM demonstrated that the case rate was driven by the number of HIV exposed infants (HEI) i.e. maternal HIV prevalence (p<0.001). In linear regression models, ART access alone explains only 17% of the case rate while HEI alone explains 81% of the case rate. In multiple regression, HEI and ART access accounts for 83% of the case rate, with HEI making the most contribution (coef. infant HIV exposure=82.8, 95% CI: 64.6, 101.1, p<0.001 vs coef. ART access=-3.0, 95% CI: -6.2, 0.3, p=0.074).Conclusion: Reducing infant HIV exposure, is critical to reducing the paediatric HIV case rate; increasing ART access is critical to reduce percent MTCT. Additionally, our study of four validated countries underscores the importance of contact tracing, strengthening programme monitoring, leadership and governance, as these are potentially-modifiable factors. [ABSTRACT FROM AUTHOR]

KBP is a Dual Amylin and Calcitonin Receptor Agonist (DACRA). DACRAs have shown efficacy on weight loss and glucose control in rats. However, it is unclear whether the maximum effect has been reached. High Fat Diet (HFD, 60% fat) fed male Sprague-Dawley rats entered a dose escalation regimen ending at 5 (normal dose), 50 or 500 µg/kg daily KBP (n=10/group). Male ZDF (fa/fa) rats received identical doses without dose escalation in a preventive study setup (n=9-10/group). In HFD rats, KBP treatment resulted in a transient decrease in food intake at each dose escalation step. At study end, KBP treatment resulted in a significant weight loss of 77-94 g (13-16%, P<0.0001) compared to vehicle. Furthermore, KBP reduced the weight of adipose tissues (P<0.05). Surprisingly, there was a trend of 5 µg/kg KBP causing a more pronounced adipose-specific weight loss compared to 500 µg/kg (subcutaneous 1.7 vs. 0.7 g, visceral 4.1 vs. 2.5 g adipose weight loss). During two OGTTs, KBP treatment significantly lowered blood glucose (BG) and insulin levels compared to vehicle indicating improved glucose tolerance. Lastly, 24h fecal energy loss increased by KBP treatment, though this trend was absent when accounting for food intake and total feces output. In ZDF rats, KBP treatment significantly improved fasting BG (endpoint vehicle 29.5, endpoint KBP average 18.3 mmol/L, tAUC P<0.0001) and HbA1c (vehicle 10.2%, KBP average 6.1%, P<0.0001) compared to vehicle, with no significant difference between treatment groups. Importantly, fasting and non-fasting insulin levels of KBP-treated rats were increased compared to vehicle in a dose-dependent manner during an OGTT, resulting in lowered BG levels. Increased insulin levels suggest that KBP protects against the known β-cell degradation in the ZDF model. Taken together, these data suggest that higher doses of KBP than previously investigated may preserve insulin secretion to a greater extent. With respect to weight loss, no additional benefit was observed from the high doses. Disclosure: N. Sonne: None. A.T. Larsen: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience. [ABSTRACT FROM AUTHOR]

Potent dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity. Notably, DACRAs activate the receptors for a prolonged time period resulting in metabolic effects superior to those of amylin. This indicates that a less frequent dosing could be feasible, although the tolerability is a question mark. In this study, we compared daily dosing to dosing every other day to characterize the tolerability and efficacy of these regimens. High fat fed Sprague Dawley rats were treated 9 weeks by s.c. injections of the DACRA KBP in two different dosing intervals corresponding to a daily dose of 1.5 nmol/kg. KBP was dosed either daily (q.d., 1.5 nmol/kg) or every other day (q.a.d, 3 nmol/kg). After 3 and 8 weeks of treatment oral glucose tolerance tests were performed 24 hours post injection of treatment. Both treatments resulted in an initial reduction in food intake. KBP q.d. resulted in a transient reduction in food intake that normalized within the first 10 days of treatment, while KBP q.a.d resulted in fluctuating food intake throughout the study. The fluctuations reflected the dosing intervals resulting in a marked suppression of food intake following dosing, however food intake normalized on non-dosing days. This difference is reflected in the accumulated food intake, where KBP q.a.d tended to have a lower food intake than KBP q.d. Both treatments resulted in sustained and significant weight loss as well as reductions in the overall adiposity. Interestingly, KBP q.a.d tended to induce a larger weight loss than KBP q.d., albeit with fluctuations reflecting the dosing intervals. In addition, KBP dose dependently improved oral glucose tolerance with significant reduced insulin levels both after 3 and 8 weeks of treatment. In conclusion, dosing KBP every other day positively affects the efficacy confirming that less frequent dosing with KBP could be feasible. Disclosure: A.T. Larsen: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. N. Sonne: None. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience. [ABSTRACT FROM AUTHOR]

Dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of T2D and obesity due to their beneficial effects on body weight, blood glucose and insulin sensitivity, effects that are superior to those of amylin. However, it is unknown how dual receptor activation by DACRAs compare to activation of either the amylin or the calcitonin receptor in vivo, and to what extent the calcitonin receptor is involved in the beneficial metabolic effects of DACRAs. In this study, we compared the effects of a highly potent DACRA, KBP, rat amylin (rAMY), rat calcitonin (rCT) and the combination of rAMY and rCT on long term efficacy on body weight, food intake and glucose tolerance. High fat fed Sprague Dawley rats were treated 4 weeks with KBP (5 µg/kg/day), rAMY (300 µg/kg/day), rCT, (300 µg/kg/day) and the combination of rAMY and rCT (300+300 µg/kg/day). To compensate for the different activity profiles, peptides were delivered by continuous subcutaneous infusion. Chronic treatment with KBP, rAMY and the combination of rAMY and rCT resulted in a 17%, 11% and 8% vehicle-corrected weight loss, respectively, while rCT alone had no effect. All treatments significantly reduced food intake in the initial phase of the study, while KBP and rAMY resulted in a prolonged reduced food intake. Interestingly, KBP was superior in terms of body weight loss (p<0.001) even though rAMY and KBP reduced the accumulated food intake equally. Moreover, KBP and rAMY improved oral glucose tolerance with significantly reduced insulin levels. Again, KBP was superior to the other treatments (p<0.001). In conclusion, dual activation of amylin and calcitonin receptors by KBP has beneficial effects on body weight and glucose tolerance superior to that of activating either receptor alone. This was despite correcting for the different activity of the peptides. Understanding of the dual or single receptor activation mechanisms is high pharmaceutical interest. Disclosure: A.T. Larsen: None. N. Sonne: None. K.V. Andreassen: Employee; Self; Nordic Bioscience. M.A. Karsdal: Employee; Self; Nordic Bioscience. K. Henriksen: Employee; Self; Nordic Bioscience. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Nordic Bioscience. Other Relationship; Self; Nordic Bioscience. [ABSTRACT FROM AUTHOR]

Simple Summary: Postweaning diarrhea due to pathogenic Escherichia coli is a common issue in swine production. Specific strains of Bacillus subtilis have been shown to reduce the incidence and severity of diarrhea and thereby improve the growth of nursery pigs. The current study aims to demonstrate the effect of B. subtilis supplementation of two strains selected to reduce the effects of pathogenic E. coli to nursery pig diets on growth performance, blood biochemicals, fecal metabolites, and microbiome. B. subtilis supplementation to nursery diets at 1.875 × 105 CFU/g diet improved early postweaning growth performance, increased blood glucose levels, and fecal short-chain fatty acid production, which is beneficial for the gut health and development for nursery pigs. But a higher dose of B. subtilis did not affect pig growth and fecal short-chain fatty acid production. These results suggest that B. subtilis supplementation to nursery pig diets at 1.875 × 105 CFU/g diet is beneficial for growth and gut health, whereas a higher dose of the probiotic may not be as effective as the recommended level. This experiment was conducted to evaluate the effects of dietary supplementation level of a two-strain Bacillus subtilis probiotic on growth performance, blood parameters, fecal metabolites, and microbiome in nursery pigs. A total of 54 weaned piglets were allotted to three treatments in three replicate pens with six pigs/pen for a 28 d feeding trial. The treatments were as follows: control: no probiotic supplementation; Pro1x: B. subtilis supplementation at 1.875 × 105 CFU/g diet; and Pro10x: B. subtilis supplementation at 1.875 × 106 CFU/g diet. Body weight at d 14 postweaning (p = 0.06) and average daily gain for d 0 to 14 postweaning (p < 0.05) were greater in the Pro1x treatment than in the other treatments. Blood glucose levels were greater in both probiotic treatments than in the control treatment at d 14 postweaning (p < 0.05). In the fecal short-chain fatty acid (SCFA) concentrations, the butyrate concentrations were greater in the Pro1x treatment than in the other treatments (p < 0.05), and the acetate, propionate, and total SCFA concentrations were greater in the Pro1x treatment than in the Pro10x treatment (p < 0.05). The beta diversity of fecal microbiome composition at d 14 postweaning based on Unweighted Unifrac analysis was dissimilar between the Pro1x and Pro10x treatments (p < 0.05). In conclusion, dietary B. subtilis supplementation of two strains selected to reduce effects of pathogenic Escherichia coli to nursery diets at 1.875 × 105 CFU/g diet improved the growth rate in the early postweaning period, increased fecal SCFA concentrations and altered the fecal microbial community composition. A higher dose of B. subtilis did not improve the performance parameters over those of the control piglets. [ABSTRACT FROM AUTHOR]

Dual amylin and calcitonin receptor agonists (DACRAs) are effective treatments for obesity and type 2 diabetes (T2D). They provide beneficial effects on body weight, glucose control, and insulin action. However, whether DACRAs protect against diabetesrelated kidney damage remains unknown. We characterize the potential of long-acting DACRAs (KBP-A, Key Bioscience Peptide- A) as a treatment for T2D-related pathological alterations of the kidney extracellular matrix (ECM) in Zucker diabetic fatty rats (ZDF). We examined levels of endotrophin (profibrotic signaling molecule reflecting collagen type VI formation) and tumstatin (matrikine derived from collagen type IVα3) in serum and evaluated kidney morphology and collagen deposition in the kidneys. We included a study in obese Sprague--Dawley rats to further investigate the impact of KBP-A on ECM biomarkers. In ZDF vehicles, levels of endotrophin and tumstatin increased, suggesting disease progression along with an increase in blood glucose levels. These rats also displayed damage to their kidneys, which was evident from the presence of collagen formation in the medullary region of the kidney. Interestingly, KBP-A treatment attenuated these increases, resulting in significantly lower levels of endotrophin and tumstatin than the vehicle. Levels of endotrophin and tumstatin were unchanged in obese Sprague--Dawley rats, supporting the relation to diabetes-related kidney complications. Furthermore, KBP-A treatment normalized collagen deposition in the kidney while improving glucose control. These studies confirm the beneficial effects of DACRAs on biomarkers associated with kidney fibrosis. Moreover, these antifibrotic effects are likely associated with improved glucose control, highlighting KBP-A as a promising treatment of T2D and its related late complications. [ABSTRACT FROM AUTHOR]

Syntheses of Rh complexes of the phosphine-amido-silane SiNP ligand are reported. The reaction of the parent (SiNP)H ligand (4) with 0.5 equiv. [(COE)RhCl]2 (COE = cis-cyclooctene) in the presence of NaN(SiME3)2 resulted in the formation of (SiNP)Rh(COE) (5). Compound 5 was converted to a series of (SiNP)Rh(P(OR)3) complexes 6–10 (R = Ph, iPr, nBu, Et, or Me) by treatment with the corresponding phosphite. NMR and XRD structural data, as well as the DFT computational analysis indicate that compounds 5–10 are divided into two structural Types (A and B), differing in the nature of the interaction of the Si–H bond of the SiNP ligand with Rh. [ABSTRACT FROM AUTHOR]

Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P<0.05), polymorphomonuclear cell infiltration (P<0.05), and white matter damage (P<0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P<0.01 and P<0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 552–563. doi:10.1038/sj.jcbfm.9600370; published online 12 July 2006 [ABSTRACT FROM AUTHOR]

A new class of selective α1 adrenoceptor antagonists derived from the antipsychotic drug sertindole is described. The most potent and selective compound 1-(2-{4-[5-aminomethyl-1-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidinyl}ethyl)-2-imidazolidinone (11) binds with 0.50 nM affinity for α1 adrenergic receptors and with more than 44 times lower affinity for dopamine D2,D3, D4 and serotonin 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors. The molecular features providing high affinity for adrenergic α1 receptors and high selectivity towards dopamine D2 and serotonin 5-HT2A and 5-HT2C receptors are discussed. [Copyright &y& Elsevier]

The long-term consequences of transient neonatal hypoglycemia are sparsely studied. We performed a follow-up of a cohort of neonates with blood glucose recordings < 1.7 mmol/L (< 30 mg/dL), treated with > 2.5 mmol/L (> 45 mg/dL), compared with healthy siblings. Exclusion criteria were gestational age < 35 weeks, severe asphyxia, head injury, and other cerebral diseases. In 71 children with neonatal hypoglycemia and 32 control siblings, Wechsler IV cognitive test, Movement ABC-2 test, and Child Behavior Checklist were performed at mean age 7.75 and 9.17 years, respectively. No significant changes were detected for cognitive function by using Wechsler IV or for behavior by using Child Behavior Checklist. In univariate analysis, the hypoglycemia group had lower age-adjusted fine motor scores by using the Movement ABC-2 test compared with control siblings, 42.6 ± 31.2 vs. 57.2 ± 30.8 percentile (p = 0.03). In the sibling-paired analysis, the decrease in total motor score was highly significant, p = 0.009, driven by a decrease in fine motor score, p = 0.008. In the hypoglycemia group, adjusted analysis showed a lower fine motor function for boys, β = − 16.4, p = 0.048. Conclusion: Neonatal hypoglycemia treated with > 2.5 mmol/L was associated with lower fine motor scores within the normal range, particularly in boys. No associations with cognitive function or behavior were detected. What is Known: • Transient neonatal hypoglycemia is associated with acute neurologic dysfunction and long-term neurodevelopment impairment in 18 months of age. What is New: • Neonatal hypoglycemia treated with > 2.5 mmol/L is associated with lower fine motor function within the normal range, particularly in boys, but not to changes in cognitive function or behavior. [ABSTRACT FROM AUTHOR]

Development of a properly functioning gastrointestinal tract (GIT) at an early age is critical for the wellbeing and lifetime productivity of dairy cattle. The role of early microbial colonization on GIT development in neonatal cattle and the associated molecular changes remain largely unknown, particularly for the small intestine. In this study, we performed artificial dosing of exogenous rumen fluid during the early life of the calf, starting at birth through the weaning transition at 8 wk. Six calves were included in this study. At 8 wk of age, tissue from the ileum was collected and subjected to host transcriptome and microbial metatranscriptome analysis using RNA sequencing. A total of 333 genes showed significant differential expression (DE) (fold-change ≥2; adjusted P < 0.1, mean read-count ≥10) between the treated and control calves. Gene ontology analysis indicated that these DE genes are predominantly associated with processes related to the host immune response (P < 0.0001). Association analysis between the host gene expression and the microbial genus abundance identified 57 genes as having significant correlation with the ileum microbial genera (P < 0.0001). Of these, three genes showed significant association with six microbial genera: lysozyme 2 (LYZ2), fatty acid binding protein 5 (FABP5), and fucosyltransferase (FUT1). Specifically, the profound increase in expression of LYZ2 in treated calves suggests the initiation of antibacterial activity and innate response from the host. Despite the limitation of a relatively small sample size, this study sheds light on the potential impact of early introduction of microbes on the small intestine of calves. [ABSTRACT FROM AUTHOR]

Treatment of the complex 1 Cp*Ru(NO)(OTf) 2 (OTf = OSO 2 CF 3 , Cp* = η 5 -C(CH 3 ) 5 ) with neat 2-propanol results in the rapid quantitative formation of the Ru(0) complex [Cp*Ru(μ-NO)] 2 and (CH 3 ) 2 C O. Formation of H 2 and CHDCl 2 is detected when the reaction between 1 and 2-propanol occurs in CDCl 3 , indicating possible formation of a short-lived metal hydride species. Similar results are observed upon treatment of 1 with ethanol and methanol, with formation of acetaldehyde and formaldehyde, respectively. The kinetics of the oxidation of 2-propanol by complex 1 is studied by 1 H NMR spectroscopy in CH 2 Cl 2 at variable temperatures and the reaction is found to be first-order in complex 1 and in 2-propanol. The kinetic isotope effect for the reaction of 1 with (CD 3 ) 2 CD-OD at −11 °C is determined to be k H / k D = 2.0 (3). A mechanism for alcohol oxidation by electrophilic ruthenium (II) complexes via a β-hydrogen elimination step is proposed. The pre-equilibrium exchange step between complex Cp*Ru(NO)(OTf) 2 ( 1 ) and alcohol-coordinated species is examined by 19 F and 1 H NMR spectroscopy in CH 2 Cl 2 solution, where triflate substitution is found to be exothermic and entropically unfavorable. The synthesis and solid state structure of the chelate-stabilized complex diol salt [Cp*Ru(NO)(HO–CH 2 CH 2 –OH)][2OTf] are discussed. [ABSTRACT FROM AUTHOR]

Understanding how genetics influences obesity, brain activity and eating behaviour will add important insight for developing strategies for weight-loss treatment, as obesity may stem from different causes and as individual feeding behaviour may depend on genetic differences. To this end, we examined how an obesity risk allele for the FTO gene affects brain activity in response to food images of different caloric content via functional magnetic resonance imaging (f MRI). Thirty participants homozygous for the rs9939609 single nucleotide polymorphism were shown images of low- or high-calorie food while brain activity was measured via f MRI. In a whole-brain analysis, we found that people with the FTO risk allele genotype ( AA) had increased activity compared with the non-risk ( TT) genotype in the posterior cingulate, cuneus, precuneus and putamen. Moreover, higher body mass index in the AA genotype was associated with reduced activity to food images in areas important for emotion (cingulate cortex), but also in areas important for impulse control (frontal gyri and lentiform nucleus). Lastly, we corroborate our findings with behavioural scales for the behavioural inhibition and activation systems. Our results suggest that the two genotypes are associated with differential neural processing of food images, which may influence weight status through diminished impulse control and reward processing. [ABSTRACT FROM AUTHOR]

Abstract: The present review starts describing nitroxyl (azanone, 1HNO) biological relevance, in relation with NO physiology, from a chemical reactivity perspective. After a description of commonly used azanone donors and their characteristics, the overlapping molecular targets of HNO and NO are presented with an emphasis on heme models and proteins. We present also a brief description of metalloporphyrins and the main characteristics of their nitrosyl complexes, and then describe the reactivity of azanone towards Fe, Ru, Mn and Co porphyrins, briefly mentioning heme proteins, and focusing on 1HNO trapping and its discrimination from NO. A comparison of reaction kinetics and/or nitrosyl product stability with non-heme models is also described. We illustrate the promiscuity of iron porphyrins, the stabilization properties of Ru and the discriminating behavior of Mn and Co porphyrins, which allows the design of optical and electrochemical selective 1HNO sensors. Finally, a comparative analysis and future perspectives are presented, focusing on the in vivo reactivity of azanone and its putative endogenous production. [Copyright &y& Elsevier]

Synthesis, structure, and NMR spectroscopic data for [(closo-CB11H6Br6)PtMe3] are reported. This neutral platinum(IV) complex contains the closo-CB11H6Br6– anion bonded to the trimethylplatinum(IV) cation via three boron-bound bromines. Closo-CB11H6Br6–, which often acts as weakly coordinating or even non-coordinating anion, adopts here a role still very rare for this anion: it acts as a tripodal capping ligand enabling a pseudo-octahedral geometry at a d6 metal center. Three bromines from the lower hemisphere of the hexahalogenated carboranate coordinate to Pt(IV), and distortions from ideal octahedral angles at Pt are marginal (<3°). Pt-Br bond lengths are 2.7279(18), 2.7129(17), and 2.7671(18) Å. Using the 2JPtH coupling constant of Pt-bonded methyl groups (79.0 Hz) as indicator of the donor strength of the tripodal cap, the prediction is obtained that closo-CB11H6Br6– is a relatively weak donor toward the trimethylplatinum(IV) cation. Ligand competition equilibria can be expected to depend on both the intrinsic donor strengths of competing ligands and on the effects of charge and geometry. We observe that closo-CB11H6Br6– is capable of replacing acetone from Me3Pt(acetone)3+, whereas BF4– counterion is unable to replace acetone under similar conditions. [ABSTRACT FROM AUTHOR]

Abstract: The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K i =5 nM) and competitive antagonism (K b =8 nM) at dopamine D4 receptors combined with potent 5-HT uptake inhibition (IC50 =3.2 nM) and moderate α1-adrenoceptor affinity (K i =45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED50 =4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED50 =13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability. [Copyright &y& Elsevier]

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO. [ABSTRACT FROM AUTHOR]

Reported here are self-exchange reactions between iron 2,2'-bi(tetrahydro)pyrimidine (H[sub 2]bip) complexes and between cobalt 2,2'-biimidazoline (H[sub 2]bim) complexes. The ¹H NMR resonances of [Fe[sup II](H[sub 2-] bip)[sub 3]][sup 2+] are broadened upon addition of [Fe[sup III](H[sub 2]bip)[sub 3]][sup 3+], indicating that electron self-exchange occurs with k[sub Fe,e-] = (1.1 ± 0.2) × 10[sup 5] M[sup -1] s[sup -1] at 298 K in CD[sub 3]CN. Similar studies of [Fe[sup II](H[sub 2]bip)[sub 3]][sup 2+] plus [Fe[sup III](Hbip)(H[sup 2-] bip)[sub 2]][sup 2+] indicate that hydrogen-atom self-exchange (proton-coupled electron transfer) occurs with k[sub Fe, H...] = (1.1 ± 0.2) × 10[sup 4] M[sup -1] S[sup -1] under the same conditions. Both self-exchange reactions are faster at lower temperatures, showing small negative enthalpies of activation: δH[sup ‡](e[sup -]) = -2.1 ± 0.5 kcal mol[sup -1] (288320 K) and δH[sup †](H...) = 1.5 ± 0.5 kcal mol[sup -1] (260-300 K). This behavior is concluded to be due to the faster reaction of the low-spin states of the iron complexes, which are depopulated as the temperature is raised. Below about 290 K, rate constants for electron self-exchange show the more normal decrease with temperature. There is a modest kinetic isotope effect on H-atom self-exchange of 1.6 ± 0.5 at 298 K that is close to that seen previously for the fully high-spin iron biimidazoline complexes. The difference in the measured activation parameters, Ea[sup D] - Ea[sup H], is -1.2 ± 0.8 kcal mo1[sup -1], appears to be inconsistent with a semiclassical view of the isotope effect, and suggests extensive tunneling. Reactions of [Co(H[sub 2]bim)[sub 3]][sup 2+]-d[sub 24] with [Co(H[sub 2]bim)[sub 3]][sup 3+] or [Co(Hbim)(H[sub 2]bim)[sub 2]][sup 2+] occur with scrambling of ligands indicating inner-sphere processes. The self-exchange rate constant for outer-sphere electron... [ABSTRACT FROM AUTHOR]

Large, inert, weakly basic carborane anions of the icosahedral type CHB[sub 11]R[sub 5]X[sub 6]- (R = H, Me; X = CI, Br) allow ready isolation and structural characterization of discrete salts of the solvated proton, [H(solvent)[sub x]][CHB[sub 11]lR[sub 5]X[sub 6]], (solvent = common O-atom donor). These oxonium ion Brensted acids are convenient reagents for the tuned delivery of protons to organic solvents with a specified number of donor solvent molecules and with acidities leveled to those of the chosen donor solvent. They have greater thermal stability than the popular [H(OEt[sub 2])[sub 2]][BAr[sup F]] acids based on fluorinated tetraphenylborate counterions because carborane anions can sustain much higher levels of acidity. When organic O-atom donors such as diethyl ether, tetrahydrofuran, benzophenone, and nitrobenzene are involved, the coordination number of the proton (x) in [H(solvent)[sub x]][sup +] is two. A mixed species involving the [H(H[sub 2]O)(diethyl ether)][sup +] ion has also been isolated. These solid-state structures provide expectations for the predominant molecular structures of solvated protons in solution and take into account that water is an inevitable impurity in organic solvents. The O···O distances are all short, lying within the range from 2.35 to 2.48 Å. They are consistent with strong, linear O···H···O hydrogen bonding. Density functional theory calculations indicate that all H(solvent)[sub 2][sup +] cations have low barriers to movement of the proton within an interval along the O···H···O trajectory, i.e., they are examples of so-called SSLB H-bonds (short, strong, low-barrier). Unusually broadened IR bands, diagnostic of SSLB H-bonds, are observed in these H(solvent)[sub 2][sup +] cations. [ABSTRACT FROM AUTHOR]

The title structure, [Ru2(C10H15)2(NO)2], consists of the two Ru atoms doubly bridged via the N atoms of the two NO groups, with two pentamethylcyclopentadienyl (Cp*) rings protruding away from the bridged system on opposite sides. The asymmetric unit contains two independent dimer molecules with an average Ru—Ru distance of 2.538 (7) Å and an average Ru—N—Ru angle of 97.2 (3)°. The compound was obtained as the product of a facile reaction between Cp*Ru(NO)(OSO2CF3)2 and excess neat 2-propanol. The crystals were grown from CH2Cl2 solution at ambient temperature under a nitrogen atmosphere. [ABSTRACT FROM AUTHOR]

Cancer patients undergo long periods of treatment and follow-up, and it is challenging to keep track of appointments, treatment plans etc. This paper report from a study involving 41 patients and next-of-kin focusing on their strategies for managing the patient journey. Most patients take an active role, employing a variety of tools. The national patient portal is seen as useful for accessing information and keeping an overview but does not alone meet their information needs.

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for the treatment of type 2 diabetes and obesity due to their beneficial effects on body weight, glucose control, and insulin action. However, how the metabolic benefits are maintained after long-lasting treatment is unknown. This study investigates the long-term anti-obesity and anti-diabetic treatment efficacy of the DACRA KBP-336 alone and combined with the GLP-1 analog semaglutide. Zucker diabetic Sprague Dawley (ZDSD) rats with obesity and diabetes received KBP-336 (4.5 nmol/kg Q3D), semaglutide (50 nmol/kg Q3D), or the combination for 7 mo, and the treatment impact on body weight, food intake, glucose control, and insulin action was evaluated. Furthermore, serum levels of the cardiac fibrosis biomarker endotrophin were evaluated. KBP-336, semaglutide, and the combination lowered body weight significantly compared with the vehicle, with the combination inducing a larger and more sustained weight loss than either monotherapy. All treatments resulted in reduced fasting blood glucose levels and HbA1c levels and improved glucose tolerance compared with vehicle-treated rats. Furthermore, all treatments protected against lost insulin secretory capacity and improved insulin action. Serum levels of endotrophin were significantly lowered by KBP-336 compared with vehicle. This study shows the benefit of combining KBP-336 and semaglutide to obtain significant and sustained weight loss, as well as improved glucose control. Furthermore, KBP-336-driven reductions in circulating endotrophin indicate a clear reduction in the risk of complications. Altogether, KBP-336 is a promising candidate for the treatment of obesity and type 2 diabetes both alone and in combination with GLP-1 analogs. NEW & NOTEWORTHY These studies describe the benefit of combining dual amylin and calcitonin receptor agonists (DACRA) with semaglutide for long-term treatment of obesity and type 2 diabetes. Combination treatment induced sustained weight loss and improved glucose control. A DACRA-driven reduction in a serological biomarker of cardiac fibrosis indicated a reduced risk of complications. These results highlight DACRAs as a promising candidate for combination treatment of obesity and type 2 diabetes and related long-term complications.

Objective: To evaluate effectiveness of a standardized patient actor (SP) training intervention to improve quality of preexposure prophylaxis (PrEP) services for adolescent girls and young women (AGYW) in Kenya., Design: Cluster randomized trial and mystery shopper evaluation., Methods: Twelve of 24 maternal child health and family planning facilities were randomized to SP training. Providers at intervention facilities participated in 2-day training in adolescent health, PrEP guidelines, values clarification, and communication skills, followed by role-playing and de-briefing with trained actors. Control facilities received standard national training. The primary outcome was quality of care, assessed by unannounced SPs (USPs) or "mystery shoppers" blinded to intervention arm. Quality was measured in two domains: guideline adherence and communication skills. Intent to treat analysis compared postintervention quality scores by randomization arm, clustering on facility, and adjusting for baseline scores and USP., Results: Overall, 232 providers consented to USP visits, and 94 providers completed the training. Following training, USPs posed as AGYW seeking PrEP in 142 encounters (5-6 encounters per site). The mean quality score was 73.6% at intervention sites and 58.4% at control sites [adjusted mean difference = 15.3, 95% confidence interval (CI): 9.4-21.1, P  < 0.001]. Mean guideline adherence scores were 57.2% at intervention sites and 36.2% at control sites (adjusted mean difference = 21.0, 95% CI: 12.5-29.4, P  < 0.001). Mean communication scores were 90.0% at intervention sites and 80.5% at control sites (adjusted mean difference = 9.5, 95% CI: 5.5-13.6, P  < 0.001)., Conclusions: SP training significantly improved quality of PrEP care for AGYW in Kenya. Incorporating SP training and unannounced SP evaluation could improve PrEP uptake among AGYW., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats., Methods: We evaluated KBP-336's effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology., Results: After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues., Conclusion: Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect., (© 2024. The Author(s).)

Background and Objectives: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue., Methods: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336., Results: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and β-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT., Conclusions: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Purpose: Insulin therapies for Type 1 diabetes (T1D) have limitations, such as glucose fluctuations, hypoglycaemia, and weight gain. Only pramlintide is approved with insulin. However, its short half-life limits efficacy, requiring multiple daily injections and increasing hypoglycaemia risk. New strategies are needed to improve glycaemic control. Dual amylin and calcitonin receptor agonists are potent insulin sensitizers developed for Type 2 diabetes (T2D) as they improve glucose control, reduce body weight, and attenuate hyperglucagonemia. However, it is uncertain if they could be used to treat T1D., Experimental Approach: Sprague Dawley rats received a single intravenous injection of streptozotocin (STZ) (50 mg·kg -1 ) to induce T1D. Humulin (1 U/200 g·day -1 or 2 U/200 g·day -1 ) was continuously infused, while half of the rats received additional KBP-336 (4.5 nmol·kg -1 Q3D) treatment. Bodyweight, food intake, and blood glucose were monitored throughout the study. An oral glucose tolerance test was performed during the study., Key Results: Treatment with Humulin or Humulin + KBP-336 improved the health of STZ rats. Humulin increased body weight in STZ rats, but KBP-336 attenuated these increases and maintained a significant weight loss. The combination exhibited greater blood glucose reductions than Humulin-treated rats alone, reflected by improved HbA1c levels and glucose control. The combination prevented hyperglucagonemia, reduced amylin levels, and increased pancreatic insulin content, indicating improved insulin sensitivity and beta-cell preservation., Conclusion and Implications: The insulin sensitizer KBP-336 lowered glucagon secretion while attenuating insulin-induced weight gain. Additionally, KBP-336 may prevent hypoglycaemia and improve insulin resistance, which could be a significant advantage for individuals with T1D seeking therapeutic benefits., (© 2024 British Pharmacological Society.)