Investigating surface binding effects: antibacterial efficacy of bound 8-hydroxyquinoline against Staphylococcus aureus and Escherichia coli.

AIMS: To investigate the binding of the antimicrobial compound 8-hydroxyquinoline (8HQ) to a material interface and to determine whether immobilization affects the antibacterial efficacy. METHODS AND RESULTS: The 8HQ derivative 5-carboxy-8-hydroxyquinoline (5C8HQ) was attached to silica beads through amide bond coupling at the carboxyl moiety of 5C8HQ. Attachment of 5C8HQ was confirmed using a combination of mass spectrometry, thermogravimetric analysis, colorimetric testing and Soxhlet extraction. Computational modelling results indicated that this substitution did not compromise the active sites on the molecule, whereas other positions on the ring system could potentially inhibit antimicrobial activity. The antibacterial effect of 8HQ and the 5C8HQ-modified silica complex against Escherichia coli 15597 (ATCC® 25922) and Staphylococcus aureus (ATCC 25923) was evaluated. CONCLUSIONS: The test results show that the immobilized 8HQ continues to exhibit antibacterial activity, however, quantifying the efficacy compared to free 8HQ bears further investigation. The expected antibacterial mechanism requires that the metal chelation site of 8HQ be retained and available after attachment to a surface. The retention of antibacterial activity after surface bonding represents a novel mechanism of action not previously reported. SIGNIFICANCE AND IMPACT OF THE STUDY: Recent changes in regulations due to environmental concerns prompted many companies and organizations to explore antimicrobial treatments that are chemically bound to the product. Chemically bonding biocidal compounds to a surface limits environmental release; however, molecular mechanisms that drive antibacterial activity when compounds are immobilized are limited. The results reported here demonstrate that the 8HQ reactive site retains antibacterial efficacy even after covalent attachment to a surface. This approach supersedes other antimicrobial treatments where the active component is gradually released from the material surface in order to elicit antimicrobial effects. This specific antibacterial activity of bound 8HQ represents a novel mechanism of action not previously reported, and a potential conduit to a new class of bound antimicrobial materials.

An automated approach to determine antibody endpoint titers for COVID-19 by an enzyme-linked immunosorbent assay.

While a variety of therapeutic options continue to emerge for COVID-19 treatment, convalescent plasma (CP) has been used as a possible treatment option early in the pandemic. One of the most significant challenges with CP therapy, however, both when defining its efficacy and implementing its approach clinically, is accurately and efficiently characterizing an otherwise heterogenous therapeutic treatment. Given current limitations, our goal is to leverage a SARS antibody testing platform with a newly developed automated endpoint titer analysis program to rapidly define SARS-CoV-2 antibody levels in CP donors and hospitalized patients. A newly developed antibody detection platform was used to perform a serial dilution enzyme-linked immunosorbent assay (ELISA) for immunoglobulin (Ig)G, IgM, and IgA SARS-CoV-2 antibodies. Data were then analyzed using commercially available software, GraphPad Prism, or a newly developed program developed in Python called TiterScape, to analyze endpoint titers. Endpoint titer calculations and analysis times were then compared between the two analysis approaches. Serial dilution analysis of SARS-CoV-2 antibody levels revealed a high level of heterogeneity between individuals. Commercial platform analysis required significant time for manual data input and extrapolated endpoint titer values when the last serial dilution was above the endpoint cutoff, occasionally producing erroneously high results. By contrast, TiterScape processed 1008 samples for endpoint titer results in roughly 14 minutes compared with the 8 hours required for the commercial software program analysis. Equally important, results generated by TiterScape and Prism were highly similar, with differences averaging 1.26 ± 0.2 percent (mean ± SD). The pandemic has created unprecedented challenges when seeking to accurately test large numbers of individuals for SARS-CoV-2 antibody levels with a rapid turnaround time. ELISA platforms capable of serial dilution analysis coupled with a highly flexible software interface may provide a useful tool when seeking to define endpoint titers in a high-throughput manner. Immunohematology 2021;37:33-43.While a variety of therapeutic options continue to emerge for COVID-19 treatment, convalescent plasma (CP) has been used as a possible treatment option early in the pandemic. One of the most significant challenges with CP therapy, however, both when defining its efficacy and implementing its approach clinically, is accurately and efficiently characterizing an otherwise heterogenous therapeutic treatment. Given current limitations, our goal is to leverage a SARS antibody testing platform with a newly developed automated endpoint titer analysis program to rapidly define SARS-CoV-2 antibody levels in CP donors and hospitalized patients. A newly developed antibody detection platform was used to perform a serial dilution enzyme-linked immunosorbent assay (ELISA) for immunoglobulin (Ig)G, IgM, and IgA SARS-CoV-2 antibodies. Data were then analyzed using commercially available software, GraphPad Prism, or a newly developed program developed in Python called TiterScape, to analyze endpoint titers. Endpoint titer calculations and analysis times were then compared between the two analysis approaches. Serial dilution analysis of SARS-CoV-2 antibody levels revealed a high level of heterogeneity between individuals. Commercial platform analysis required significant time for manual data input and extrapolated endpoint titer values when the last serial dilution was above the endpoint cutoff, occasionally producing erroneously high results. By contrast, TiterScape processed 1008 samples for endpoint titer results in roughly 14 minutes compared with the 8 hours required for the commercial software program analysis. Equally important, results generated by TiterScape and Prism were highly similar, with differences averaging 1.26 ± 0.2 percent (mean ± SD). The pandemic has created unprecedented challenges when seeking to accurately test large numbers of individuals for SARS-CoV-2 antibody levels with a rapid turnaround time. ELISA platforms capable of serial dilution analysis coupled with a highly flexible software interface may provide a useful tool when seeking to define endpoint titers in a high-throughput manner. Immunohematology 2021;37:33­43.

Control and formation mechanism of extended nanochannel geometry in colloidal mesoporous silica particles.

A large class of colloidal multi-micron mesoporous silica particles have well-defined cylindrical nanopores, nanochannels which self-assembled in the templated sol-gel process. These particles are of broad interest in photonics, for timed drug release, enzyme stabilization, separation and filtration technologies, catalysis, etc. Although the pore geometry and mechanism of pore formation of such particles has been widely investigated at the nanoscale, their pore geometry and its formation mechanism at a larger (extended) scale is still under debate. The extended geometry of nanochannels is paramount for all aforementioned applications because it defines accessibility of nanochannels, and subsequently, kinetics of interaction of the nanochannel content with the particle surrounding. Here we present both experimental and theoretical investigation of the extended geometry and its formation mechanism in colloidal multi-micron mesoporous silica particles. We demonstrate that disordered (and consequently, well accessible) nanochannels in the initially formed colloidal particles gradually align and form extended self-sealed channels. This knowledge allows to control the percentage of disordered versus self-sealed nanochannels, which defines accessibility of nanochannels in such particles. We further show that the observed aligning the channels is in agreement with theory; it is thermodynamically favored as it decreases the Gibbs free energy of the particles. Besides the practical use of the obtained results, developing a fundamental understanding of the mechanisms of morphogenesis of complex geometry of nanopores will open doors to efficient and controllable synthesis that will, in turn, further fuel the practical utilization of these particles.

The oral health of people with learning disabilities - a user-friendly questionnaire survey.

IMPETUS FOR ACTION: To conduct a user-friendly questionnaire survey of the oral health and service needs of adults with learning disabilities. SOLUTION: Researchers collaborated with local self-advocacy services to develop a questionnaire adapted from one used in a regional postal survey. The questionnaire, which covered dental status, oral health and dental services use, was sent to a random sample of people from the learning disability case register. OUTCOME: Of 2,000 questionnaires mailed, 117 were returned undelivered and 625 were completed (response rate 31.3%). The self-reported dental status of people with learning disabilities appeared similar to that of the 2008 postal survey of the general population in Sheffield. The major difference in dental status was 11.5% of people with learning disabilities wore upper dentures and 7.2% wore lower dentures, compared to 21.2% and 12.1% of the general population in Sheffield. CHALLENGES: Using the case register as a recruitment instrument may have excluded people with learning disabilities not registered. Time and finances only permitted one mailing. Analysis on the basis of deprivation could not be conducted. FUTURE IMPLICATIONS AND LEARNING POINTS: Contrary to current practice, it is possible to include people with learning disabilities in oral health surveys. A multidisciplinary team was essential for enabling the progression and implementation of inclusive research and for people with learning disabilities and their supporters to engage meaningfully. This level of collaboration appears necessary if we are committed to ensuring that people with learning disabilities and their supporters are made visible to policy and decision-makers.

The effect of antenatal lifestyle advice for women who are overweight or obese on secondary measures of neonatal body composition: the LIMIT randomised trial.

OBJECTIVE: To evaluate the effect of providing antenatal dietary and lifestyle advice on neonatal anthropometry, and to determine the inter-observer variability in obtaining anthropometric measurements. DESIGN: Randomised controlled trial. SETTING: Public maternity hospitals across metropolitan Adelaide, South Australia. POPULATION: Pregnant women with a singleton gestation between 10(+0) and 20(+0) weeks, and body mass index (BMI) ≥25 kg/m(2). METHODS: Women were randomised to either Lifestyle Advice (comprehensive dietary and lifestyle intervention over the course of pregnancy including dietary, exercise and behavioural strategies, delivered by a research dietician and research assistants) or continued Standard Care. Analyses were conducted using intention-to-treat principles. MAIN OUTCOME MEASURES: Secondary outcome measures for the trial included assessment of infant body composition using body circumference and skinfold thickness measurements (SFTM), percentage body fat, and bio-impedance analysis of fat-free mass. RESULTS: Anthropometric measurements were obtained from 970 neonates (488 Lifestyle Advice Group, and 482 Standard Care Group). In 394 of these neonates (215 Lifestyle Advice Group, and 179 Standard Care Group) bio-impedance analysis was also obtained. There were no statistically significant differences identified between those neonates born to women receiving Lifestyle Advice and those receiving Standard Care, in terms of body circumference measures, SFTM, percentage body fat, fat mass, or fat-free mass. The intra-class correlation coefficient for SFTM was moderate to excellent (0.55-0.88). CONCLUSIONS: Among neonates born to women who are overweight or obese, anthropometric measures of body composition were not modified by an antenatal dietary and lifestyle intervention.

The acceptability of healthcare: from satisfaction to trust.

The assessment of healthcare quality increasingly emphasises lay acceptability, as evidenced by the emergence of patient satisfaction and patient-centred care in the literature and in policy. In this paper we aim to provide a conceptual overview of acceptability and propose ways to enhance its assessment. Firstly, we map how acceptability's importance in quality assessments has increased and how the term acceptability has been used as synonymous with patient satisfaction, despite it being a broader concept. We then critique the concept of patient satisfaction and its measurement and challenge its use as an indicator of acceptability and quality. By drawing on our research and those of others, the second half of the paper describes how trust in clinicians and health services has emerged as a related concept, including a theoretical discussion of trust in healthcare outlining how it can be built, undermined and abused. We propose trust as an alternative indicator of acceptability in healthcare quality and review its measurement. Finally, we consider how healthcare policy may impact on trust and make recommendations for future research.

Maternal body size prior to pregnancy, gestational diabetes and weight gain: associations with insulin resistance in children at 9-10 years.

AIMS: To investigate whether maternal body size pre-pregnancy, gestational diabetes and weight gain are independently associated with subsequent insulin resistance in children; and to examine the potential mediating role of child's body size in any associations. METHODS: At 9-10 years, 443 children took part in a follow-up of a prospective cohort. Of those, 163 children elected to provide a fasting blood sample and child insulin resistance was estimated by homeostasis model assessment. Generalized linear models with log link function and Gaussian family were used to assess associations with antenatal exposures. Potential confounders were considered as well as the role of the child's size. RESULTS: Prior to pregnancy, 23% of mothers were overweight and another 17% obese. All women were screened for gestational diabetes, with 6% diagnosed. On average, women gained an estimated 14 kg during pregnancy. Gestational diabetes was positively associated with child insulin resistance. In addition, maternal pre-pregnancy body mass index (BMI) was associated with child insulin resistance in a non-linear manner: a positive, progressive association was observed until BMI of 30 kg/m² was reached, but not thereafter. Estimated gestational weight gain was not associated with child insulin resistance. These findings were not accounted for by size of the child at birth or at 9-10 years. CONCLUSIONS: Maternal body size prior to pregnancy is positively associated with increases in child insulin resistance, at least until the 'obese' category is reached. This is independent of gestational diabetes and not mediated by body size of the child, suggesting genetic and/or developmental programming origins.

Performance of the plant-based repellent TT-4302 against mosquitoes in the laboratory and field and comparative efficacy to 16 mosquito repellents against Aedes aegypti (Diptera: Culicidae).

Repellent efficacy of the plant-based repellent, TT-4302 (5% geraniol), was compared with 16 other products in laboratory arm-in-cage trials against Aedes aegypti (L). Eight repellents (Badger, BioUD, Burt's bees, California Baby, Cutter Natural, EcoSMART, Herbal Armor, and SkinSmart) exhibited a mean repellency below 90% to Ae. aegypti at 0.5 h after application. Three repellents (Buzz Away Extreme, Cutter Advanced, and OFF! Botanicals lotion) fell below 90% repellency 1.5 h after application. TT-4302 exhibited 94.7% repellency 5 h posttreatment, which was a longer duration than any of the other repellents tested. The positive control, 15% DEET (OFF! Active), was repellent for 3 h before activity dropped below 90%. Additional arm-in-cage trials comparing TT-4302 with 15% DEET were carried out against Anopheles quadrimaculatus Say. At 6 h after treatment, TT-4302 provided 95.2% repellency while DEET exhibited 72.2%. In North Carolina field trials, TT-4302 provided 100% repellency 5 h after application against Aedes albopictus Skuse while DEET provided 77.6% repellency. These results demonstrate that TT-4302 is an efficacious plant-based repellent that provides an extended duration of protection compared with many other commercially available products.

Activity of the plant-based repellent, TT-4302 against the ticks Amblyomma americanum, Dermacentor variabilis, Ixodes scapularis and Rhipicephalus sanguineus (Acari: Ixodidae).

The plant-based repellent TT-4302 (5 % geraniol) was compared to deet (15 %) in laboratory two-choice bioassays against the ticks Amblyomma americanum, Dermacentor variabilis, Ixodes scapularis, and Rhipicephalus sanguineus. At 2.5 and 3.5 h after treatment of filter paper with TT-4302, 100 % repellency was observed for all species at both time points with the exception of I. scapularis at the 3.5 h evaluation where repellency was 95.8 %. Deet was 100 % repellent at both time points for D. variabilis and R. sanguineus and was 100 % repellent at the 2.5 h evaluation for I. scapularis. Repellency of deet to A. americanum was 88.9 and 95.8 % at 2.5 and 3.5 h, respectively which was not significantly different than that of TT-4302. No significant difference against I. scapularis was observed between TT-4302 and deet at 3.5 h after treatment where deet was 87.5 % repellent. A variant of TT-4302, TT-4228 was tested in the laboratory against A. americanum and was compared to deet (15 %) in field trials against wild populations of ticks in North Carolina, USA. In the laboratory, TT-4228 was 94.4 and 87.5 % repellent at 2.5 and 3.5 h after treatment, respectively. In the field where the predominant tick species was A. americanum, significantly fewer ticks were collected from socks worn by human volunteers that were treated with TT-4228 compared to those treated with deet 2.5 or 3.5 h after treatment. Significantly fewer ticks were recovered from socks treated with TT-4228 than their paired untreated controls 2.5 or 3.5 h after treatment and repellencies were 90 and 70 %, respectively. Fewer ticks were collected from deet-treated compared to their paired untreated socks 2.5 h after application; however, no significant difference was found in the number of ticks collected from deet-and untreated socks 3.5 h after treatment.

Assessing acute thermal assays as a rapid screening tool for coral restoration.

Escalating environmental threats to coral reefs coincides with global advancements in coral restoration programs. To improve long-term efficacy, practitioners must consider incorporating genotypes resilient to ocean warming and disease while maintaining genetic diversity. Identifying such genotypes typically occurs under long-term exposures that mimic natural stressors, but these experiments can be time-consuming, costly, and introduce tank effects, hindering scalability for hundreds of nursery genotypes used for outplanting. Here, we evaluated the efficacy of the acute Coral Bleaching Automated Stress System (CBASS) against long-term exposures on the bleaching response of Acropora cervicornis, the dominant restoration species in Florida's Coral Reef. Comparing bleaching metrics, Fv/Fm, chlorophyll, and host protein, we observed similar responses between the long-term heat and the CBASS treatment of 34.3 °C, which was also the calculated bleaching threshold. This suggests the potential of CBASS as a rapid screening tool, with 90% of restoration genotypes exhibiting similar bleaching tolerances. However, variations in acute bleaching phenotypes arose from measurement timing and experiment heat accumulation, cautioning against generalizations solely based on metrics like Fv/Fm. These findings identify the need to better refine the tools necessary to quickly and effectively screen coral restoration genotypes and determine their relative tolerance for restoration interventions.

Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment.

AIM: The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. METHODS: Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. RESULTS: Circulating TB12, HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p < 0.001), but not in insulin-treated women. CONCLUSIONS: Total, but not bioavailable, vitamin B12 stores were depleted during pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation.

Spanish version of the Sleep Self-Report (SSR): factorial structure and psychometric properties.

BACKGROUND: The Sleep Self-Report (SSR) is a questionnaire initially created for use with a sample from the USA to assess sleep patterns and problems in school-aged children. The objective of this study was to validate the SSR among a Spanish sample. METHODS: Participants were 1228 Spanish children from 8 to 12 years of age who completed the questionnaires at school anonymously. RESULTS: Internal consistency was good (ω = 0.85). Convergent validity with anxiety (r = 0.54) and perceived welfare (r = -0.53) measures, and divergent validity with a measure of academic performance and positive influence of peers (r = -0.22) were acceptable. Exploratory analysis suggested a factorial structure composed by four subscales: sleep quality, sleep anxiety, bedtime refusal and sleep routines. Confirmatory analysis indicated a good fit for the model (RMSEA = 0.04; GFI = 0.95; AGFI = 0.93; χ(2)/gl = 2.48). CONCLUSIONS: The SSR has demonstrated to have good psychometric properties in the Spanish-speaking sample of children. The factorial structure supported by exploratory and confirmatory analysis examines the most relevant areas of sleep in children. The satisfactory psychometric properties support the use of the Spanish version of the SSR by researchers and clinicians.

Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation.

Osteoclasts are bone-resorbing cells derived from haematopoietic precursors of the monocyte-macrophage lineage. Mice lacking Fos (encoding c-Fos) develop osteopetrosis due to an early differentiation block in the osteoclast lineage. c-Fos is a component of the dimeric transcription factor activator protein-1 (Ap-1), which is composed mainly of Fos (c-Fos, FosB, Fra-1 and Fra-2) and Jun proteins (c-Jun, JunB and JunD). Unlike Fra-1 (encoded by Fosl1), c-Fos contains transactivation domains required for oncogenesis and cellular transformation. The mechanism by which c-Fos exerts its specific function in osteoclast differentiation is not understood. Here we show by retroviral-gene transfer that all four Fos proteins, but not the Jun proteins, rescue the differentiation block in vitro. Structure-function analysis demonstrated that the major carboxy-terminal transactivation domains of c-Fos and FosB are dispensable and that Fra-1 (which lacks transactivation domains) has the highest rescue activity. Moreover, a transgene expressing Fra-1 rescues the osteopetrosis of c-Fos-mutant mice in vivo. The osteoclast differentiation factor Rankl (also known as TRANCE, ODF and OPGL; refs 8-11) induces transcription of Fosl1 in a c-Fos-dependent manner, thereby establishing a link between Rank signalling and the expression of Ap-1 proteins in osteoclast differentiation.

Diet-induced paternal obesity in the absence of diabetes diminishes the reproductive health of two subsequent generations of mice.

BACKGROUND: Obesity and related conditions, notably subfertility, are increasingly prevalent. Paternal influences are known to influence offspring health outcome, but the impact of paternal obesity and subfertility on the reproductive health of subsequent generations has been overlooked. METHODS: A high-fat diet (HFD) was used to induce obesity but not diabetes in male C57Bl6 mice, which were subsequently mated to normal-weight females. First-generation offspring were raised on a control diet and their gametes were investigated for signs of subfertility. Second-generation offspring were generated from both first generation sexes and their gametes were similarly assessed. RESULTS: We demonstrate a HFD-induced paternal initiation of subfertility in both male and female offspring of two generations of mice. Furthermore, we have shown that diminished reproductive and gamete functions are transmitted through the first generation paternal line to both sexes of the second generation and via the first generation maternal line to second-generation males. Our previous findings that founder male obesity alters the epigenome of sperm, could provide a basis for the developmental programming of subfertility in subsequent generations. CONCLUSIONS: This is the first observation of paternal transmission of diminished reproductive health to future generations and could have significant implications for the transgenerational amplification of subfertility observed worldwide in humans.

'Too withdrawn' or 'too friendly': considering social vulnerability in two neuro-developmental disorders.

In some neuro-developmental disorders, the combined effect of intellectual disability and atypicalities of social cognition may put individuals at increased vulnerability in their social environment. The neuro-developmental disorders Williams syndrome, characterised by 'hypersociability', and autism spectrum disorders, characterised by 'social withdrawal', are at two extremes of atypical social functioning in humans. In this article, we use Williams syndrome and autism spectrum disorders as exemplars to demonstrate how atypicalities of social cognition may contribute to social vulnerability in these populations. The lives of individuals with both these disorders are marred by an increased risk of social isolation, bullying, unsteady relationships, employment difficulties and abuse. While different behavioural interventions have been tried to improve social functioning in these populations, there has been great variability in their success. Finally, we discuss different issues regarding social independence of these individuals; including employment, safety and decision making.

Pharmacokinetics and dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles.

A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg/kg (100 µL/kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (t(lag) ) of 0.333 h in the 1.3 mg/kg group and 0 in the other two groups. The mean C(max) increased with dose and were 2.28, 2.67, and 4.71 ng/mL in the 1.3, 2.6 and 5.2 mg/kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg/kg dose groups, respectively. The mean AUC(0-LLOQ) from lowest to highest dose groups were 157, 268, and 645 ng·h/mL and were dose proportional with a R(2) value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg/kg (50 µL/kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg/kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg/kg group.

The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth.

Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming.

Nuclear corrections in neutrino-nucleus deep inelastic scattering and their compatibility with global nuclear parton-distribution-function analyses.

We perform a global χ² analysis of nuclear parton distribution functions using data from charged current neutrino-nucleus (νA) deep-inelastic scattering (DIS), charged-lepton-nucleus (ℓ(±)A) DIS, and the Drell-Yan (DY) process. We show that the nuclear corrections in νA DIS are not compatible with the predictions derived from ℓ(±)A DIS and DY data. We quantify this result using a hypothesis-testing criterion based on the χ² distribution which we apply to the total χ² as well as to the χ² of the individual data sets. We find that it is not possible to accommodate the data from νA and ℓ(±)A DIS by an acceptable combined fit. Our result has strong implications for the extraction of both nuclear and proton parton distribution functions using combined neutrino and charged-lepton data sets.

Safety evaluation and treatment affect of LY2190416, a CB-1 antagonist/inverse agonist in growing beagle dogs.

The objective of this study was to assess the safe use of LY2190416, a cannabinoid receptor 1 receptor antagonist/inverse agonist, for obesity management in dogs. Twenty-four clinically normal young beagle dogs were administered LY2190416 at doses of 3, 9, or 18 mg/kg or placebo, orally, once daily for 13 weeks. Food consumption and body weight were determined, and dogs were evaluated for changes in hematology, clinical chemistry, urinalysis, and serum cortisol. LY2190416 had no significant effect on hematology, clinical chemistry, urinalysis, and serum cortisol. All dogs consumed 100% of their entire daily allowance throughout the study. All dogs gained weight during the study, but treated dogs gained less than control dogs by the end of the study. During the first month, dogs exhibited a dose-dependent decrease in rate of weight gain (19.7 g/day for control dogs vs. 10.6 g/day for the 18 mg/kg dose group). LY2190416 was found to be safe at doses up to 18 mg/kg administered daily for 3 months. Results suggest that LY2190416 decreases rate of weight gain without affecting appetite or causing significant adverse health effects in normal growing dogs. Possible mechanisms for a proposed metabolic effect are discussed.

Comparison of pharmacodynamics between insulin glargine 100 U/mL and insulin glargine 300 U/mL in healthy cats.

Insulin glargine (IGla) is a synthetic human-recombinant insulin analog that is used routinely in people as a q24h basal insulin. The 300 U/mL (U300) formulation of IGla is associated with longer duration of action and less within-day variability, making it a better basal insulin compared with the 100 U/mL (U100) formulation. We hypothesized that in healthy cats, IGlaU300 has a flatter time-action profile and longer duration of action compared with IGlaU100. Seven healthy neutered male, purpose-bred cats were studied in a randomized, crossover design. Pharmacodynamics of IGlaU100 and IGlaU300 (0.8 U/kg, subcutaneous) were determined by the isoglycemic clamp method. The time-action profile of IGlaU300 was flatter compared with IGlaU100 as demonstrated by lower peak (5.6 ± 1.1 mg/kg/min vs 8.3 ± 1.9 mg/kg/min, respectively; P = 0.04) with no difference in total metabolic effect (ME; P = 0.7) or duration of action (16.8 h ± 4.7 h vs 13.4 h ± 2.6 h; P = 0.2). The greater fraction of ME in the 12- to 24-h period postinjection (35 ± 23% vs 7 ± 8% respectively; P = 0.048) and lower intraday GIR% variability (7.8 ± 3.7% vs 17.4 ± 8.2% respectively; P = 0.03) supports a flatter time-action profile of IGlaU300. There were no differences in onset and end of the action. In summary, although both formulations have a similar duration of action that is well below 24 h, the ME of IGlaU300 is more evenly distributed over a 24 h period in healthy cats, making it a better candidate for once-daily injection in diabetics compared with IGlaU100.