Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL(-1) against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.

A prospective cohort study of antipsychotic medications in pregnancy: the first 147 pregnancies and 100 one year old babies

BACKGROUND: Many women diagnosed with varying psychiatric disorders take antipsychotic medications during pregnancy. The safety of antipsychotic medications in pregnancy is largely unknown.

METHODS: We established the National Register of Antipsychotic Medications in Pregnancy in 2005. Women who are pregnant and taking an antipsychotic medication are interviewed every 6 weeks during pregnancy and then followed until their babies are one year old. The baby's progress is closely followed for the first year of life.

FINDINGS: As of April 18 2012, 147 pregnancies had been followed through to completion. There were 142 live births and data is available for 100 one year old babies. 18% of babies were born preterm, with a higher dose of antipsychotic medication correlating to an increased likelihood of premature delivery; 43% of babies required special care nursery or intensive care after birth; 37% had any degree of respiratory distress and 15% of babies developed withdrawal symptoms. Congenital anomalies were seen in eight babies. Most pregnancies resulted in the birth of live, healthy babies. The use of mood stabilisers or higher doses of antipsychotics during pregnancy increased the likelihood of babies experiencing respiratory distress or admission to Special Care Nursery or Neonatal Intensive Care Units.

CONCLUSION: There is a great need for safety and efficacy information about the use of antipsychotic medications in pregnancy. Live, healthy babies are the most common outcome following the use of antipsychotic medication in pregnancy, but clinicians should be particularly mindful of neonatal problems such as respiratory distress.

Tissue distribution of lignans in rats in response to diet, dose−response, and competition with isoflavones

This paper investigates the occurrence and distribution of the lignan metabolites enterodiol (END) and enterolactone (ENL) and the isoflavone daidzein (DAID) in rat tissues by use of liquid chromatography−electrospray ionization mass spectrometry (LC−ESI/MSn) following a variety of dietary regimes. Furthermore, we examined the dose−response and distribution of END and ENL in liver, testes, prostate, and lung, and we investigated the effects of competition between lignans and isoflavones on metabolite distribution. In liver, testes, prostate, and lung tissue, dose-related increases in END concentration were observed. In the testes, coadministration of 60 mg/kg secoisolariciresinol diglycoside (SDG) with 60 mg/kg isoflavones produced alterations in the resulting metabolite profile, causing increased END concentration and decreased DAID concentration. Results indicate lignan accumulation in tissues occurs, and coadministration of lignans with isoflavones affects the metabolite profile, with effects dependent on tissue type.

Dose-response associations between screen time and overweight among youth

Objective. To examine dose-response associations between screen time and overweight, independent of physical activity and dietary intake.

Methods. Participants were 580 Dutch youth (13 years; 48% boys). Body mass index, waist circumference and skinfold thickness at four sites determined weight status. Questionnaires examined television viewing and computer use, participation in organized sport and high caloric snack and sugar-containing beverage consumption.

Results. There were no significant associations among boys. Compared with girls spending less than two hours/day in screen time, those who spent three to four hours/day were more likely to be classified as overweight by waist circumference (odds ratio [OR]=3.4; 95% confidence intervals [CI]=1.1-10.7; p=0.03), and this likelihood increased substantially among those spending more than four hours/day (OR=5.5; 95% CI=2.1-14.1; p≤0.0001).

Conclusions. Girls who spend three or more hours/day in screen time are at increased risk of being classified as overweight by waist circumference.

Reconstruction of in vivo time-evolving neuroendocrine dose - response properties unveils admixed deterministic and stochastic elements

Homeostasis in the intact organism is achieved implicitly by repeated incremental feedback (inhibitory) and feedforward (stimulatory) adjustments enforced via intermittent signal exchange. In separated systems, neurohormone signals act deterministically on target cells via quantifiable effector-response functions. On the other hand, in vivo interglandular signaling dynamics have not been estimable to date. Indeed, experimentally isolating components of an interactive network definitionally disrupts time-sensitive linkages. We implement and validate analytical reconstruction of endogenous effector-response properties via a composite model comprising (i) a deterministic basic feedback and feedforward ensemble structure; (ii) judicious statistical allowance for possible stochastic variability in individual biologically interpretable dose–response properties; and (iii) the sole data requirement of serially observed concentrations of a paired signal (input) and response (output). Application of this analytical strategy to a prototypical neuroendocrine axis in the conscious uninjected horse, sheep, and human (i) illustrates probabilistic estimation of endogenous effector dose–response properties; and (ii) unmasks statistically vivid (2- to 5-fold) random fluctuations in inferred target-gland responsivity within any given pulse train. In conclusion, balanced mathematical formalism allows one to (i) reconstruct deterministic properties of interglandular signaling in the intact mammal and (ii) quantify apparent signal-response variability over short time scales in vivo. The present proof-of-principle experiments introduce a previously undescribed means to estimate time-evolving signal-response relationships without isotope infusion or pathway disruption.

Evaluating irradiation dose for sterility induction and quality control of mass-produced fruit fly Bactrocera tryoni (Diptera : Tephritidae)

The sterile insect technique has been routinely used to eradicate fruit fly Bactrocera tryoni (Froggatt) incursions. This study considers whether fly quality in a mass-rearing facility can be improved by reducing irradiation doses, without sacrificing reproductive sterility. Pupae were exposed to one of five target irradiation dose ranges: 0, 40-45, 50-55, 60-65, and 70-75 Gy. Pupae were then assessed using routine quality control measures: flight ability, sex ratio, longevity under nutritional stress, emergence, and reproductive sterility. Irradiation did not have a significant effect on flight ability or sex ratio tests. Longevity under nutritional stress was significantly increased at 70-75 Gy, but no other doses differed from 0 Gy. Emergence was slightly reduced in the 50-55, 60-65, and 70-75 Gy treatments, but 40-45 Gy treatments did not differ from 0 Gy, though confounding temporal factors complicate interpretation. Reproductive sterility remained acceptable (> 99.5%) for all doses--40-45 Gy (99.78%), 50-55 Gy (100%), 60-65 Gy (100%), and 70-75 Gy (99.99%). We recommend that B. tryoni used in sterile insect technique releases be irradiated at a target dose of 50-55 Gy, providing improved quality and undiminished sterility in comparison with the current 70-75 Gy standard while also providing a substantial buffer against risk of under dosing.

Prespecified dose-response analysis for A Very Early Rehabilitation Trial (AVERT)

OBJECTIVE:
Our prespecified dose-response analyses of A Very Early Rehabilitation Trial (AVERT) aim to provide practical guidance for clinicians on the timing, frequency, and amount of mobilization following acute stroke.

METHODS:
Eligible patients were aged ≥18 years, had confirmed first (or recurrent) stroke, and were admitted to a stroke unit within 24 hours of stroke onset. Patients were randomized to receive very early and frequent mobilization, commencing within 24 hours, or usual care. We used regression analyses and Classification and Regression Trees (CART) to investigate the effect of timing and dose of mobilization on efficacy and safety outcomes, irrespective of assigned treatment group.

RESULTS:
A total of 2,104 patients were enrolled, of whom 2,083 (99.0%) were followed up at 3 months. We found a consistent pattern of improved odds of favorable outcome in efficacy and safety outcomes with increased daily frequency of out-of-bed sessions (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.18, p < 0.001), keeping time to first mobilization and mobilization amount constant. Increased amount (minutes per day) of mobilization reduced the odds of a good outcome (OR 0.94, 95% CI 0.91 to 0.97, p < 0.001). Session frequency was the most important variable in the CART analysis, after prognostic variables age and baseline stroke severity.

CONCLUSION:
These data suggest that shorter, more frequent mobilization early after acute stroke is associated with greater odds of favorable outcome at 3 months when controlling for age and stroke severity.

CLASSIFICATION OF EVIDENCE:
This study provides Class III evidence that shorter, more frequent early mobilization improves the chance of regaining independence after stroke.

Vitamin D status of women in the Geelong Osteoporosis Study : association with diet and casual exposure to sunlight

Objective: To assess vitamin D intake and casual exposure to sunshine in relation to serum 25-hydroxyvitamin D (25OHD) levels.

Design: Cross-sectional study of a population-based, random sample of women aged 20-92 years, assessed between 1994 and 1997.

Setting and participants: 861 women from the Barwon Statistical Division (population, 218 000), which includes the city of Geelong (latitude 38° south) in Victoria.

Main outcome measures: Vitamin D intake; serum 25OHD level; season of assessment; exposure to sunshine.

Results: Median intake of vitamin D was 1.2 μg/day (range, 0.0-11.4 μg/day). Vitamin D supplements, taken by 7.9% of participants, increased intake by 8.1% to 1.3 μg/day (range, 0.0-101.2 μg/day) (P < 0.001). A dose-response relationship in serum 25OHD levels was observed for sunbathing frequency before and after adjusting for age (P < 0.05). During winter (May-October), serum 25OHD levels were dependent on vitamin D intake (partial r2 = 0.01; P < 0.05) and were lower than during summer (November-April) (age-adjusted mean, 59 nmol/L [95% CI, 57-62] v 81 nmol/L [95% CI, 78-84]; P < 0.05). No association was detected between serum 25OHD and vitamin D intake during summer. The prevalences of low concentrations of serum 25OHD were, for <28 nmol/L, 7.2% and 11.3% overall and in winter, respectively; and, for <50 nmol/L, 30.0% and 43.2% overall and in winter, respectively.

Conclusions: At latitude 38° south, the contribution of vitamin D from dietary sources appears to be insignificant during summer. However, during winter vitamin D status is influenced by dietary intake. Australia has no recommended dietary intake (RDI) for vitamin D, in the belief that adequate vitamin D can be obtained from solar irradiation alone. Our results suggest that an RDI may be needed.

Vitamin D-fortified milk achieves the targeted serum 25-hydroxyvitamin D concentration without affecting that of parathyroid hormone in New Zealand toddlers

For young children, the level of vitamin D required to ensure that most achieve targeted serum 25-hydroxyvitamin D [25(OH)D] ≥50 nmol/L has not been studied. We aimed to investigate the effect of vitamin D-fortified milk on serum 25(OH)D and parathyroid hormone (PTH) concentrations and to examine the dose–response relationship between vitamin D intake from study milks and serum 25(OH)D concentrations in healthy toddlers aged 12–20 mo living in Dunedin, New Zealand (latitude 46°S). Data from a 20-wk, partially blinded, randomized trial that investigated the effect of providing red meat or fortified toddler milk on the iron, zinc, iodine, and vitamin D status in young New Zealand children (n = 181; mean age 17 mo) were used. Adherence to the intervention was assessed by 7-d weighed diaries at wk 2, 7, 11, 15, and 19. Serum 25(OH)D concentration was measured at baseline and wk 20. Mean vitamin D intake provided by fortified milk was 3.7 μg/d (range, 0–10.4 μg/d). After 20 wk, serum 25(OH)D concentrations but not PTH were significantly different in the milk groups. The prevalence of having a serum 25(OH)D <50 nmol/L remained relatively unchanged at 43% in the meat group, whereas it significantly decreased to between 11 and 15% in those consuming fortified study milk. In New Zealand, vitamin D intake in young children is minimal. Our findings indicate that habitual consumption of vitamin D-fortified milk providing a mean intake of nearly 4 μg/d was effective in achieving adequate year-round serum 25(OH)D for most children.

Effects of acute alkalosis and acidosis on performance

Ingestion of agents that modify blood buffering action may affect high-intensity performance. Here we present a meta-analysis of the effects of acute ingestion of three such agents - sodium bicarbonate, sodium citrate and ammonium chloride - on performance and related physiological variables (blood bicarbonate, pH and lactate). A literature search yielded 59 useable studies with 188 observations of performance effects. To perform the mixed- model meta-analysis, all performance effects were converted into a percentage change in mean power and were weighted using standard errors derived from exact p-values, confidence limits (CLs) or estimated errors of measurement. The fixed effects in the meta-analytic model included the number of performance-test bouts (linear), test duration (log linear), blinding (yes/no), competitive status (athiete/nonathlete) and sex (male/female). Dose expressed as buffering mmoL/kg/body mass (BM) was included as a strictly proportional linear effect interacted with all effects except blinding. Probabilistic inferences were derived with reference to thresholds for small and moderate effects on performance of 0.5% and 1.5%, respectively. Publication bias was reduced by excluding study estimates with a standard error >2.7%. The remaining 38 studies and 137 estimates for sodium bicarbonate produced a possibly mod- erate performance enhancement of 1.7% (90% CL ± 2.0%) with a typical dose of 3.5mmoL/kg/BM (-0.3g/kgIBM) in a single 1-minute sprint, following blinded consumption by male athletes. In the 16 studies and 45 estimates for sodium citrate, a typical dose of l.SmmoL/kgIBM (-0.5gIkgJBM) had an unclear effect on performance of 0.0% (±1.3%), while the five studies and six estimates for ammonium chloride produced a possibly moderate impairment of 1.6% (±1.9%) with a typical dose of 5.5mmoL/kgIBM (-0.3glkg/BM). Study and subject characteristics had the following modifying small effects on the enhancement of performance with sodium bicarbonate: an increase of 0.5% (±0.6%) with a 1 mmoL/kg/BM increase in dose; an increase of 0.6% (±0.4%) with five extra sprint bouts; a reduction of 0.6% (±0.9%) for each 10-fold increase in test duration (e.g. 1-10 minutes); reductions of 1.1% (± 1 .1%) with nonathletes and 0.7% (±1.4%) with females. Unexplained variation in effects between research settings was typically ± 1.2%. The only noteworthy effects involving physiological variables were a small correlation between performance and pre-exercise increase in blood bicarbonate with sodium bi- carbonate ingestion, and a very large correlation between the increase in blood bicarbonate and time between sodium citrate ingestion and exercise. The approximate equal and opposite effects of sodium bicarbonate and am- monium chloride are consistent with direct performance effects of pH, but sodium citrate appears to have some additional metabolic inhibitory effect. Important future research includes studies of sodium citrate ingestion several hours before exercise and quantification of gastrointestinal symptoms with sodium bicarbonate and citrate. Although individual responses may vary, we recommend ingestion of 0.3-0.5 glkg/BM sodium bicarbonate to improve mean power by 1.7% (±2.0%) in high-intensity races of short duration. ABSTRACT FROM AUTHOR