A neotropical perspective on the uniqueness of the Holocene among interglacials.

Understanding how tropical systems have responded to large-scale climate change, such as glacial-interglacial oscillations, and how human impacts have altered those responses is key to current and future ecology. A sedimentary record recovered from Lake Junín, in the Peruvian Andes (4085 m elevation) spans the last 670,000 years and represents the longest continuous and empirically-dated record of tropical vegetation change to date. Spanning seven glacial-interglacial oscillations, fossil pollen and charcoal recovered from the core showed the general dominance of grasslands, although during the warmest times some Andean forest trees grew above their modern limits near the lake. Fire was very rare until the last 12,000 years, when humans were in the landscape. Here we show that, due to human activity, our present interglacial, the Holocene, has a distinctive vegetation composition and ecological trajectory compared with six previous interglacials. Our data reinforce the view that modern vegetation assemblages of high Andean grasslands and the presence of a defined tree line are aspects of a human-modified landscape.

Effects of Fermented Papaya Preparation (FPP) on Safety Outcomes in Older Adults - A Short Report of a Placebo-Controlled Clinical Trial.

Fermented Papaya Preparation (FPP®) has shown antioxidative and anti-inflammatory effects in preclinical and clinical aging studies. However, clinical trials are needed to fully evaluate the safety of FPP® in moderate-functioning, generally healthy older adults. In this randomized (9g/day of FPP® or placebo), crossover design study, we enrolled 30 older moderate-functioning older adults (70-100 years old). The participants completed both a treatment and a placebo condition. After eight (8) weeks on each of these regimens (with a 4-week wash-out period in between), participants had their venous blood drawn for assessment of blood chemistries, metabolic outcomes and inflammatory biomarkers. Participants were asked to report any adverse events during the course of the study and complete post-treatment outcome assessments for anthropometric and metabolic outcomes. The major finding related to safety was that there were no adverse changes in blood chemistries and few adverse events in the FPP® condition, which did not differ from placebo (p>0.05). There were no serious adverse effects in either condition. Twenty-nine (29) participants (mean age 78.2±5.3 yrs) completed the study with 94% adherence to the dosing regimen. There were no significant effects of FPP® on anthropometric and metabolic outcomes. In addition, no effects on markers of inflammation were observed. Our trial demonstrates FPP® supplementation is safe and feasible in adults ages 70 years and older. Based on these findings and the positive effects FPP has demonstrated in previous trials, future trials should examine the effects of FPP® in older adults with impaired health status and/or older adults who may have insufficient anti-oxidant protection due to their genetic background.

Distal-less 3 haploinsufficiency results in elevated placental oxidative stress and altered fetal growth kinetics in the mouse.

Distal-less 3 (Dlx3)(-/-) mice die at E9.5 presumably due to an abnormal placental phenotype including reduced placental vasculature and secretion of placental growth factor. To examine the role of Dlx3 specifically within the epiblast, Dlx3 conditional knockout mice were generated using an epiblast-specific Meox2(CreSor) allele. Dlx3(-/fl), Meox2(CreSor) animals were born at expected frequencies and survived to weaning providing indirect evidence that loss of Dlx3 within the trophoectoderm plays a critical role in fetal survival in the Dlx3(-/-) mouse. We next examined the hypothesis that loss of a single Dlx3 allele would have a negative impact on placental and fetal fitness. Dlx3(+/-) mice displayed reduced fetal growth beginning at E12.5 compared with Dlx3(+/+) controls. Altered fetal growth trajectory occurred coincident with elevated oxidative stress and apoptosis within Dlx3(+/-) placentas. Oral supplementation with the superoxide dismutase mimetic, Tempol, rescued the fetal growth and placental cell death phenotypes in Dlx3(+/-) mice. To determine the potential mechanisms associated with elevated oxidative stress on the Dlx3(+/-) placentas, we next examined vascular characteristics within the feto-placental unit. Studies revealed reduced maternal spiral artery luminal area in the Dlx3(+/-) mice receiving water; Dlx3(+/-) mice receiving Tempol displayed maternal spiral artery luminal area similar to control Dlx3(+/+) mice. We conclude that reduced Dlx3 gene dose results in diminished fetal fitness associated with elevated placental cell oxidative stress and apoptosis coincident with altered vascular remodeling. Administration of antioxidant therapy ameliorated this feto-placental phenotype, suggesting that Dlx3 may be required for adaptation to oxidative stresses within the intrauterine environment.

Optimisation and validation of a medium-throughput electrophysiology-based hNav1.5 assay using IonWorks.

INTRODUCTION: The safety implications of blocking the human cardiac Na(+) channel (hNav1.5) make it prudent to test for this activity early in the drug discovery process and design-out any potential liability. This needs a method with adequate throughput and a demonstrable predictive value to effects in native cardiac tissues. Here we describe the validation of a method that combines the ability to screen tens of compounds a day, with direct assessment of channel function. METHODS: The electrophysiological and pharmacological properties of hNav1.5 were compared using two methods: conventional, low-throughput electrophysiology and planar-array-based, medium-throughput electrophysiology (IonWorks HT). A pharmacological comparison was also made between IonWorks HT and canine cardiac Purkinje Fibre action potential upstroke data. RESULTS: Activation curve parameters for hNav1.5 in IonWorks HT were not statistically different (p>0.05) from those generated using conventional electrophysiology. IonWorks HT V(1/2)=-22+/-0.8 mV, slope=6.9+/-0.2 (n=11); conventional electrophysiology V(1/2)=-20+/-1.6 mV, slope=6.4+/-0.3 (n=11). Potency values for a range of hNav1.5 blockers determined using IonWorks HT correlated closely with those obtained using conventional electrophysiology (R=0.967, p<0.001). The assay was able to distinguish between highly use-dependent blockers (e.g. tetracaine) and blockers that do not display strong use-dependence (e.g. quinidine). Comparison of the degree of hNav1.5 inhibition and decrease in canine Purkinje fibre action potential upstroke velocity (V(max)) showed that the IonWorks HT assay would have predicted the outcome in Purkinje fibres in the majority of cases, with false negative and positive rates estimated at 8 and 7%, respectively. Finally, hNav1.5 pharmacology was similar when determined using either IonWorks HT or IonWorks Quattro, although the latter yielded more consistent data. DISCUSSION: The assay described combines a functional assessment of hNav1.5 with medium-throughput. Furthermore the assay was able to reveal information on the use-dependency of compound block, as well as predicting Na(+) channel effects in more integrated systems such as the cardiac Purkinje fibre action potential. This makes it possible to determine quantitative potency data, and mechanistic information about use-dependence, in a timeframe short enough to influence medicinal chemistry.

Injury prevention training: a cluster randomised controlled trial assessing its effect on the knowledge, attitudes, and practices of midwives and health visitors.

OBJECTIVE: To evaluate the effectiveness of injury prevention training. DESIGN: Cluster randomised controlled trial. SETTING: Primary care facilities in the East Midlands area of the United Kingdom. SUBJECTS: Midwives and health visitors. INTERVENTION: Evidence based training session on the risks associated with baby walkers. MAIN OUTCOME MEASURES: The primary outcome measures were knowledge of baby walker use and walker related injury, attitudes towards walkers and towards walker education, and practices relating to walker health education. RESULTS: Trained midwives and health visitors had greater knowledge of the risks associated with baby walkers than untrained midwives and health visitors (difference between the means 0.22; 95% confidence interval (CI) 0.12 to 0.33). Trained health visitors had more negative attitudes to baby walkers (difference between the means 0.35; 95% CI 0.10 to 0.59) and more positive attitudes towards baby walker health education (difference between the means 0.31; 95% CI 0.00 to 0.62) than untrained health visitors. Midwives who had been trained were more likely to discuss baby walkers in the antenatal period than those who were not trained (odds ratio 9.92; 95% CI 2.02 to 48.83). CONCLUSIONS: Injury prevention training was associated with increased knowledge, more negative attitudes towards walkers, and more positive attitudes towards walker education. Trained midwives were more likely to give advice antenatally. Training did not impact on other practices. Larger trials are required to assess the impact of training on parental safety behaviours, the adoption of safety practices, and injury reduction.

Through the years: a longitudinal study of physical education teachers from a research-based preparation program.

This study investigated factors that enhanced and constrained the career development of six teachers, who had graduated from the same university teacher education program, in their induction years (Woods & Earls, 1995) and again later in their career cycles. Three participants were physical education teachers (PETs), and three were former physical education teachers (FPETs). Fessler's (1985) Teacher Career Stage Model provided the theoretical framework. Data sources were: interviews with teachers and their teacher educators and direct observations of lessons. Results indicated that the PETs continued to have skill development as their primary teaching objective. The teachers maintained many of their teaching skills, and shifted between the career cycles of "competency building" and "enthusiastic and growing." All three FPETs left their physical education positions during the career frustration stage and at the time of publication were in the career exit stage.

Inhibition of brown fat activity during hypothalamic stimulation in the rat.

Previous work has shown that low-level electrical stimulation of the ventromedial hypothalamus (VMH) in anesthetized rats produces a sustained decrease (phase 1) in interscapular brown adipose tissue (IBAT) temperature followed by a rise (phase 2) after the stimulus has stopped [Woods, A. J., and M. J. Stock. Am. J. Physiol. 266 (Regulatory, Integrative Comp. Physiol. 35): R328-R337, 1994]. In this study, rat oxygen consumption was found to decrease (24%) and then increase (74%) during phase 1 and 2, respectively. The effect of norepinephrine, alpha-adrenoceptor antagonists, substance P, and neuropeptide Y, with and/or without VMH stimulation, suggested that vasoconstriction was unlikely to account for the phase 1 decreases in thermogenesis and temperature. However, measurement with radio-labeled microspheres showed that IBAT capillary blood flow was reduced by 70% during phase 1, and this, plus a 50% decrease in blood oxygen extraction, indicated that phase 1 could be due to vasodilatation of arteriovenous anastomoses. It was postulated that phase 1 resulted from release of neuropeptides, such as substance P, causing diversion of arterial blood away from IBAT capillaries, thereby increasing convective heat loss and inhibiting heat production during phase 1.

Biphasic brown fat temperature responses to hypothalamic stimulation in rats.

Low-level electrical stimulation (monophasic square-wave pulses: 15 Hz, 7.0 microA, 0.5 ms) of the ventromedial hypothalamus (VMH) in anesthetized rats produced a decrease (phase 1) in interscapular brown adipose tissue (IBAT) temperature that was sustained for as long as the stimulus was applied (2-45 min). A rise in IBAT temperature (phase 2) occurred only after the stimulation had stopped. VMH stimulations ipsilateral and contralateral to a lateral hypothalamic (LH) lesion indicated that the phase 1 response required an intact LH, and denervation of IBAT showed that both phases required an intact sympathetic innervation. Central intracerebroventricular injections of amphetamine and dopamine produced decreases in IBAT temperature similar in magnitude to the phase 1 response to electrical stimulation of the VMH. This, as well as the observation that pimozide blocked phase 1, suggested that dopaminergic pathways were responsible for mediating the phase 1 decrease in IBAT temperature. The peripheral mechanisms responsible for phase 1 are unknown, but a vascular component might explain the unexpected decrease in IBAT temperature seen during sustained VMH stimulation.