Numerical simulations of the impact of the 20 March 2015 eclipse on UK weather.

Short lead-time forecasts using the operational United Kingdom variable-resolution (UKV) configuration of the Met Office's numerical weather prediction model, with horizontal grid-length 1.5 km over the UK, with and without a representation of the 20 March 2015 eclipse, have been used to simulate the impact of the eclipse on UK weather. The major impact was surface-driven through changes to surface heat and moisture fluxes that changed the boundary-layer development. In cloud-free areas, the nocturnal stable boundary layer persisted or quickly re-established during the eclipse. Surface temperatures were reduced by 7-8°C, near-surface air temperature by 1-3°C, and near-surface winds were backed, typically by 20°. Impacts on wind speed were small and variable, and would have been very difficult to detect. Smaller impacts occurred beneath cloud. However, the impact was enhanced because most of the incoming radiation that reached the surface was driving surface sensible heat flux rather than moisture flux, and the near-surface air temperature impact (0.5-1°C) agrees reasonably well with observations. The modelled impact of the eclipse was substantially reduced in urban areas due to their large thermal inertia. Experience from other assessments of the model suggests that this lack of response may be exaggerated. Surface impacts propagated upwards and downstream with time, resulting in a complex pattern of response, though generally near-surface temperature differences persisted for many hours after the eclipse. The impact on atmospheric pressure fields was insufficient to account for any significant perturbations to the wind field when compared with the direct impacts of surface stress and boundary-layer mixing.This article is part of the themed issue 'Atmospheric effects of solar eclipses stimulated by the 2015 UK eclipse'.

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.

Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma.

OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.

Developmental expression of the homeobox protein Distal-less 3 and its relationship to progesterone production in mouse placenta.

Distal-less 3 (Dlx3) is a homeobox factor that functions as a placental-specific transcriptional regulator. Dlx3 null mice (-/-) have compromised placental development and do not survive in utero past embryonic day (E) 9.5. The current studies were undertaken to examine the expression of Dlx3 in mouse placenta during gestation, and to determine whether Dlx3 was involved in placental progesterone production. Dlx3 was not detectable at E8.5 but was detected in E9.5 placenta with continuing but diminished expression through E15.5. Dlx3 immuno-localization was restricted to the labyrinth, was nuclear and was found in cytokeratin-positive cells. Previous studies in choriocarcinoma cell lines support the conclusion that Dlx3 is required for expression of 3'-hydroxysteroid dehydrogenase VI (3betaHSD VI), an obligate enzyme in the production of progesterone by trophoblast giant cells. In a rat trophoblast stem cell line (Rcho-1), Dlx3 expression was non-detectable in Rcho-1 cells induced to differ-entiate using mitogen withdrawal. In vitro progesterone production in placental cultures and 3betaHSD VI mRNA from Dlx3 (+/+), (+/-) and (-/-) mice were equivalent. In situ hybridization for 3betaHSD VI revealed mRNA expression restricted to trophoblast giants cells with no detectable expression in the labyrinth suggesting that Dlx3 and 3betaHSD VI were not colocalized within the placenta. These studies support the conclusion that Dlx3 protein expression is restricted to the labyrinth region of the murine placenta into late gestation and that Dlx3 does not appear to be expressed in trophoblast giant cells. Further, loss of Dlx3 was not correlated with synthesis of progesterone from E9.5 mouse placentas.

Outcomes for patients with dementia from the Cleveland Alzheimer's Managed Care Demonstration.

This investigation evaluates effects of care consultation delivered within a partnership between a managed health care system and Alzheimer's Association chapter. Care consultation is a multi-component telephone intervention in which Association staff work with patients and caregivers to identify personal strengths and resources within the family, health plan, and community. The primary hypothesis is that care consultation will decrease utilization of managed care services and improve psychosocial outcomes. A secondary modifying-effects hypothesis posits benefits will be greater for patients with more severe memory impairment. The sample is composed of managed care patients whose medical records indicate a diagnosis of dementia or memory loss. Patients were randomly assigned to an intervention group, which was offered care consultation in addition to usual managed care services, or to a control group, which was offered only usual managed care services. Data come from two in-person interviews with patients, and medical and administrative records. Results supporting the primary hypothesis show intervention group patients feel less embarrassed and isolated because of their memory problems and report less difficulty coping. Findings consistent with the modifying-effects hypothesis show intervention group patients with more severe impairment have fewer physician visits, are less likely to have an emergency department visit or hospital admission, are more satisfied with managed care services, and have decreased depression and strain.

Pubertal alterations in growth and body composition. VI. Pubertal insulin resistance: relation to adiposity, body fat distribution and hormone release.

OBJECTIVE: To investigate the independent influence of alterations in fat mass, body fat distribution and hormone release on pubertal increases in fasting serum insulin concentrations and on insulin resistance assessed by the homeostasis model (HOMA). DESIGN AND SUBJECTS: Cross-sectional investigation of pre- (n=11, n=8), mid- (n=10, n=11), and late-pubertal (n=10, n=11) boys and girls with normal body weight and growth velocity. MEASUREMENTS: Body composition (by a four-compartment model), abdominal fat distribution and mid-thigh interfascicular plus intermuscle (extramyocellular) fat (by magnetic resonance imaging), total body subcutaneous fat (by skinfolds), mean nocturnal growth hormone (GH) release and 06:00 h samples of serum insulin, sex steroids, leptin and insulin-like growth factor-I (IGF-I). RESULTS: Pubertal insulin resistance was suggested by greater (P<0.001) fasting serum insulin concentrations in the late-pubertal than pre- and mid-pubertal groups while serum glucose concentrations were unchanged and greater (P<0.001) HOMA values in late-pubertal than pre- and mid-pubertal youth. From univariate correlation fat mass was most related to HOMA (r=0.59, P<0.001). Two hierarchical regression models were developed to predict HOMA. In one approach, subject differences in sex, pubertal maturation, height and weight were held constant by adding these variables as a block in the first step of the model (r(2)=0.36). Sequential addition of fat mass (FM) increased r(2) (r(2)((inc)remental)=0.08, r(2)=0.44, P<0.05) as did the subsequent addition of a block of fat distribution variables (extramyocellular fat, abdominal visceral fat, and sum of skinfolds; r(2)(inc)=0.11, r(2)=0.55, P<0.05). Sequential addition of a block of hormone variables (serum IGF-I and log((10)) leptin concentrations; r(2)(inc)=0.04, P>0.05) did not reliably improve r(2) beyond the physical characteristic and adiposity variables. In a second model, differences in sex and pubertal maturation were again held constant (r(2)=0.25), but body size differences were accounted for using percentage fat data. Sequential addition of percentage body fat (r(2)((inc)remental)=0.11, r(2)=0.36, P<0.05), then a block of fat distribution variables (percentage extramyocellular fat, percentage abdominal visceral fat, and percentage abdominal subcutaneous fat; r(2)(inc)=0.08, r(2)=0.44, P=0.058), and then a block of serum IGF-I and log((10)) leptin concentrations (r(2)(inc)=0.07, r(2)=0.51, P<0.05) increased r(2). Mean nocturnal GH release was not related to HOMA (r=-0.04, P=0.75) and therefore was not included in the hierarchical regression models. CONCLUSION: Increases in insulin resistance at puberty were most related to FM. Accumulation of fat in the abdominal visceral, subcutaneous and muscular compartments may increase insulin resistance at puberty beyond that due to total body fat. Serum concentrations of leptin and IGF-I may further modulate HOMA beyond the effects of adiposity and fat distribution. However, the results are limited by the cross-sectional design and the use of HOMA rather than a criterion measure of insulin resistance.

Stabilization of p53 by p14ARF without relocation of MDM2 to the nucleolus.

The alternative product of the human INK4a/ARF locus, p14ARF, has the potential to act as a tumour suppressor by binding to and inhibiting the p53 antagonist MDM2. Current models propose that ARF function depends on its ability to sequester MDM2 in the nucleolus. Here we describe situations in which stabilization of MDM2 and p53 occur without relocalization of endogenous MDM2 from the nucleoplasm. Conversely, forms of ARF that do not accumulate in the nucleolus retain the capacity to stabilize MDM2 and p53. We therefore propose that nucleolar localization is not essential for ARF function but may enhance the availability of ARF to inhibit MDM2.

What residents are not learning: observations in an NICU.

In light of the November 1999 report of the Institute of Medicine on medical errors as a leading cause of death and injury, and the July 2000 report of the Accreditation Council for Graduate Medical Education citing violations of work-hour standards for residents and interns, there is a clear need for substantial changes in residency training. The author, a clinical bioethicist, uses his extended observations at a neonatal intensive care unit (NICU) of a major U.S. teaching hospital to outline specific concerns about residents' and interns' training, medical and otherwise, that create unnecessary hazards and other difficulties in the medical care of children. These concerns-which arise from constructive criticisms he makes of specific NICU procedures, methods, approaches, and policies-apply directly to training residents in several areas of medicine and more generally to all residents' training, and echo many of the issues stated in the reports mentioned above. The author maintains that a well-rounded medical education, fostering not only clinical skills but others (e.g., skills in teaching; in communication; in collaborating with nurses, social workers, and others; in working with families; in showing compassion; in dealing with confidentiality issues; in using common sense; in being the patient's advocate), is crucial for producing well-rounded physicians. He emphasizes that in order for such a well-rounded education to occur, the residency program-which in many cases means the attending physicians-must teach and model these varied skills and attitudes to their trainees.

Cost-effectiveness of preimmunization hepatitis B screening in high-risk adolescents.

OBJECTIVE: The goals of this study were to estimate seroprevalence of prior hepatitis B infection among high-risk adolescents and to determine the cost-effectiveness of prevaccination immunity screening. METHODS: The authors computed a "break-even" seroprevalence level calculated from current vaccine and administration costs. They then conducted a seroprevalence study of hepatitis B core antibody using sera previously submitted for syphilis serology from four-hundred adolescent and adult clients of sexually transmitted disease clinics. Finally, the authors compared age group-specific seroprevalence rates to the computed break-even seroprevalence. RESULTS: Levels of prior hepatitis B infection for all age groups were lower than the break-even seroprevalence standard from which cost-effectiveness was calculated. CONCLUSIONS: From the findings of this study, the authors concluded that routine preimmunization screening for prior hepatitis B infection would not be cost-effective for this population.

Alterations in growth and body composition during puberty. IV. Energy intake estimated by the youth-adolescent food-frequency questionnaire: validation by the doubly labeled water method.

BACKGROUND: Estimates of energy intake are required for an understanding of growth and disease; however, few methods of energy intake in children have been validated. OBJECTIVE: Our objective was to validate energy intake estimated by the Youth-Adolescent Food-Frequency Questionnaire (YAQ) against the criterion total energy expenditure (TEE) by doubly labeled water (DLW). DESIGN: Twenty-three boys and 27 girls (8.6-16.2 y of age) completed the YAQ and TEE measurements in 1 y. RESULTS: Energy intake by the YAQ (10. 03 +/- 3.12 MJ) and energy expenditure by DLW (9.84 +/- 1.79 MJ) were similar (P: = 0.91) with large lower (-6.30 MJ) and upper (6.67 MJ) +/-2 SD limits of agreement. When within-subject CVs of repeated measures of the DLW and YAQ methods were used, 25 of the 50 subjects were deemed to have misreported their energy intake. The discrepancy in energy intake (YAQ - TEE) was related to body weight (r = -0.25, P: = 0.077) and percentage body fat (r = -0.24, P: = 0.09) but not to age (r = -0.07, P: = 0.63) or the time between measures. From logistic regression, fatter boys were more likely to underreport energy intake than were fatter girls. CONCLUSION: The YAQ provides an accurate estimation of mean energy intake for a group but not for an individual.

Pubertal alterations in growth and body composition. V. Energy expenditure, adiposity, and fat distribution.

We determined whether activity energy expenditure (AEE, from doubly labeled water and indirect calorimetry) or physical activity [7-day physical activity recall (PAR)] was more related to adiposity and the validity of PAR estimated total energy expenditure (TEE(PAR)) in prepubertal and pubertal boys (n = 14 and 15) and girls (n = 13 and 18). AEE, but not physical activity hours, was inversely related to fat mass (FM) after accounting for the fat-free mass, maturation, and age (partial r = -0.35, P < or = 0.01). From forward stepwise regression, pubertal maturation, AEE, and gender predicted FM (r(2) = 0.36). Abdominal visceral fat and subcutaneous fat were not related to AEE or activity hours after partial correlation with FM, maturation, and age. When assuming one metabolic equivalent (MET) equals 1 kcal. kg body wt(-1). h(-1), TEE(PAR) underestimated TEE from doubly labeled water (TEE bias) by 555 kcal/day +/- 2 SD limits of agreement of 913 kcal/day. The measured basal metabolic rate (BMR) was >1 kcal. kg body wt(-1). h(-1) and remained so until 16 yr of age. TEE bias was reduced when setting 1 MET equal to the measured (bias = 60 +/- 51 kcal/day) or predicted (bias = 53 +/- 50 kcal/day) BMR but was not consistent for an individual child (+/- 2 SD limits of agreement of 784 and 764 kcal/day, respectively) or across all maturation groups. After BMR was corrected, TEE bias remained greatest in the prepubertal girls. In conclusion, in children and adolescents, FM is more strongly related to AEE than activity time, and AEE, pubertal maturation, and gender explain 36% of the variance in FM. PAR should not be used to determine TEE of individual children and adolescents in a research setting but may have utility in large population-based pediatric studies, if an appropriate MET value is used to convert physical activity data to TEE data.

Growth and pubertal development in children and adolescents: effects of diet and physical activity.

The longitudinal growth of an individual child is a dynamic statement of the general health of that child. Measurements should be performed often and accurately to detect alterations from physiologic growth. Although any single point on the growth chart is not very informative, when several growth points are plotted over time, it should become apparent whether that individual's growth is average, a variant of the norm, or pathologic. Somatic growth and maturation are influenced by several factors that act independently or in concert to modify an individual's genetic growth potential. Linear growth within the first 2 y of life generally decelerates but then remains relatively constant throughout childhood until the onset of the pubertal growth spurt. Because of the wide variation among individuals in the timing of the pubertal growth spurt, there is a wide range of physiologic variations in normal growth. Nutritional status and heavy exercise training are only 2 of the major influences on the linear growth of children. In the United States, nutritional deficits result from self-induced restriction of energy intake. That single factor, added to the marked energy expenditure of training and competition for some sports, and in concert with the self-selection of certain body types, makes it difficult to identify the individual factors responsible for the slow linear growth of some adolescent athletes, for example, those who partake in gymnastics, dance, or wrestling.

Nonclassic 11 beta-hydroxylase deficiency: report of two patients and review.

Congenital adrenal hyperplasia (CAH) is well recognized as a disorder which can result in virilization of females, accelerated skeletal maturation and resultant adult short stature in both genders, and, in certain varieties, life-threatening adrenal crisis. Among the enzymatic defects resulting in CAH, nonclassic or partial 11 beta-hydroxylase deficiency is a relatively uncommon etiology. However, the subtlety with which it can present and the difficulties associated with its diagnosis can delay its identification and result in a significant reduction in adult stature. This paper describes the presentation and evaluation of two children with partial 11 beta-hydroxylase deficiency, discusses its pathogenesis, and compares the disorder with the more common varieties of congenital adrenal hyperplasia.

The ethics of medical marijuana: government restrictions vs. medical necessity.

Marijuana is listed by the Drug Enforcement Agency (DEA) as an illegal Schedule I drug which has no currently accepted medical use. However, on March 17, 1999, 11 independent scientists appointed by the Institute of Medicine reported that medical marijuana was effective in controlling some forms of pain, alleviating nausea and vomiting due to chemotherapy, treating wasting due to AIDS, and combating muscle spasms associated with multiple sclerosis. There was also no evidence that using marijuana would increase illicit drug use or that it was a "gateway" drug. Despite this evidence the DEA refuses to reclassify marijuana as a Schedule II drug, which would allow physicians to prescribe unadulterated and standardized forms of marijuana. After reviewing the pertinent scientific data and applying the principle of double effect, there is a proportionate reason for allowing physicians to prescribe marijuana. Seriously ill patients have the right to effective therapies. To deny patients access to such a therapy is to deny them dignity and respect as persons.

Preliminary validation of a short-term morphological assay to evaluate adverse effects on amphibian metamorphosis and thyroid function using Xenopus laevis.

Short-term static-renewal studies were performed on Xenopus laevis embryos with 16 selected test materials from day 50 (stage 60) to day 64 (stage 66) (14-day test) to evaluate effects on tail resorption and thyroid function. Of the 16 test materials, nine were found to inhibit significantly the rate of tail resorption, four were found to stimulate metamorphosis and three had no appreciable effect on the rate of metamorphosis. In an effort to determine if the morphological effects observed were related to alteration in thyroid activity, measurement of triiodothyronine (T3) in the test organisms and coadministration studies using thyroxine (agonist) or propylthiouracil (antagonist) were performed based on the morphological response noted during tail resorption. Of the nine compounds found to inhibit the rate of tail resorption, six were found to reduce the levels of T3. In each case, the inhibitory response could be at least partially alleviated by the co-administration of thyroxine. Larvae exposed to the four stimulatory agents had somewhat elevated levels of T3 and were responsive to propylthiouracil antagonism. These results suggest that 12 of the 14 compounds tested in this study that altered the rate of tail resorption did so via the thyroid axis. Overall, the X. laevis model appeared to be a suitable system for evaluating the impact of environmental agents and chemical products on thyroid function.

The ethics of alternative medicine therapies.

It is estimated that 42% of the American public is using some form of alternative medicine, which reflects the changing needs and values in our society. Unfortunately, Western medicine has failed to see alternative medicine as complementary and integrative with conventional medicine. This is due to the fact that there is very little scientific data available regarding the safety, efficacy, optimal dosage and side-effects or interactions of these alternative medicine therapies. Many physicians dismiss a patient's questions concerning alternative medicine because the physician believes it is "quackery," without any proof to support this claim. This violates the patient's right to full disclosure of all possible treatment options and encourages patients to use these therapies without their physician's knowledge. As a result, it is estimated that 46% of those using alternative medicine do so without the supervision of their primary care physicians or alternative medicine practitioners. At the present time there is no regulatory process to ensure the safety and efficacy of these alternative medicine therapies. Manufacturers do not have to prove that their product works, but they must ensure that their product is not harmful. The combination of failure to inform physicians of usage and the possibility of adverse reactions with prescription drugs is placing the lives of many Americans in jeopardy. Ethically, consumers have the right to use alternative medicine therapies as a matter of autonomy, but they also have the duty not to harm themselves. To ensure their safety, alternative medicine therapies must be evaluated in regards to safety and efficacy so that they can be integrated into conventional medicine. The Federal Drug Administration has the ethical responsibility to take the lead in this area. To protect the common good, there is a need to know not only what alternative medicine can do for us but what it can do to us.