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K R Smith

Publications and source records attributed to K R Smith.

At least 19 recordsLinked to original sources
PubMed2006

Simultaneous downregulation of CDK inhibitors p18(Ink4c) and p27(Kip1) is required for MEN2A-RET-mediated mitogenesis.

Multiple endocrine neoplasia type 2A (MEN2A) is predisposed by mutations in the RET proto-oncogene. Low expression of the cyclin-dependent kinase inhibitor (CDKI) p27(Kip1) is present in thyroid tumors, and recent evidence demonstrates p27 downregulation by the active RET mutant, RET/PTC1, found in papillary thyroid carcinoma. This implicates decreased p27 activity as an important event during thyroid tumorigenesis. However, p27(-/-) mice develop MEN-like tumors only in combination with loss of another CDKI, p18(Ink4c). This suggests that p18 and p27 functionally collaborate in suppression of tumorigenesis, that loss of both is critical in the development of MEN tumors and that both p18 and p27 are regulated by RET. We report that induction of the constitutively active MEN2A-specific RET mutant, RET2A(C634R), correlates with reduced p18/p27, and elevated cyclin D protein levels, leading to increased CDK activity, increased pRb phosphorylation and proliferation under growth arrest conditions. Mechanistically, RET2A represses p18/p27 mRNA levels while elevating cyclin D1 mRNA levels. RET2A expression also correlates with decreased p27 protein stability. RET2A-mediated regulation of p18 and p27, but not of cyclins D1 and D2, requires functional mitogen-activated protein kinase signaling. Additionally, RET2A-dependent p18 repression is required and sufficient to increase cell proliferation. Perhaps most significantly, MEN2A adrenal tumors also display these changes in cell cycle expression profile, demonstrating the biological relevance of our cell culture studies. Our results demonstrate for the first time that RET2A regulates p18, and suggest that loss of not only p27 but also of p18 expression is a key step in MEN tumorigenesis.

Adrenal Gland Neoplasms↗
PubMed2006

China at the crossroads: the economics of tobacco and health.

OBJECTIVE: To analyse economic aspects of tobacco control policy issues in China. METHODS: Published and collected survey data were used to analyse economic consequences of smoking. Economic analysis was used to address the role of tobacco farmers and the cigarette industry in the Chinese economy. RESULTS: In the agricultural sector, tobacco has the lowest economic rate of return of all cash crops. At the same time, the tobacco industry's tax contribution to the central government has been declining. CONCLUSION: Economic gains become less important as the negative health impact of smoking on the population garners more awareness. China stands at a crossroads to implement the economic promises of the World Health Organization's Framework Convention on Tobacco Control and promote the health of its population.

China↗
PubMed2002

Indoor air pollution in developing countries: recommendations for research.

Available studies indicate that indoor air pollution (IAP) from household cooking and space heating apparently causes substantial ill-health in developing countries where the majority of households rely on solid fuels (coal or biomass as wood, crop residues, and dung), but there are many remaining uncertainties. To pin down impacts in order to effectively target interventions, research is particularly needed in three areas: (1) epidemiology: case-control studies for tuberculosis (TB) and cardiovascular disease in women and randomized intervention trials for childhood acute respiratory diseases and adverse pregnancy outcomes; (2) exposure assessment: techniques and equipment for inexpensive exposure assessment at large scale, including national level surveys; (3) interventions: engineering and dissemination approaches for improved stoves, fuels, ventilation, and behavior that reliably and economically reduce exposure. There are also important potential synergisms between efforts to reduce greenhouse gas emissions and those to reduce health-damaging emissions from solid-fuel stoves. The substitution of biomass by coal being considered in some countries should be pursued with caution because of the known serious health effects of household coal use.

Adult↗
PubMed2002

Uncertainties on predicted concentrations of radionuclides in terrestrial foods and ingestion doses.

Models are routinely used to calculate doses following routine releases and potential accidental releases of radionuclides. These models contain a number of parameters. Values for many of these are not accurately known. The primary aim of this study was to determine the level of uncertainty on predicted concentrations of radionuclides in foods, and doses to individuals consuming those foods, arising from uncertainties on the model input parameter values. A secondary objective was to identify those input parameters whose uncertainty makes a major contribution to the overall uncertainty on the predicted endpoints. The methodology adopted and results obtained are presented for the following radionuclides: 90Sr, 131I, 137Cs and 239Pu. The estimated uncertainty ratios (the ratio of the 95th to the 5th percentile) are frequently very large, often two to three orders of magnitude. The results of this study may be used to identify areas where further research could improve assessment capabilities.

Accidents↗
PubMed2002

Intramedullary interlocking nail stabilisation of 21 humeral fractures in 19 dogs and one cat.

OBJECTIVE: To assess the suitability of the intramedullary interlocking nail to stabilise humeral diaphyseal fractures in dogs and cats. METHOD: This multi-centre study retrospectively examined medical records, between June 1994 and May 2001, of 19 dogs and one cat, in which a total of 21 humeral fractures were stabilised with intramedullary interlocking nails. RESULTS: Animals ranged in body-weight from 4 to 97 kg. Eighteen (86%) of the fractures were comminuted. Adjunctive stabilisation was used in twelve (57%) fractures and bone grafts in nine (43%) fractures. A rapid return of function was noted in the majority of animals, with 14 (67%) having good or excellent function within four days of surgery. In two fractures the repair collapsed when a single proximal transcortical screw was placed cranial to the tricipital line of the humerus. This suggests that if a single transcortical screw is placed proximally the screw should be distal or caudal to the tricipital line in order to engage sufficient cortical bone. Eighteen (86%) of the fractures healed when stabilised with intramedullary interlocking nails. Three fractures did not heal. One was in a dog where a pathological fracture was temporarily stabilised with an intramedullary interlocking nail, one in a dog that died of an abdominal crisis three weeks after surgery and one in a dog in which fracture stabilisation collapsed due to incorrect implant selection. CONCLUSION: Intramedullary interlocking nails are well suited to the stabilisation of humeral diaphyseal fractures in dogs and cats.

Animals↗
PubMed2001

Early postnatal ethanol intubation blunts GABA(A) receptor up-regulation and modifies 3alpha-hydroxy-5alpha-pregnan-20-one sensitivity in rat MS/DB neurons.

Previously we found postnatal binge-like ethanol exposure using an artificial-rearing method in the rat delayed developmental up-regulation of GABA(A) receptors (GABA(A)Rs) in both medial septum/diagonal band (MS/DB) and cerebellar Purkinje neurons. In the present study, the impact of ethanol on developing GABA(A)Rs in MS/DB neurons was further tested under conditions not requiring anesthesia or maternal deprivation. Nursing rat pups received ethanol (4.5-5.25 g/kg/day) on postnatal days (PD) 4-9, which was administrated manually by oral intragastric intubation. This treatment caused dose-dependent blunting of peak GABA(A) receptor whole cell currents in acutely dissociated MS/DB cells on PD 12-15. The threshold with oral intubation was slightly higher than previously observed for artificial-rearing (4.9 vs. 4.5 g/kg/day). The previously observed reduced sensitivity of GABA(A)Rs to Zn(2+)-inhibition after ethanol was not found with the intubation model. In studies only carried out using the intubation method, 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha-OH-DHP) caused an allosteric concentration-dependent potentiation of currents activated by non-saturated concentrations of GABA. A bicuculline sensitive direct activation of GABA(A)Rs also occurred with higher concentrations of 3alpha-OH-DHP alone. Ethanol intubation up-regulated allosteric neurosteroid potentiation with low concentrations of GABA, but did not change direct agonist actions of 3alpha-OH-DHP. Finally, 3alpha-OH-DHP did not prime ethanol insensitive GABA(A)Rs to become sensitivity to acute ethanol potentiation. These results indicate ethanol consistently blunts postnatal GABA(A) receptor up-regulation across early postnatal binge-type ethanol exposure models and may increase positive modulation of GABA(A) receptors by endogenous neurosteroids.

Age Factors↗
PubMed2001

Indoor respirable particulate matter concentrations from an open fire, improved cookstove, and LPG/open fire combination in a rural Guatemalan community.

Improved biomass cookstoves have the potential to reduce pollutant emissions and thereby reduce pollution exposure among populations in developing countries who cook daily with biomass fuels. However, evaluation of such interventions has been very limited. This article presents results from a study carried out in 30 households in rural Guatemala. Twenty-four hour PM3.5 concentrations were compared over 8 months for three fuel/cookstove conditions (n = 10 households for each condition): a traditional open fire cookstove, an improved cookstove called the plancha mejorada, and a liquefied petroleum gas (LPG) stove/open fire combination. Twenty-four hour geometric mean PM3.5 concentrations were 1560 micrograms/m3 (n = 58; 95% C.I. 1310, 1850), 280 micrograms/m3 (n = 59; 95% C.I. 240-320), and 850 micrograms/m3 (n = 60; 95% C.I. 680-1050) for the open fire, plancha, and LPG/open fire combination, respectively. A generalized estimating equation model showed a 45% reduction in PM3.5 concentrations for the LPG/open fire combination as compared to the open fire alone. The difference approached significance (p < 0.0737). The plancha showed an 85% reduction in PM3.5 concentrations as compared to the open fire (p < 0.0001). An analysis of the interaction of time with stove type showed that the temporal trend in pollution did not significantly differ among the three stove types. The reduced PM3.5 concentrations were maintained over time. Season did not affect pollutant concentrations. Of the two interventions, the plancha appears to offer the best prospects for achieving substantial reductions in indoor air pollution levels, although issues of cost and stove maintenance remain to be addressed.

Air Pollution, Indoor↗
PubMed2001

Lack of effect of induction of hypothermia after acute brain injury.

BACKGROUND: Induction of hypothermia in patients with brain injury was shown to improve outcomes in small clinical studies, but the results were not definitive. To study this issue, we conducted a multicenter trial comparing the effects of hypothermia with those of normothermia in patients with acute brain injury. METHODS: The study subjects were 392 patients 16 to 65 years of age with coma after sustaining closed head injuries who were randomly assigned to be treated with hypothermia (body temperature, 33 degrees C), which was initiated within 6 hours after injury and maintained for 48 hours by means of surface cooling, or normothermia. All patients otherwise received standard treatment. The primary outcome measure was functional status six months after the injury. RESULTS: The mean age of the patients and the type and severity of injury in the two treatment groups were similar. The mean (+/-SD) time from injury to randomization was 4.3+/-1.1 hours in the hypothermia group and 4.1+/-1.2 hours in the normothermia group, and the mean time from injury to the achievement of the target temperature of 33 degrees C in the hypothermia group was 8.4+/-3.0 hours. The outcome was poor (defined as severe disability, a vegetative state, or death) in 57 percent of the patients in both groups. Mortality was 28 percent in the hypothermia group and 27 percent in the normothermia group (P=0.79). The patients in the hypothermia group had more hospital days with complications than the patients in the normothermia group. Fewer patients in the hypothermia group had high intracranial pressure than in the normothermia group. CONCLUSIONS: Treatment with hypothermia, with the body temperature reaching 33 degrees C within eight hours after injury, is not effective in improving outcomes in patients with severe brain injury.

Acute Disease↗
PubMed2001

Carbon monoxide as a tracer for assessing exposures to particulate matter in wood and gas cookstove households of highland Guatemala.

Kitchen-area 22-h gravimetric PM2.5 and passive diffusion stain-tube carbon monoxide (CO) concentrations were measured in homes with open fire and improved wood cookstoves in two studies. In the first study (Guat-2), which also studied homes with gas cookstoves, three samples were collected per stove condition from each of three test houses. In the second study (Guat-3), one sample was collected per house from 15 open fire and 25 improved-stove houses. CO personal samples were also taken for mother and child in both studies. Spearman correlation coefficients (R) between kitchen-area CO and PM2.5 levels in homes using open fires or impoved wood cookstoves were high ranging from 0.92 (Guat-2) to 0.94 (Guat-3), as were those between the personal samples for mother and child ranging from 0.85 (Guat-3) to 0.96 (Guat-2). In general, the correlations were lower for less-polluted conditions. The study found that CO is a good proxy for PM2.5 in homes using open fires or planchas (improved wood cookstove with chimney) but not under gas stove use conditions. It also determined that mother personal CO is a good proxy for child's (under 2 years of age) personal CO and that area CO measurements are not strongly representative of personal CO measurements. These results generally support the use of Draeger CO passive diffusion tubes as a proxy for PM2.5 in such cases where a single type of emission source is the predominant source for CO and PM2.5.

Air Pollution, Indoor↗
PubMed2001

Three-dimensional localization: from image-guided surgery to information-guided therapy.

Image-guided surgery has become the standard of care for intracranial procedures. However, significant development is required before the benefits of this technology are brought to the majority of patients undergoing surgery. This article categorizes the areas wherein progress is needed, and indicates recent advances that may form the basis for the broad acceptance of this exciting technology. Emphasis is placed on a technique whereby preoperative imaging can be updated using low-resolution intraoperative imaging to reflect changes in anatomy caused by surgery, and on transforming image-guided surgery to information-guided therapy, in which diverse sources can be brought to bear at the time of greatest possible benefit, when the patient's anatomy is exposed for therapeutic intervention.

Brain↗
PubMed2001

Children's, adolescents', and young adults' thinking about different types of disagreements.

Individuals' thinking about different types of disagreements was examined. Ninety-six participants in third grade (mean age = 8 years 9 months), seventh grade (mean age = 13 years 2 months), and college (mean age = 21 years 10 months) judged the acceptability of believing and acting on different types of beliefs with which they disagree, the attributes of the persons with whom they disagree, and the relative importance of cultural uniformity or diversity of belief. Findings indicated that participants' thinking did not simply become more tolerant with age; their thinking at all ages was constrained by both the realm over which there was disagreement and the form of the disagreement. At all ages, participants judged that some disagreements were acceptable and some unacceptable, described disagreeing others in terms of different (more or less positive) attributes, and judged that diversity of belief was important in some realms but uniformity was preferable in others.

Adolescent↗
PubMed2001

Familial excess longevity in Utah genealogies.

We evaluated the influence of family history on longevity by examining longevity in a cohort of 78,994 individuals drawn from the Utah Population Database (UPDB) who were born between 1870 and 1907, and lived to at least age 65. We examined Mendelian genetic and social modes of transmission of excess longevity (the difference between observed and expected longevity) by varying weighted kinship contributions over different classes of relatives. The genetic component of the variation in excess longevity measured as heritability, h2, was approximately 0.15 (95% confidence interval [CI] 0.12-0.18). Among siblings of probands who reached the 97th percentile of excess longevity (+ 14.8 years, currently age 95 for men and 97 for women), the relative risk of recurrence (lambdas) was 2.30 (95% CI 2.08-2.56). In sibships whose relatives were in the top 15% of the distribution for familial excess longevity, the value of lambdas increased substantially, indicating that considering the longevity of distant relatives may be helpful in the selection of families in which to identify genes influencing aging and longevity.

Aged↗
PubMed2001

Solitary intramedullary neurosarcoidosis: role of MRI in early detection.

BACKGROUND: Intramedullary neurosarcoidosis may be the first manifestation of the disease and may mimic a tumor clinically and radiographically. Two patients who presented with cervical intramedullary lesions on magnetic resonance imaging (MRI) scans were found to have neurosarcoidosis. CLINICAL PRESENTATION: Two patients with negative past medical history presented with progressive myelopathic features, and intramedullary cervical lesions were detected on MRI scan; the diagnosis was made on biopsy of the lesions. Early therapeutic intervention led to a favorable outcome. CONCLUSION: Intra-medullary neurosarcoidosis, especially in the cervical cord, can be the initial presentation of the disease, mimicking a tumor. MRI scan, biopsy, and, in fewer cases, angiotensin-converting enzyme levels can help with the diagnosis and may lead to a favorable outcome.

Cervical Vertebrae↗
PubMed2001

Arsenite stimulates plasma membrane NADPH oxidase in vascular endothelial cells.

Low-level arsenite treatment of porcine aortic endothelial cells (PAEC) stimulated superoxide accumulation that was attenuated by inhibitors of NAD(P)H oxidase. To demonstrate whether arsenite stimulated NADPH oxidase, intact PAEC were treated with arsenite for up to 2 h and membrane fractions were prepared to measure NADPH oxidase activity. Arsenite (5 microM) stimulated a twofold increase in activity by 1 h, which was inhibited by the oxidase inhibitor diphenyleneiodonium chloride. Direct treatment of isolated membranes with arsenite had no effect. Analysis of NADPH oxidase components revealed that p67(phox) localized exclusively to membranes of both control and treated cells. In contrast, cytosolic Rac1 translocated to the membrane fractions of cells treated with arsenite or angiotensin II but not with tumor necrosis factor. Immunodepletion of p67(phox) blocked oxidase activity stimulated by all three compounds. However, depleting Rac1 inhibited responses only to arsenite and angiotensin II. These data demonstrate that stimulus-specific activation of NADPH oxidase in endothelial cells was the source of reactive oxygen in endothelial cells after noncytotoxic arsenite exposure.

Animals↗
PubMed2001

The genetics of reproductive isolation and the potential for gene exchange between Drosophila pseudoobscura and D. persimilis via backcross hybrid males.

Hybrid male sterility, hybrid inviability, sexual isolation, and a hybrid male courtship dysfunction reproductively isolate Drosophila pseudoobscura and D. persimilis. Previous studies of the genetic bases of these isolating mechanisms have yielded only limited information about how much and what areas of the genome are susceptible to interspecies introgression. We have examined the genetic basis of these barriers to gene exchange in several thousand backcross hybrid male progeny of these species using 14 codominant molecular genetic markers spanning the five chromosomes of these species, focusing particularly on the autosomes. Hybrid male sterility, hybrid inviability, and the hybrid male courtship dysfunction were all associated with X-autosome interactions involving primarily the inverted regions on the left arm of the X-chromosome and the center of the second chromosome. Sexual isolation from D. pseudoobscura females was primarily associated with the left arm of the X-chromosome, although both the right arm and the center of the second chromosome also contributed to it. Sexual isolation from D. persimilis females was primarily associated with the second chromosome. The absence of isolating mechanisms being associated with many autosomal regions, including some large inverted regions that separate the strains, suggests that these phenotypes may not be caused by genes spread throughout the genome. We suggest that gene flow between these species via hybrid males may be possible at loci spread across much of the autosomes.

Alleles↗
PubMed2001

Intercenter variance in clinical trials of head trauma--experience of the National Acute Brain Injury Study: Hypothermia.

OBJECT: In a recently conducted trial of hypothermia in patients with severe brain injury, differences were found in the effects of hypothermia treatment among various centers. This analysis explores the reasons for such differences. METHODS: The authors reviewed data obtained in 392 patients treated for severe brain injury. Prerandomization variables, critical physiological variables, treatment variables, and accrual methodologies were investigated among various centers. Hypothermia was found to be detrimental in patients older than the age of 45 years, beneficial in patients younger than 45 years of age in whom hypothermia was present on admission, and without effect in those in whom normothermia was documented on admission. Marginally significant differences (p < 0.054) in the intercenter outcomes of hypothermia-treated patients were likely the result of wide differences in the percentage of patients older than 45 years of age and in the percentage of patients in whom hypothermia was present on admission among centers. The trial sensitivity was likely diminished by significant differences in the incidence of mean arterial blood pressure (MABP) less than 70 mm Hg (p < 0.001) and cerebral perfusion pressure (CPP) less than 50 mm Hg (p < 0.05) but not intracranial pressure (ICP) greater than 25 mm Hg (not significant) among patients in the various centers. Hours of vasopressor usage (p < 0.03) and morphine dose (p < 0.001) and the percentage of dehydrated patients varied significantly among centers (p < 0.001). The participation of small centers increased intercenter variance and diminished the quality of data. CONCLUSIONS: For Phase III clinical trials we recommend: 1) a detailed protocol specifying fluid and MABP, ICP, and CPP management: 2) continuous monitoring of protocol compliance; 3) a run-in period for new centers to test accrual and protocol adherence; and 4) inclusion of only centers in which patients are regularly randomized.

Adult↗
PubMed2000

National burden of disease in India from indoor air pollution.

In the last decade, a number of quantitative epidemiological studies of specific diseases have been done in developing countries that for the first time allow estimation of the total burden of disease (mortality and morbidity) attributable to use of solid fuels in adult women and young children, who jointly receive the highest exposures because of their household roles. Few such studies are available as yet for adult men or children over 5 years. This paper evaluates the existing epidemiological studies and applies the resulting risks to the more than three-quarters of all Indian households dependent on such fuels. Allowance is made for the existence of improved stoves with chimneys and other factors that may lower exposures. Attributable risks are calculated in reference to the demographic conditions and patterns of each disease in India. Sufficient evidence is available to estimate risks most confidently for acute respiratory infections (ARI), chronic obstructive pulmonary disease (COPD), and lung cancer. Estimates for tuberculosis (TB), asthma, and blindness are of intermediate confidence. Estimates for heart disease have the lowest confidence. Insufficient quantitative evidence is currently available to estimate the impact of adverse pregnancy outcomes (e.g., low birthweight and stillbirth). The resulting conservative estimates indicate that some 400-550 thousand premature deaths can be attributed annually to use of biomass fuels in these population groups. Using a disability-adjusted lost life-year approach, the total is 4-6% of the Indian national burden of disease, placing indoor air pollution as a major risk factor in the country.

Adult↗