The function and stability of the tumor suppressor p53 are tightly controlled by the negative regulator mouse double minute 2 (Mdm2), which binds to p53, blocking DNA binding and targeting p53 for ...proteosome-mediated degradation. Following DNA damage or cellular stress, p53 is phosphorylated within the Mdm2 binding domain on threonine 18 and serine 20. To analyze the roles of these phosphorylation events, residues 18 and 20 were mutated to alanines. Transient transfection into p53-null cells demonstrated that the T18A protein can be expressed stably, but the S20A protein is very unstable, precluding further analysis. When expressed stably at low basal levels in p53-null human fibroblasts or fibrosarcoma cells, the T18A mutant accumulated 5–10-fold less well than wild-type p53 following exposure to UV. Analysis of p53-dependent transcription following UV revealed that the phosphorylation of threonine 18 is required for transactivation of the p21, Hdm2 (the human ortholog of Mdm2), and GADD45 genes. The phosphorylation of serine 33, another early event following DNA damage, is not required for p53 accumulation or p53-dependent transactivation following UV.
The population-based National Down Syndrome Project combined epidemiological and molecular methods to study congenital heart defects in Down syndrome.
Between 2000 and 2004, six sites collected DNA, ...clinical, and epidemiological information on parents and infants. We used logistic regression to examine factors associated with the most common Down syndrome-associated heart defects.
Of 1469 eligible infants, major cardiac defects were present in 44%; atrioventricular septal defect (39%), secundum atrial septal defect (42%), ventricular septal defect (43%), and tetralogy of Fallot (6%). Atrioventricular septal defects showed the most significant sex and ethnic differences with twice as many affected females (odds ratio, 1.93; 95% confidence interval, 1.40–2.67) and, compared with whites, twice as many blacks (odds ratio, 2.06; 95% confidence interval, 1.32–3.21) and half as many Hispanics (odds ratio, 0.48; 95% confidence interval, 0.30–0.77). No associations were found with origin of the nondisjunction error or with the presence of gastrointestinal defects.
Sex and ethnic differences exist for atrioventricular septal defects in Down syndrome. Identification of genetic and environmental risk factors associated with these differences is essential to our understanding of the etiology of congenital heart defects.
Previously, we found that the protein kinase C (PKC) inhibitor H7 stimulates p53 to accumulate in a form incapable of inducing
transcription from p53-dependent promoters. We concluded that H7 ...inhibits constitutive C-terminal phosphorylation of p53,
which regulates its turnover in unstressed cells. We now show that p53 and its inhibitor MDM2 (HDM2 in human cells) are together
in the nuclei of H7-treated cells and can be co-immunoprecipitated. Despite this association of p53 with the ubiquitin ligase
MDM2, ubiquitinated p53 was not detected in H7-treated cells. Furthermore, co-treatment with H7 and the proteosome inhibitor
LLnL prevented the accumulation of ubiquitinated p53 that was observed in cells treated solely with LLnL. In addition, treatment
of cells with the PKC activator phorbol ester stimulated the ubiquitination of p53 and reduced its ability to accumulate after
stress. H7 did not induce the phosphorylation of human p53 on Ser-15 (Ser-18 in mouse protein), a modification that occurs
in response to DNA damage and leads to the release of MDM2 and to transactivation by p53. We conclude that phosphorylation
of the C-terminal domain of p53 by PKC increases its ubiquitination and degradation in unstressed cells.
During two separate
Karenia brevis red tide events, we measured the levels of brevetoxins in air and water samples, conducted personal interviews, and performed pulmonary function tests on people ...before and after they visited one of two Florida beaches. One hundred and twenty-nine people participated in the study, which we conducted during red tide events in Sarasota and Jacksonville, FL, USA. Exposure was categorized into three levels: low/no exposure, moderate exposure, and high exposure. Lower respiratory symptoms (e.g. wheezing) were reported by 8% of unexposed people, 11% of the moderately exposed people, and 28% of the highly exposed people. We performed nasal–pharyngeal swabs on people who experienced moderate or high exposure, and we found an inflammatory response in over 33% of these participants. We did not find any clinically significant changes in pulmonary function test results; however, the study population was small. In future epidemiologic studies, we plan to further investigate the human health impact of inhaled brevetoxins.
Unlike other waste streams, municipal solid waste (MSW) is collected manually, and MSW collection has recently been found to be among the highest‐risk occupations in the United States. However, as ...for other occupational groups, actual total injury rates, including the great majority of injuries not compensated and those compensated by other insurance, are not known. In this article a predictive Bayesian method of assessing total injury rates from available information without computation is presented, and used to assess the actual numbers of musculoskeletal and dermal injuries requiring clinical care of MSW workers in Florida. Closed‐form predictive Bayesian distributions that narrow progressively in response to information, representing both uncertainty and variability, are presented. Available information included workers' compensation (WC) data, worker population data, and safety records for one private and one public collection agency. Subjective input comprised epidemiological and medical judgment based on a review of 165 articles. The number of injuries was assessed at 3,146 annually in Florida, or 54 ± 18 injuries per 100 workers per year with 95% confidence. Further, WC data indicate that the injury rate is 50% higher for garbage collectors specifically, indicating a rate of approximately 80 per 100 workers. Results, though subject to uncertainty in worker numbers and classification and reporting bias, agreed closely with a survey of 251 MSW collectors, of whom 75% reported being injured (and 70% reported illness) within the past 12 months. The approach is recommended for assessment of total injury rates and, where sufficient information exists, for the more difficult assessment of occupational disease rates.
The accuracy and comprehensibility with which a molecular genetics test result is reported are as important as the result itself. It is from this report that a healthcare provider will present ...genetic information to a patient and their family and make decisions for further testing, diagnosis, and treatment. The purpose of this chapter is to outline the necessary components of a molecular genetics test report and give examples to illustrate their importance.
Injury and disease distributions amongst municipal solid waste (MSW) workers in Florida were analyzed from data from the Florida Workers’ Compensation scheme between 1993 to 1997. Municipal solid ...waste workers in Florida were most commonly exposed to musculoskeletal and dermal injury risks such as strains or sprains, contusions, fractures, and lacerations. Strains or sprains represented 47.7% of all the reported injuries, similar to the proportion found for other Florida industrial workers (45.7%). Waste collectors (drivers or helpers) had a higher risk of injury than other workers in the MSW industry. Whilst injury rates for all Florida industrial workers decreased, the injury rates of MSW workers almost doubled from 1993 to 1997. It was noted that workers’ compensation claims represent only a fraction of total injuries. Possible reasons for the high risks were discussed. Occupational diseases amongst MSW workers are believed to be under reported. Further studies on different waste management worker subpopulations are needed to provide detailed information to reduce these risks.
Injury and disease distributions amongst municipal solid waste (MSW) workers in Florida were analyzed from data from the Florida Workers' Compensation scheme between 1993 to 1997. Municipal solid ...waste workers in Florida were most commonly exposed to musculoskeletal and dermal injury risks such as strains or sprains, contusions, fractures, and lacerations. Strains or sprains represented 47.7% of all the reported injuries, similar to the proportion found for other Florida industrial workers (45.7%). Waste collectors (drivers or helpers) had a higher risk of injury than other workers in the MSW industry. Whilst injury rates for all Florida industrial workers decreased, the injury rates of MSW workers almost doubled from 1993 to 1997. It was noted that workers' compensation claims represent only a fraction of total injuries. Possible reasons for the high risks were discussed. Occupational diseases amongst MSW workers are believed to be under reported. Further studies on different waste management worker subpopulations are needed to provide detailed information to reduce these risks.
Age-specific structured encounter forms for well-child examinations have been shown to improve thoroughness of documentation among pediatric house staff. This study evaluated the influence of such ...forms on completeness of documentation by practicing pediatricians.
In this before-after trial at 5 urban community health clinics, participants were 8 pediatricians practicing for at least 1 year. Brief group training sessions on use of the forms were provided to the participating physicians. Completeness of documentation was defined as the proportion of elements from a full well-child examination recorded in the medical record.
After introduction of the standardized forms, completeness of documentation significantly increased for all components.
The use of age-specific structured encounter forms improved the completeness of documentation of pediatric well-child examinations done by pediatricians.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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