Pretreatment minimal staging and prognostic factors for non-small cell lung cancer.
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Carcinoma, Non-Small-Cell Lung↗
Biomedical subjects
R Stephens
Publications and source records attributed to R Stephens.
Quality of life assessment in clinical trials--guidelines and a checklist for protocol writers: the U.K. Medical Research Council experience. MRC Cancer Trials Office.
Many clinical trials groups now routinely consider including Quality of Life (QoL) assessment in trials. Indeed, several have policies stating that QoL should be considered as a potential endpoint in all new trials and that if it is not to be evaluated the applicants should justify not doing so. However, inclusion of QoL in clinical trials presents a number of difficult organisational issues, and serious problems in compliance have frequently been reported. Thus, in multicentre clinical trials many of the expected QoL questionnaires fail to be successfully completed and returned, although a few groups have claimed high success rates. However, it is well recognised that if questionnaires are missing, there may be bias in the interpretation of trial results, and the estimates of treatment differences and the overall level of QoL may be inaccurate and misleading. Hence it is important to seek methods of improving compliance, at the level of both the participating institution and the patient. We describe a number of methods for addressing these issues, which we suggest should be considered by all those writing clinical trial protocols involving QoL assessment. These are based upon over a decade of experience with assessing QoL in Medical Research Council (MRC) cancer clinical trials. In particular, we provide a checklist for points that should be covered in protocols. Examples are given from a range of current MRC Cancer Trials Office protocols, which it is proposed might act as templates when writing new protocols.
Clinical Protocols↗
Marketing clinical trials.
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Clinical Trials as Topic↗
School-associated violent deaths in the United States, 1992 to 1994.
OBJECTIVES: To conduct the first nationwide investigation of violent deaths associated with schools in the United States, to quantify the risk of school-associated violent death, and to identify epidemiologic features of these deaths. DESIGN: Descriptive case series. SETTING: United States, July 1, 1992, through June 30, 1994. METHODS: School-associated violent deaths were identified by study collaborators and through 2 online news databases. Police reports, medical examiners' records, and interviews with police and school officials provided detailed information about each case. RESULTS: In a 2-year period, 105 school-associated violent deaths were identified. The estimated incidence of school-associated violent death was 0.09 per 100 000 student-years. Students in secondary schools, students of minority racial and ethnic backgrounds, and students in urban school districts had higher levels of risk. The deaths occurred in communities of all sizes in 25 different states. Homicide was the predominant cause of death (n = 85 [80.9%]), and firearms were responsible for a majority (n = 81 [77.1%]) of the deaths. Most victims were students (n = 76 [72.4%]). Both victims and offenders tended to be young (median ages, 16 and 17 years, respectively) and male (82.9% and 95.6%, respectively). Approximately equal numbers of deaths occurred inside school buildings (n = 31 [29.5%]), outdoors but on school property (n = 37 [35.2%]), and at off-campus locations while the victim was in transit to or from school (n = 37 [35.2%]). Equal numbers of deaths occurred during classes or other school activities (n = 46 [43.8%]) and before or after official school activities (n = 46 [43.8%]). CONCLUSIONS: School-associated violent deaths were more common than previously estimated. The epidemiologic features of these deaths were similar to those of homicides and suicides that occur elsewhere. A comprehensive approach that addresses violent injury and death among young people at school and elsewhere in the community is suggested.
Adolescent↗
Identification of residues that control specific binding of the Shc phosphotyrosine-binding domain to phosphotyrosine sites.
The Shc adaptor protein contains two phosphotyrosine [Tyr(P)]binding modules--an N-terminal Tyr(P) binding (PTB) domain and a C-terminal Src homology 2 (SH2) domain. We have compared the ability of the Shc PTB domain to bind the receptors for nerve growth factor and insulin, both of which contain juxtamembrane Asn-Pro-Xaa-Tyr(P) motifs implicated in PTB binding. The Shc PTB domain binds with high affinity to a phosphopeptide corresponding to the nerve growth factor receptor Tyr-490 autophosphorylation site. Analysis of individual residues within this motif indicates that the Asn at position -3 [with respect to Tyr(P)], in addition to Tyr(P), is critical for PTB binding, while the Pro at position -2 plays a less significant role. A hydrophobic amino acid 5 residues N-terminal to the Tyr(P) is also essential for high-affinity binding. In contrast, the Shc PTB domain does not bind stably to the Asn-Pro-Xaa-Tyr(P) site at Tyr-960 in the activated insulin receptor, which has a polar residue (Ser) at position -5. Substitution of this Ser at position -5 with Ile markedly increased binding of the insulin receptor Tyr-960 phosphopeptide to the PTB domain. These results suggest that while the Shc PTB domain recognizes a core sequence of Asn-Pro-Xaa-Tyr(P), its binding affinity is modulated by more N-terminal residues in the ligand, which therefore contribute to the specificity of PTB-receptor interactions. An analysis of residues in the Shc PTB domain required for binding to Tyr(P) sites identified a specific and evolutionarily conserved Arg (Arg-175) that is uniquely important for ligand binding and is potentially involved in Tyr(P) recognition.
3T3 Cells↗
Computer services to patients' homes through their telephones. Application to other disease management efforts.
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Chronic Disease↗
Abnormalities on neurological examination among sheep farmers exposed to organophosphorous pesticides.
OBJECTIVES: Organophosphates are effective pesticides which are frequently used in several agricultural settings. Although their acute effects are well characterised, it remains unclear whether long term exposure can damage the human nervous system. This study sought to investigate their long term effects by comparing abnormalities on neurological examination between groups of workers exposed to organophosphates and an unexposed group. METHODS: 146 exposed sheep farmers and 143 unexposed quarry workers were recruited into a cross sectional study of symptoms and neuropsychological effects of long term exposure to organophosphates in sheep dip. From a symptom questionnaire given immediately after dipping the 10 most symptomatic and 10 least symptomatic farmers were selected. Several months later each of these, along with 10 of the unexposed quarry workers, underwent a standardised neurological examination similar to that which might be used in clinical practice, at at time as remote as possible from recent exposure to organophosphates so as to exclude any acute effects. RESULTS: All 30 selected subjects agreed to participate. The components of the examination which showed a significant difference were two point discrimination on the dorsum of the hand (symptomatic farmers 22 mm; asymptomatic farmers 13 mm; quarry workers 8 mm) and the dorsum of the foot (symptomatic farmers 34 mm; asymptomatic farmers 10 mm; quarry workers 11 mm), and mean calf circumference (symptomatic farmers 35.0 cm; asymptomatic farmers 36.3 cm; quarry workers 38.6 cm). Overall the prevalence of neurological abnormalities was low. CONCLUSIONS: The differences in neurological examination detected between groups were subtle and their clinical significance was unclear. However, they do suggest evidence of an adverse neurological effect from exposure to organophosphates. Further, larger scale studies will be required before it is possible to confirm or refute the differences detected.
Adult↗
Neuropsychological effects of long-term exposure to organophosphates in sheep dip.
Organophosphate-based pesticides are widely used throughout the world. The acute effects of over-exposure to such compounds are well known. Concern has also been expressed that long-term exposure may result in damage to the nervous system. In a cross-sectional study, we compared neuropsychological performance in 146 sheep farmers who were exposed to organophosphates in the course of sheep dipping with 143 non-exposed quarry workers (controls). The farmers performed significantly worse than controls in tests to assess sustained attention and speed of information processing. These effects remained after adjustment for covariates. The farmers also showed greater vulnerability to psychiatric disorder than did the controls as measured by the General Health Questionnaire. There were no observed effects on short-term memory and learning. Repeated exposure to organophosphate-based pesticides appears to be associated with subtle changes in the nervous system. Measures should be taken to reduce exposure to organophosphates as far as possible during agricultural operations.
Adolescent↗
A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides.
BACKGROUND: Signal transduction by growth factor receptor protein-tyrosine kinases is generally initiated by autophosphorylation on tyrosine residues following ligand binding. Phosphotyrosines within activated receptors form binding sites for the Src homology 2 (SH2) domains of cytoplasmic signalling proteins. One such protein, Shc, is tyrosine phosphorylated in response to a large number of growth factors and cytokines. Phosphorylation of Shc on tyrosine residue Y317 allows binding to the SH2 domain of Grb2, and hence stimulation of the Ras pathway. Shc is therefore implicated as an adaptor protein able to couple normal and oncogenic protein-tyrosine kinases to Ras activation. Shc itself contains an SH2 domain at its carboxyl terminus, but the function of the amino-terminal half of the protein is unknown. RESULTS: We have found that the Shc amino-terminal region binds to a number of tyrosine-phosphorylated proteins in v-src-transformed cells. This domain also bound directly to the activated epidermal growth factor (EGF) receptor. A phosphotyrosine (pY)-containing peptide modeled after the Shc-binding site in polyoma middle T antigen (LLSNPTpYSVMRSK) was able to compete efficiently with the activated EGF receptor for binding to the Shc amino terminus. This competition was dependent on phosphorylation of the tyrosine residue within the peptide, and was abrogated by deletion of the leucine residue at position -5. The Shc amino-terminal domain also bound to the autophosphorylated nerve growth factor receptor (Trk), but bound significantly less well to a mutant receptor in which tyrosine Y490 in the receptor's Shc-binding site had been substituted by phenylalanine. CONCLUSION: These data implicate the amino-terminal region of Shc in binding to activated receptors and other tyrosine-phosphorylated proteins. Binding appears to be specific for phosphorylated tyrosine residues within the sequence NPXpY, which is conserved in many Shc-binding sites. The Shc amino-terminal region bears only very limited sequence identify to known SH2 domains, suggesting that it represents a new class of phosphotyrosine-binding modules. Consistent with this view, the amino-terminal Shc domain is highly conserved in a Drosophila Shc homologue. Binding of Shc to activated receptors through its amino terminus could leave the carboxy-terminal SH2 domain free for other interactions. In this way, Shc may function as an adaptor protein to bring two tyrosine-phosphorylated proteins together.
3T3 Cells↗
Subungual melanoma: a relation to direct injury?
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Adult↗
A survey of the radiographic practices of general dentists for edentulous patients.
OBJECTIVE: The objective of the study was to evaluate the radiographic practice of general dentists for edentulous patients. STUDY DESIGN: A questionnaire was sent to a sample of graduates from the two Ontario dental schools. RESULTS: The adjusted response rate for the survey was 80%. Fifty-three percent of the respondents used screening radiography for new patients. The overwhelming choice for these dentists was the panoramic film. There was a significant positive association between ownership of a panoramic unit and use of this radiograph. Dentists who do not own a panoramic unit rarely chose to refer their patients for this radiograph either routinely or selectively. When dentists, rather than the auxiliaries, made the greater proportion of the radiographs, they tended to use selective radiography. Most dentists chose selective radiography for the recall patient. CONCLUSIONS: Almost half the dentists did not follow the Food and Drug Administration/American Dental Association guideline of screening radiography for the new edentulous patient. Of those dentists who did follow the guideline the vast majority both owned panoramic units and chose to use a panoramic survey. Most dentists followed the guideline for selective radiography for the recall patient.
American Dental Association↗
Characterization of membrane bound carbonic anhydrase IV (CA IV) located on the external surface of lung pulmonary endothelial cells.
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Animals↗
Case report: congenital adrenal hyperplasia and malignant Leydig cell tumor.
Leydig cell tumors are very rarely seen testicular tumors and can be difficult to distinguish from testicular tumors of the adrenogenital syndrome. Testicular tumors of the adrenogenital syndrome are confined to patients with congenital adrenal hyperplasia. The authors report a case of a patient with malignant Leydig cell tumor and a history of congenital adrenal hyperplasia (adrenogenital syndrome). To the authors' knowledge, this has not been reported previously.
Adrenal Hyperplasia, Congenital↗
Workshop on perinatal exposure to dioxin-like compounds. I. Summary.
An international workshop reviewed 20 ongoing or recently completed studies of the effects of perinatal exposures to dioxins, dibenzofurans, and PCBs on the reproductive, endocrine, neurodevelopmental, and immune systems. Many of the observed effects are consistent with these compounds acting as "environmental hormones" or endocrine disrupters. This report summarizes the conclusions and future directions described at the workshop.
Animals↗
Equine infectious anemia virus trans-regulatory protein Rev controls viral mRNA stability, accumulation, and alternative splicing.
The cis- and trans-acting components of the Rev regulatory pathway employed by equine infectious anemia virus (EIAV) to regulate and coordinate viral gene expression were examined in complementation experiments. Viral protein expression and mRNA expression were compared in cells transiently transfected with wild-type or mutant proviruses in combination with Rev expression plasmids. Mutation of the predicted rev gene abolished Gag protein synthesis, and this defect was complemented, in trans, by Rev. Analysis of viral mRNAs from transfected cells confirmed that EIAV expresses five major mRNAs: the full-length and singly spliced mRNAs contain introns and encode viral structural proteins while the three fully spliced mRNAs, encoding nonstructural genes, are generated by alternative splicing. Compared to cells transfected with the wild-type provirus, the intron-containing mRNAs produced from the rev-minus mutant were present at reduced levels in the nuclear RNA fraction and were not detected in the cytoplasm. This pattern of viral mRNA synthesis was restored to the wild-type pattern by providing Rev in trans. In contrast to the intron-containing mRNAs, cytoplasmic accumulation of the multiply spliced class of mRNAs was independent of Rev. Closer examination of the multiply spliced class of viral mRNAs by reverse transcriptase-PCR analysis revealed a Rev-dependent alternative splicing phenomenon. In the absence of Rev, proviruses expressed a four-exon mRNA at high levels; the addition of Rev caused both a decrease in the levels of the four-exon mRNA and the appearance of a related mRNA lacking exon 3. The cis-acting RNA elements that mediate Rev responsiveness were studied with deleted proviruses, which revealed that EIAV contains at least two elements located near the ends of envelope gene. Unlike the Rev-responsive elements in other retroviruses, the cis-acting regions of EIAV do not appear to form complex secondary structures.
Alternative Splicing↗
Clinical trials and clinical practice.
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Clinical Trials as Topic↗
Abundant urokinase activity on the surface of mononuclear cells from blood and bone marrow of acute leukemia patients.
We have examined the mononuclear cell fraction from 35 individuals, 18 with hematologic malignancies and 17 healthy controls for the presence of cell surface-associated plasminogen activator (PA) activity. PA activity was found on the cell surface of 10 out of 12 samples from patients with acute leukemia. In addition to active urokinase (uPA) found on the cell surface in four out of five acute myeloid leukemia patients, tissue-type PA activity was detected in the same samples (3 of 5). Two out of four samples from acute lymphoid leukemia displayed only uPA activity and three out of three samples from biphenotypic leukemia were also clearly uPA-positive. Plasmin activity was not detected in any of the samples. PA activity was not found on the surface of mononuclear cells from either patients with chronic lymphoid leukemia or healthy controls and, in this respect, the cell surface-bound uPA activity behaved as a marker for acute leukemia. The finding of PA activity on the cell surface in acute leukemia suggests that there may be continuous generation of plasmin with consequent consumption of plasma plasmin inhibitors.
Bone Marrow↗