The implications of the 1992 Presidential election for health care reform.
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Attitude↗
Biomedical subjects
M Smith
Publications and source records attributed to M Smith.
Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas.
Recent studies of the p53 tumor suppressor locus (designated TP53) in primary hepatocellular carcinoma (PHC) have identified a high frequency of codon 249 mutations. Due to the geographic location from which the samples were obtained and the substitution observed, the mutation was suggested to be attributable to aflatoxin B1 (AFB1) exposure. To determine the generality of this phenomenon, we have examined PHC tissues from 107 geographically and ethnically diverse sources. The frequency of p53 gene mutations was evaluated by using PCR/restriction-digest methods, GC-clamp (G+C-rich sequence) denaturing gradient gel electrophoresis, and DNA sequencing. The mutation rate observed in tumors from high-AFB1-exposure regions (25%) was more than double the rate observed in low-exposure regions (12%) but lower than the 50% frequency previously reported. Codon 249 mutations occurred at a much lower frequency than previously reported (2 of 107 samples examined). These results suggest that changes in DNA encoding p53 may not represent primary oncogenic effects but instead represent genetic changes related to tumor progression. High AFB1 levels may facilitate the generation of these progressional changes, but not by inducing a specific p53 gene mutation at codon 249 as previously reported.
Base Sequence↗
Association of pp60src with Triton X-100-insoluble residue in human blood platelets requires platelet aggregation and actin polymerization.
Protein-tyrosine phosphorylation during platelet activation is inhibited under conditions that inhibit platelet binding of fibrinogen and aggregation. We suggested that pp60src, a major platelet tyrosine kinase, or its protein substrates might become associated with the cytoskeleton upon platelet stimulation, and that this might be related to aggregation. By Western blotting with an anti-Src monoclonal antibody, we found time-dependent association of pp60src with the cytoskeleton (10,000 x g Triton X-100-insoluble matrix) but not the "membrane" cytoskeleton (100,000 x g Triton X-100-insoluble matrix) in platelets activated by U46619 (PGH2 analog). Cytoskeletal association and platelet aggregation were inhibited by the peptide Arg-Gly-Asp-Ser (RGDS) (but not by Arg-Gly-Glu-Ser (RGES)), by 10E5 antibody against glycoprotein (Gp) IIb/IIIa, and by EGTA. U46619-induced association of pp60src with cytoskeleton but not secretion or aggregation was inhibited by cytochalasin D (2 microM). Both cytochalasin D and RGDS inhibited "slow" tyrosine phosphorylation of platelet proteins. Association of pp60src with cytoskeleton induced by U46619 or ADP was not blocked by aspirin. Aspirin blocked epinephrine-induced association of pp60src with the cytoskeleton during a second phase of aggregation when an initial phase had occurred without shape change or secretion. Association of GpIIb/IIIa with the cytoskeleton also accompanied platelet aggregation, shape change, and actin polymerization; this was shown with anti-GpIIb and anti-GpIIIa antibodies. Association of pp60src and GpIIb/IIIa with the cytoskeleton and slow tyrosine phosphorylation are related phenomena.
Actins↗
Thrombospondin levels in patients with malignancy.
Thrombospondin (TSP), a large glycoprotein present in platelets, and various normal and tumor tissues, has recently been shown to promote cell adhesion and platelet aggregation. Most importantly because TSP has been shown to promote metastasis of melanoma tumor cells to the lung in a murine model (1) and since thromboembolic events commonly occur in patients afflicted with metastatic tumors, we explored the role of TSP in human cancer by measuring TSP blood levels in patients with various malignant neoplasms. Blood TSP levels were measured by indirect enzyme-linked immunoadsorbent assay (ELISA) from 20 control subjects, 22 patients with gastrointestinal (GI) cancer, 18 patients with breast cancer, and 17 patients with lung cancer. Control subjects consisted both of healthy subjects and acutely ill patients with no malignancies. TSP levels of both healthy and acutely ill controls were found to range between 245-440 ng/ml with a mean of 365 ng/ml. In contrast, elevated levels of TSP greater than the mean value of 400 ng/ml for controls ranging between 590-3,650 ng/ml were found in 20/22 (91%) patients with GI malignancies, 13/18 (72%) patients with breast cancer, and 15/17 (88%) with lung cancer. Mean TSP levels of GI, breast, and lung cancer patients were 3, 2, and 3 fold greater than controls, respectively. Increased blood TSP levels in patients were not due to increased levels of platelets since both control and patient groups had platelet counts within the normal range. These results suggest that TSP may play a role in tumor cell metastasis in man and could serve as a blood marker for metastasis.
Adult↗
Determination of evolved 14CO2 in decarboxylase reactions with application to measurement of [14C]oxalic acid.
An assay is described for the determination of the radioactive purity of [14C]oxalic acid preparations and the quantity of [14C]oxalic acid in biological samples. In this method oxalate decarboxylase is used to convert oxalate to formate and CO2. The entire procedure is carried out in a scintillation vial. The 14CO2 released in the enzymic reaction is allowed to diffuse off in a fume hood following acidification. Scintillation fluid is added to reacted and unreacted vials and the radioactivity measured. The loss of radioactivity from the reacted versus the unreacted vials provides the quantity of evolved 14CO2. This value is equal to 50% of the [14C]-oxalate (dpm) present. The radioactive purity of four preparations of [U-14C]oxalic acid was 99.0% while a fifth batch had a purity of 88%. A single batch of [U-14C]oxalic acid had a radioactive purity of 99.0% following storage of an aqueous solution, at -20 degrees C for 7 years. Recovery of [14C]oxalic acid from rat fecal extracts was 101.3%. Eight replicate analyses of a [U-14C]oxalic acid preparation gave a coefficient of variation of 0.3%. Following subcutaneous infusion of [U-14C]oxalic acid to rats, 100.2 +/- 2.9%, mean +/- SD, of the 14C in fecal extracts was present as [14C]oxalic acid (n = 10). The procedure provides a rapid, sensitive, and specific method to determine [14C]oxalic acid. It avoids the time consuming and inconvenient procedure for trapping and counting the evolved 14CO2. The approach used to determine the evolved 14CO2 may find application in other radiochemical methods that require its measurement.
Animals↗
Effect of activity on circadian variation in time of onset of acute myocardial infarction.
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Chi-Square Distribution↗
Heterogeneity in filamentous actin content among individual human blood platelets.
The content of filamentous actin in individual platelets was measured by flow cytometry, using a fluorescent probe specific for filamentous actin (F-actin), 7-nitrobenz-2-oxa-1,3-phallacidin (NBD-phallacidin). NBD-phallacidin binding to fixed platelets was specific in that either pretreatment of platelets with unlabeled phallacidin or absorption of NBD-phallacidin by rabbit skeletal F-actin, but not globular actin (G-actin), resulted in a significant loss in the bound fluorescent probe. Mean NBD-phallacidin binding to fixed platelets varied with the agonist and paralleled the changes in F-actin reported with the DNAse I inhibition assay. (1) NBD-phallacidin binding increased with stimulation by ADP, U46619 (a prostaglandin H2 analogue), or collagen and paralleled shape change. (2) Epinephrine did not increase NBD-phallacidin binding. (3) Platelets treated at 4 degrees C contained more F-actin than did platelets kept at 37 degrees C. (4) Cytochalasin D (10 mumol/L) inhibited the increase of phallacidin binding to individual platelets stimulated by either ADP or U46619. In measurements of cytosolic free calcium concentration ([Ca2+]i) by flow cytometry in Indo-1-loaded platelets, ADP's dose-response for actin polymerization was similar to that for calcium mobilization. As shown by flow cytometry, a tail population that had a minimal increase in F-actin upon stimulation with ADP or U46619 also contained the platelets with the least forward and right angle light scattering, which are functions of platelet size and shape. When platelets treated with NBD-phallacidin were incubated with S12-murine monoclonal antibody (a marker of alpha-granule secretion detected by phycoerythrin-conjugated antimouse IgG second antibody), phallacidin fluorescence paralleled S12 binding. Thus, human blood platelets are heterogeneous in regard to actin polymerization at rest and in association with platelet activation; different degrees of phallacidin binding may identify functionally different platelet populations.
Actins↗
Detection of herpesvirus DNA in the large intestine of patients with ulcerative colitis and Crohn's disease using the nested polymerase chain reaction.
The prevalence of herpesvirus DNA was examined in inflammatory bowel disease tissue. DNA was extracted from resection and biopsy specimens of the large intestine from patients with ulcerative colitis (n = 21), patients with Crohn's disease (n = 29), and patients with noninflammatory bowel disease (controls) (n = 21). The nested polymerase chain reaction was used to detect viral DNA using primer pairs specific for either cytomegalovirus (CMV), herpes simplex virus 1 (HSV1), human herpesvirus 6 (HHV6), varicella zoster virus (VZV), or Epstein Barr virus (EBV). HSV1 and VZV DNA were not detected in any of tissue samples. There was a high prevalence of CMV (81%), HHV6 (76%), and EBV (76%) DNA in ulcerative colitis tissue compared to Crohn's disease tissues (CMV 66%, HHV6 45%, EBV 55%). Control tissue had a relatively low frequency of CMV (29%) and EBV (19%) DNA but a prevalence of HHV6 DNA similar to that of ulcerative colitis (86%). However, the simultaneous presence of HHV6 and CMV and/or EBV DNA in ulcerative colitis tissue (76%) was much greater than in either Crohn's disease tissues (38%) or control tissue (29%) (P < 0.05). There was a low prevalence of CMV, HHV6, and EBV DNA in peripheral blood mononuclear cells from all patient groups. CMV and EBV are capable of reactivating HHV6: the high prevalence of coexistent HHV6 infection with either or both of these two viruses in ulcerative colitis tissue suggests that they may play a synergistic role in the pathogenesis of this disease.
Adolescent↗
Neural tube and other developmental anomalies in the guinea pig following maternal hyperthermia during early neural tube development.
Guinea pigs were exposed to hyperthermia for 1 hr once or twice on day 11, 12, 13, or 14 (E11-E14) of pregnancy. The mean rectal temperatures were elevated by 3.4 degrees C-4.0 degrees C. This treatment resulted in a marked elevation of rates of resorption and developmental defects in embryos examined at day E23. The defects observed were those affecting the neural tube (NTD) (exencephaly, encephaloceles, and microphthalmia), kyphosis/scoliosis, branchial arch defects, and pericardial edema. Embryos with NTD and kyphosis/scoliosis have not been found among newborn guinea pigs to date following maternal heat exposure on days E12-E14. It appears that embryos with these defects are filtered out by resorption or abortion by days E30-E35.
Abortion, Spontaneous↗
Autism and tuberous sclerosis.
Autism is a behavior disorder with genetic influences indicated from twin and family studies and from the co-occurrence of autism with known genetic disorders. Tuberous sclerosis complex (TSC) is a known genetic disorder with behavioral manifestations including autism. A literature review of these two disorders substantiates a significant association of autism and TSC with 17-58% of TSC subjects manifesting autism and 0.4-3% of autistic subjects having TSC. In initial data collected on 13 TSC probands and 14 autistic probands in our family study of autism and TSC, we identified 7 TSC subjects with autism. The seven TSC autistic probands are similar to non-TSC autistic probands on the Social and Communication domains of the Autism Diagnostic Inventory (ADI) (Le Couteur et al., 1989), but show fewer Repetitive Rituals. There are more male TSC probands with autism than female, despite an equal sex ratio among TSC probands. The TSC probands with autism have significantly more seizures and mental retardation than those without autism; however, the extent and etiology of associations require further study. Our preliminary findings suggest that a fruitful approach for delineating genetic influences in autism may come from further investigation of possible mechanisms underlying the association of autism and TSC.
Autistic Disorder↗
Computer assessment of life-style in a gastroenterology clinic.
To examine the potential benefit of a computer-assisted interview about life-style in gastroenterology practice, 34 consecutive patients attending a gastroenterology clinic were questioned by a computer using software designed to obtain a comprehensive history of alcohol, caffeine, cigarette, and illicit drug use, together with an assessment of exercise, sexual activity, and nutrition. Comparisons of the information obtained by the computer with clinical records revealed that physicians documented only 3% of the patients as problem drinkers, 3% as caffeine abusers, and 17% as smokers, whereas the computer identified 10% of the patients as problem drinkers, 27% as caffeine abusers, and 43% as smokers. These findings imply that patients may be more apt to tell more about adverse life-style to the computer than to a physician during clinical interview. In a sample patient population from a gastroenterology clinic, a microcomputer provides an acceptable, efficient, and potentially cost-effective way to assess life-style.
Adult↗
Restrained front seat car occupant fatalities--the nature and circumstances of their injuries.
The circumstances of a rural and urban sample of fatalities in vehicles less than six years old is described. The data originate from an in-depth, multidisciplinary study of accidents conducted in England since 1983. The sample is biased towards collisions that result in occupant injury, and this paper will concentrate on those accidents in which an occupant has been fatally injured. The initial police reporting of the fatalities included 11% of the deaths occurring from natural causes. Of the crash-related deaths with complete data, some 43% were frontal and lateral impacts, and they are analysed in greater detail. Thirty-six percent of restrained occupants died in lateral collisions. In both frontal and lateral crashes, large amounts of intrusion result in direct loading of the head and chest, particularly. Under-run crashes with large trucks constitute 30% of frontal death cases, and only 12% of fatalities received fatal injuries from belt loads. Of those cases, additional loading by unrestrained rear passengers could have been an important feature. Multiplicity of severe injuries is the rule for restrained fatalities, with head injuries as the most common cause of death. Eighty-two percent died within an hour of their crashes. Some consequences for vehicle compatibility in crashes are discussed.
Accidents, Traffic↗
Smooth muscle and epithelial cells express specific binding sites for the C1q component of complement.
In injury and inflammation, interactions of complement C1q with C1q receptors may provide attachment sites for cell localization and tissue regeneration. Cultured smooth muscle cells (58%), epithelial cells (26%), and endothelial cells (25%) attach to C1q-coated surfaces, while only 6% of cultured B cells (Raji) attach. Endothelial and Raji cells express C1q receptors, but C1q receptors (C1qR) on smooth muscle cells and epithelial cells have not previously been demonstrated. Evidence is provided that smooth muscle cells express an average of 1.5 x 10(6) C1qR/cell (K alpha = 10(8) M-1) and that epithelial cells express an average of 0.7 x 10(6) C1qR/cell (K alpha = 1.4 x 10(8) M-1). Binding properties of C1qR, and immunoreactivity to anti-C1qR antibodies, are characterized. The antibodies specifically recognize a 67-kDa component of smooth muscle cell lysates and inhibit cell attachment to C1q substrates. We conclude that distribution of C1qR may be ubiquitous; binding properties, size, and antigenicity of various C1qR may be related, but adhesive function may be tissue specific.
Animals↗
Modularisation--its versatility and value.
The issue of credit accumulation is topical and offers real prospects for nursing education to be considered as a part of an academic continuum in keeping with higher education. It cannot easily be considered without taking into account modularisation which offers a structure for the justification and award of credits. Modularisation of courses holds exciting prospects and offers a practical, logical approach to course development. Modules can be versatile and used in very cost-effective and efficient ways, both as an integral part of the course and as free-standing entities. This article considers the building of a curriculum using a modular approach. The terms module, credit and levels are examined to provide full background information. Also identified are some of the additional potential uses of modules. The work is written from the experience of developing modular courses and offers examples from an existing Diploma. There are, however, some notes of caution and these are raised to add balance to the otherwise enthusiastic discussion.
Curriculum↗
Effects of misoprostol on the pharmacokinetics of indomethacin in human volunteers.
The effects of misoprostol (200 micrograms as a single dose or q.i.d. as a multiple dose) on the pharmacokinetics of indomethacin (100 mg single-dose administration or 50 mg t.i.d. multiple-dose administration) were studied in 16 healthy human volunteers under single-dose and steady-state conditions in a randomized, double-blind, placebo-controlled, balanced three-period study design. The overall absorption as shown by the values for area under the concentration curve of indomethacin was unaffected by concurrent administration of misoprostol. However, misoprostol did significantly enhance the steady-state maximum concentration of indomethacin by 32%. Thus misoprostol does not interfere with the absorption of indomethacin despite the known inhibitory effects of this protaglandin analog on acid secretion.
Administration, Oral↗
Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder of unknown aetiology that affects numerous body systems including skin, brain and kidneys. Some TSC has been linked to chromosome 9, additional TSC genes on chromosomes 11 and 12 have been proposed, but the majority of TSC families remain unlinked. Using TSC families in which data had excluded linkage to chromosome 9, we failed to detect linkage with loci on chromosomes 11, 12 and others. One marker examined was D16S283, the closest locus on the proximal side of the polycystic kidney disease type 1 (PKD1) gene. Linkage between TSC and D16S283 demonstrated a lod score of 9.50 at theta = 0.02 with one family independently presenting a lod score of 4.44 at theta = 0.05. These data reveal an important TSC locus near the region of PKD1 on chromosome 16p13.
Alleles↗
Analysis of disulphide bridge function in recombinant bovine prolactin using site-specific mutagenesis and renaturation under mild alkaline conditions: a crucial role for the central disulphide bridge in the mitogenic activity of the hormone.
We have previously described a method for isolating Escherichia coli-produced methionyl bovine prolactin (Met-bPRL) and its renaturation using thioredoxin. This report describes an alternative renaturation procedure in which extracted Met-bPRL is incubated in air at pH 10 and 20 degrees C. Within 1 h of such treatment essentially all of the reduced Met-bPRL was converted to the oxidized form; this was accompanied by an increase to full mitogenic activity in the Nb2 cell bioassay. It was also found that, to minimize contamination by high mol. wt Met-bPRL derivatives, it is essential to have a reducing agent (dithiothreitol) present during disruption of the bacteria and to extract the protein at neutral pH. The contribution of each of the three disulphide bridges in bPRL to its bioactivity was studied with Met-bPRL variants, prepared via site-specific mutagenesis, in which cysteines were replaced by serines to prevent disulphide bond formation. Variants lacking the C4-C11 bridge, the C191-C199 bridge or both these terminal bridges were as mitogenic as authentic bPRL. (Variants lacking the C191-C199 bridge had markedly increased solubility in the presence of deoxycholate.) In contrast, variants lacking the C58-C174 bridge had greatly reduced bioactivity, indicating that integrity of the large disulphide loop is crucial to the hormone's mitogenic activity.
Animals↗
Potential precipitating factors of the onset of myocardial infarction.
Myocardial infarction (MI) usually results from thrombotic coronary artery occlusion at the site of a ruptured atherosclerotic plaque. The factors responsible for triggering MI are not known but conditions that increase serum catecholamines may be involved. Accordingly, the authors prospectively evaluated the presence of factors that may increase catecholamines immediately prior to MI in 186 patients. Myocardial infarction was documented by a rise in serum CK-MB. There were 149 men and 37 women, aged 57 +/- 12 (mean +/- SD) years. All patients were interviewed within 72 hours of admission concerning strenuous physical activity, emotional stress, and assumption of the upright posture immediately prior to the onset of symptoms. Seventy-five (40%) patients had one or more of these factors immediately prior to the onset of MI chest pain. Fourteen (8%) experienced acute emotional upset; 28 (15%) were involved in strenuous physical activity; and 39 (21%) had suddenly changed position. In the latter group, 18 changed from being supine for more than 1 hour to standing; three rose from supine to sitting; and 18 changed from prolonged sitting (greater than 60 minutes) to standing. The conclusion is that a potential triggering factor is present in many patients immediately prior to the onset of MI. A sudden change in position is the most frequent potential trigger, typically occurring the morning after awakening from sleep.
Circadian Rhythm↗