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Biomedical subjects

W E Karnes

Publications and source records attributed to W E Karnes.

At least 19 recordsLinked to original sources
PubMed1996

p53 functional loss in a colon cancer cell line with two missense mutations (218leu and 248trp) on separate alleles.

We have sequenced p53 in three colon cancer cell lines capable of autonomous proliferation. SNU-C1 and SNU-C4 cells, whose autonomous growth is dependent upon autocrine stimulation of epidermal growth factor receptor (EGFR), had wildtype p53 sequence of exons 4-9. In contrast, an EGFR ligand-independent cell line, SNU-C5, had heterozygous missense mutations affecting codons 218 (valine to leucine) and 248 (arginine to tryptophan) of p53. Bacterial cloning of p53 from SNU-C5 cells showed that the 248trp and 218leu mutants were both expressed and on separate alleles. 248trp is a common 'hot spot' mutant of p53 with variable dominant negative activity depending on the celullar context. Valine 218, in contrast, is rarely affected by mutation in cancers and is located in a region of the hydrophobic core domain away from 'hot spot' DNA contact sights. However, valine 218 is completely conserved across species, prompting us to investigate the function of 218leu in SNU-C5 cells. SNU-C5 cells exhibited complete loss of normal p53 function as evidenced by over-expression of p53 protein and by failure to show induction of p53, waf-1, mdm-2 or G1/S arrest in response to the DNA damaging agent, bleomycin. In a yeast p53 functional assay (FASAY), 50% of the clones were unable to transactivate a p53-specific promoter required for yeast colony expansion at 25, 30 or 37 degrees C. Sequencing of the p53 insert from several randomly selected wild-type and mutant yeast clones revealed that 218leu-bearing clones retained their ability to transactivate the p53-specific promoter. As expected, the 248trp-bearing clones lost this function. These data indicate that although 218leu retains normal transactivation activity on a p53 promoter in yeast at physiological temperatures, it is not capable of normal p53 function in the presence of a 248trp allele in SNU-C5 cells. It remains unclear whether the strong dominant negative activity of 248trp in SNU-C5 cells is related to the cellular context or to an unresolved abnormality of 218leu function.

Alleles↗
PubMed1994

Involuntary tonic spasms of a limb due to a brain stem lacunar infarction.

BACKGROUND AND PURPOSE: Although repetitive involuntary movements are a well-recognized manifestation of carotid occlusive disease, similar movements have not been reported with a lacunar infarction outside of the basal ganglia or subthalamic nucleus. We describe a man with tonic spasms associated with a lacunar infarction in the right ventral pons. CASE DESCRIPTION: Involuntary tonic spasms of a paretic limb developed acutely in a 69-year-old hypertensive man with a clinical presentation of pure motor hemiparesis. Magnetic resonance imaging demonstrated a lacunar infarction of the ventral pons. There was no evidence for carotid occlusive disease. An electroencephalogram recorded during the movements showed no abnormality. The abnormal movements responded well to treatment with oral diazepam. CONCLUSIONS: A brain stem lacunar infarction may be associated with involuntary tonic limb spasms clinically similar to those reported as paroxysmal symptoms of multiple sclerosis.

Aged↗
PubMed1993

Paracrine control of gastric epithelial cell growth in culture by transforming growth factor-alpha.

Studying primary cultures of replicating canine oxyntic mucosal cells, we found evidence for modulation of cell growth by endogenous factors. [3H]thymidine incorporation into DNA was rapid with cells cultured in medium free of serum or added growth factors, and growth rates of these cultures were markedly dependent on plating density, indicating mitogenic control by soluble endogenous growth factors. Data indicated that endogenous transforming growth factor-alpha (TGF-alpha) exerted mitogenic control under the following conditions. 1) TGF-alpha was detected in the cultured cells by radioimmunoassay and immunohistochemistry. 2) TGF-alpha-like immunoreactivity and receptor reactivity were present in the medium in concentrations sufficient to exert mitogenic control. 3) Receptors for TGF-alpha and epidermal growth factor (EGF) were present in the cultures. 4) Immunoabsorption by a TGF-alpha-specific antisera reduced [3H]thymidine incorporation. TGF-alpha was localized to parietal cells by immunohistochemistry and cell separation. In contrast, combined [3H]thymidine autoradiography and immunohistochemistry with anti-TGF-alpha did not detect TGF-alpha in dividing cells. We conclude that parietal cell TGF-alpha exerts paracrine control of mucosal cell growth in vitro, and we speculate that this is an important paracrine mechanism in vivo.

Cell Count↗
PubMed1993

Plasmapheresis in acute episodes of fulminant CNS inflammatory demyelination.

We present six patients with acute fulminant episodes of CNS inflammatory demyelination who responded to therapeutic plasmapheresis after failing a course of high-dose methylprednisolone administered IV. Neurologic improvement occurred in three of the patients following the second plasmapheresis. Dramatic improvement in motor function (four patients) and language (two patients) began within 2 to 14 days and persisted during the 6 to 35 months (mean, 15 months) of follow-up. Results of this uncontrolled study suggest that plasmapheresis in the absence of other immunosuppressive drugs may have a role in the treatment of severe episodes of inflammatory demyelination in a select subset of MS patients.

Adult↗
PubMed1992

Autonomous proliferation of colon cancer cells that coexpress transforming growth factor alpha and its receptor. Variable effects of receptor-blocking antibody.

Four human colon adenocarcinoma cell lines, SNU-C1, SNU-C4, SNU-C5, and NCI-H716, that are capable of proliferating autonomously in serum-free medium containing no added peptide growth factors were identified. All four cell lines show epidermal growth factor (EGF) receptors (EGFRs), express transforming growth factor alpha (TGF-alpha) messenger RNA, and release anti-TGF-alpha-immunoreactive molecules. The blocking anti-EGFR monoclonal antibody (mAb) 225 blocks autonomous proliferation of SNU-C1 and SNU-C4 cells. In both of these cell lines, the inhibitory effect of mAb 225 is reversible by the addition of EGF, TGF-alpha, or conditioned medium from any of the four cell lines. In contrast, autonomous proliferation of SNU-C5 and NCI-H716 cells is not inhibited by mAb 225 and is not affected by exogenous EGF, TGF-alpha, or conditioned medium. Together, these data confirm the previous finding that anti-EGFR antibodies can inhibit the proliferation of some carcinoma cell lines that coexpress TGF-alpha and EGFR. However, here it is shown that the mechanisms of autonomous proliferation of colon carcinoma cell lines are heterogeneous and not always sensitive to antibody disruption of TGF-alpha/EGFR autocrine interactions.

Adenocarcinoma↗
PubMed1992

Helicobacter pylori secretes a chemotactic factor for monocytes and neutrophils.

Helicobacter pylori is associated with an inflammatory reaction in the stomach and duodenum, yet the mechanism of this inflammatory infiltrate is unknown. The ability of Helicobacter pylori to secrete a factor that attracts leucocytes is investigated. Helicobacter pylori conditioned supernatant attracted neutrophils and monocytes with 50-100% of the activity of control chemotactic factor, 10(-8) M formyl-methionine-leucine-phenylalanine. Strains derived from individuals with ulcer or non-ulcer associated H pylori infections displayed similar chemotactic activity. Preliminary characterisation shows that the factor has a molecular weight of less than 3000, is heat stable, is acid resistant, and can be diluted at least 10-fold. Checkerboard analysis confirmed that the activity was chemotactic rather than chemokinetic. This chemotactic activity could play a role in the pathogenesis of Helicobacter pylori gastritis.

Chemotactic Factors↗
PubMed1991

Positive serum antibody and negative tissue staining for Helicobacter pylori in subjects with atrophic body gastritis.

Helicobacter pylori is rarely found in gastric biopsy specimens from individuals with atrophic gastritis of the body mucosa. To determine if subjects with atrophic body gastritis have evidence of previous infection with H. pylori, immunoglobulin G antibody to H. pylori was measured by enzyme-linked immunosorbent assay in sera of 399 Finnish subjects. In 124 subjects, multiple biopsy specimens from body and antrum had been evaluated for the presence of H. pylori by Giemsa staining. Antibody correlated well with H. pylori staining except in the subgroup with atrophic body gastritis, in whom the prevalence of seropositivity (86%) was significantly greater than the prevalence of positive staining (33%) (P less than 0.001). Twenty-five subjects had positive antibody and negative staining. This group had a significantly higher prevalence of atrophic body gastritis (80%), lower maximal acid output, lower serum pepsinogen I levels, and higher serum gastrin concentrations than did seropositive subjects with H. pylori. These data suggest that most patients with atrophic body gastritis, despite having a low incidence of current overt infection, have been infected with H. pylori at some point in their lives.

Adult↗
PubMed1991

Effect of age on gastric acid secretion and serum gastrin concentrations in healthy men and women.

The effects of age on basal, meal-stimulated, and human gastrin-17-stimulated gastric acid secretion rates and serum pepsinogen concentrations were evaluated in 41 healthy men and women. Older subjects (ages 44-71 years; mean, 57 years) had higher mean basal, meal-stimulated, and gastrin-17-stimulated acid secretory rates and basal serum pepsinogen I and II concentrations than younger subjects (ages 23-42 years; mean, 33 years). Age-related differences in acid secretion were especially prominent in men, and age-related differences in serum pepsinogen I and II concentrations were more prominent in women. Higher gastric acid secretion rates in older subjects could not be explained by body size (height, weight, body surface area, or fat-free body mass) or by the higher incidence of infection with Helicobacter pylori. Using a multivariate linear regression model, age had an independent positive effect on acid secretion, and H. pylori infection had an independent negative effect. It was concluded that aging is associated with an increase in gastric acid secretion in humans, especially in men, while infection with H. pylori is associated with lower acid secretion rates.

Adult↗
PubMed1991

Autocrine growth factors and solid tumor malignancy.

The ability of malignant cells to escape the constraint that normally regulate cell growth and differentiation has been a primary focus of attention for investigators of cancer cell biology. An outcome of this attention has been the discovery that the protein products of oncogenes play a role in the activation of growth signal pathways. A second outcome, possibly related to abnormal oncogene expression, has been the discovery that malignant cells frequently show an ability to regulate their own growth by the release of autocrine growth modulatory substances. Most important, the growth of certain malignant cell types has been shown to depend on autocrine growth circuits. A malignant tumor whose continued growth depends on the release of an autocrine growth factor may be vulnerable to treatment with specific receptor antagonists or immunoneutralizing antibodies designed to break the autocrine circuit. Information is rapidly emerging concerning autocrine growth factors in selected human solid tissue malignancy.

Cytokines↗
PubMed1990

Prolonged inhibition of acid secretion causes hypergastrinaemia without altering pH inhibition of gastrin release in humans.

Hypergastrinaemia induced by potent inhibitors of acid secretion is thought to occur as a result of the elimination of the inhibitory effects of intragastric acid on gastrin release. The present study was designed to determine if the mechanisms responsible for feedback inhibition of gastrin release and acid secretion by intragastric acid are preserved during four weeks of varying degrees of drug-induced acid inhibition. Forty-eight healthy male volunteers were randomly assigned to one of four treatments for four weeks: 10 mg omeprazole o.m., 20 mg omeprazole o.m., 40 mg omeprazole o.m. or 150 mg ranitidine b.d. Gastrin release and acid secretion in response to peptone meals maintained at pH 2.5 and pH 5.5 by intragastric titration, and 24-hour gastrin profiles in response to standard meals were determined before treatment, at the fourth week of treatment and two weeks after discontinuing treatment. As expected, omeprazole produced dose-related effects on acid secretion and gastrin concentrations that were largely reversed after treatment was discontinued. Gastrin release in response to pH 5.5 peptone meals remained significantly greater than gastrin release in response to pH 2.5 meals during treatment with all doses of omeprazole. The ratio of pH 5.5/pH 2.5 peptone meal-stimulated gastrin release was approximately 1.5, and remained constant for all treatment groups throughout the study period. These data indicate that four weeks of drug induced hypochlorhydria causes an apparent increase in overall G-cell function, but it does not interfere with normal feedback inhibition of gastrin release and acid secretion mediated by intragastric acidity.

Adolescent↗
PubMed1990

The gastrin hypothesis. Implications for antisecretory drug selection.

Newer potent and long-acting inhibitors of acid secretion, such as the proton pump inhibitor omeprazole, are becoming available for general use. These drugs promise to control acid-peptic disease effectively in patients who do not respond adequately to conventional short-acting H2-receptor antagonists. The safety of chronic administration of these drugs has come into question, however. Lifelong profound inhibition of acid secretion in rats induced by superpotent inhibitors of acid secretion or subtotal fundectomy is associated with the development of carcinoid tumors of enterochromaffin-like (ECL) cells in the gastric corpus. Available evidence supports a role of gastrin, which becomes chronically elevated in animals subjected to prolonged and profound hypochlorhydria. In humans, hypergastrinemic states such as Zollinger-Ellison syndrome and atrophic gastritis are associated with an increased risk of ECL-cell carcinoid tumors. Such observations have raised concern that humans may also be susceptible to carcinoid tumor formation in response to potent inhibitors of acid secretion. To date, however, no cases of carcinoid tumor have been attributed to the use of omeprazole in humans. If achlorhydric doses are not used, significant hypergastrinemia can be avoided while effectiveness of treatment is maintained. Such measures should minimize any risk of ECL-cell carcinoid tumors in humans taking potent long-term antisecretory drugs.

Achlorhydria↗
PubMed1989

Prolonged inhibition of meal-stimulated acid secretion and gastrin release following single subcutaneous administration of octreotide (SMS 201-995) in man.

Single subcutaneous doses of the somatostatin analogue, SMS 201-995, were evaluated for the degree and duration of effects on acid secretion, serum gastrin levels, and gastric emptying in eight human male subjects (mean age 44 years) over an 8-h period. All the subjects received subcutaneous 50-micrograms and 100-micrograms doses of SMS 201-995 and placebo on three separate days in a double-blind random order. Drug or placebo was administered at time 0 followed by peptone meals at time 0, 2, 4, and 6-h. Peptone meals were evacuated at time 1, 3, 5 and 7-h to create 'basal' conditions between alternate hours. Gastric acid secretion was determined hourly beginning at time--1. Both the 50-micrograms and 100-micrograms doses of SMS 201-995 significantly inhibited 'basal' and peptone meal-stimulated gastric acid secretion throughout the 8-h measurement period. The minimum effective plasma concentration of SMS 201-995 for inhibition of peptone meal-stimulated gastric acid secretion was approximately 1000 pg/ml. Peptone meal-stimulated plasma gastrin concentrations were inhibited for 5 and 7 h after 50-micrograms and 100-micrograms doses of SMS 201-995, respectively, whereas 'basal' plasma gastrins were inhibited for 4 and 6 h, respectively. Gastric emptying determined by marker dilution was not significantly enhanced compared to placebo. These results indicate prolonged and potent effects of single subcutaneous doses of SMS 201-995 on peptone-meal stimulated acid secretion and gastrin release.

Adult↗
PubMed1987

Herpes zoster arteritis: pathological findings.

This paper describes the pathological findings in two cases of delayed contralateral hemiparesis following herpes zoster arteritis. Both died of cerebral haemorrhage and a necrotizing angiitis was found involving the major vessels of the ipsilateral cerebral hemisphere. No feature of granulomatous arteritis or of encephalitis was found. It is likely that the virus spreads along intracranial branches of the ophthalmic nerve supplying the major arteries and causes the inflammatory reaction by direct invasion of vascular muscle.

Aged↗
PubMed1982

Interictal psychopathology in patients with ictal fear: a quantitative investigation.

We assessed the hypothesis that psychopathology is overrepresented in patients with temporal lobe epilepsy (TLE) who experience ictal fear. Eleven such patients were matched with two control groups: patients who had TLE without ictal fear and patients who had generalized epilepsy. On several MMPI scales, the TLE-ictal fear group scored significantly higher than the two control groups, which did not differ significantly from each other. Furthermore, the TLE-ictal fear group had more MMPI clinical scales that were pathologically elevated, had significantly more patients with histories of admission to psychiatric hospitals, and had more MMPI profiles that were psychotic than either of the control groups.

Adult↗
PubMed1981

Psychosis and epilepsy: seizure-type comparisons and high-risk variables.

Compared 153 patients with temporal lobe epilepsy (TLE) and 79 patients with generalized epilepsy on the Goldberg Index, an MMPI-derived measure of psychosis. Analysis of covariance indicated that seizure type was not related to psychosis. Multiple regression analyses indicated that, in TLE, being female was correlated positively with Goldberg Index scores. In the group with generalized epilepsy, none of the variables was associated significantly with psychosis scores.

Adult↗
PubMed1981

Angiographic findings in herpes zoster arteritis.

Four adults patients who experienced an ipsilateral hemispheric deficit 6 to 8 weeks after having developed herpes zoster ophthalmicus were seen during a six-month period. All four patients underwent full-circle angiography, including study of the extracranial arteries in the three older patients. Each examination demonstrated areas of segmental constriction of arteries on the ipsilateral side; two locations that were especially affected were the A2 segment of the pericallosal artery beneath the genu of the corpus callosum and the M4 segment of the middle cerebral artery. The cerebral arteries of the opposite hemisphere and the extracranial vessels did not contain demonstrable abnormalities. Pathological studies suggest that patients with this syndrome may have a necrotizing arteritis of ipsilateral blood vessels; in patients with disseminated zoster, a granulomatous angiitis of cerebral blood vessels has been found. We propose that the pattern of angiographic abnormalities described here is characteristic of herpes zoster arteritis; furthermore, the distribution pattern of the lesions suggests that the virus may spread to these arteries via branches of the ophthalmic division of the trigeminal nerve.

Adult↗