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Biomedical subjects

G L Shaw

Publications and source records attributed to G L Shaw.

At least 19 recordsLinked to original sources
PubMed1992

Age at onset for familial epithelial ovarian cancer.

OBJECTIVE: To provide age-specific risks for ovarian cancer for relatives of ovarian cancer case patients. To characterize the age at onset for ovarian cancer for women with a single relative vs several relatives affected with ovarian cancer. DESIGN: Three previous studies were reexamined. The cumulative probability of ovarian cancer in first-degree relatives of women with histologically confirmed epithelial ovarian cancer and matched control subjects who participated in the Cancer and Steroid Hormone (CASH) Study was determined. The age of onset of ovarian cancer in women with and without relatives with ovarian cancer in a Washington, DC, case-control study was contrasted with that of women with at least two first-degree relatives studied at the National Cancer Institute (NCI). RESULTS: The CASH Study data showed that first-degree relatives of women with ovarian cancer had an increased risk for ovarian cancer, especially at older ages, when compared with relatives of control subjects. However, the median age at onset was the same among women in the Washington, DC, study with and without an affected relative. Among the women with an extensive family history of ovarian cancer studied at the NCI, the age at onset was considerably younger (47 years) than is typical for this disease (59 years). Of these, 17% had been diagnosed as having primary ovarian cancer by age 40 years. CONCLUSIONS: Women who have one first-degree relative affected by ovarian cancer are at greater risk for ovarian cancer but not at an age earlier than the general population. The small proportion of women who have several affected relatives are, however, at a greater risk of early onset of ovarian cancer. Prophylactic oophorectomy may be reasonable for these women.

Adult↗
PubMed1992

Candidate biomarkers for application as intermediate end points of lung carcinogenesis.

The need for validated intermediate end point markers to facilitate lung cancer chemointervention research is compelling. Three major classes of lung markers are relevant for this application. Since lung cancer includes four distinct histologies, markers that map degrees of histologic differentiation are important. Many of the markers for squamous differentiation overlap with the candidates for application in the study of head and neck cancer. Production of tissue-specific cell products especially for surfactant or CEA is of interest, because the gene structure is known and many differentiation-related polymorphisms exist. This strategy would be useful for adenomatous type tissue. A second type of marker is the broad group of differentiation markers. The carbohydrate or blood group-like antigens comprise a representative example. Carbohydrate structures are expressed in a specific sequence during fetal processes, and this sequence appears to reverse with the development of a cancer. Retrodifferentiation of specific differentiation markers is the basis of a major effort to effect earlier lung cancer detection using sputum immunocytochemistry. The final class includes markers which affect either positive or negative aspects of growth. Candidates in this area include growth factors or their receptors, or genes that regulate growth. If the intermediate end point marker reflects tumor biology and that biology is in the causal path of tumor progression, serial observation of that parameter should indicate the success of the intervention. In all three of these examples, the clinical material to be analyzed could be sputum specimens, bronchial biopsies or resected lung tissue. Systematic analysis of these markers in context of intervention trials is required to validate their utility.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1992

Reversal of epileptic state by patterned electrical stimulation suggested by trion model calculations.

The trion model is based on the Mountcastle columnar organizational principle of cortex. A trion represents an idealized minicolumn with three levels of firing activity and is highly structured in time and in spatial connections. A network of trions has a large repertoire of quasi-stable, periodic spatial-temporal firing patterns, MPs, which can be excited and each MP can be readily enhanced by a Hebb learning rule. A particular MP present in most repertoires has all trions firing together in synchrony, which we identify as the 'Epileptic' MP (EMP). In trion model simulations, the EMP can be enhanced via the Hebb rule after electrical stimulation so that an epileptic focus with after discharge (about 3-6 Hz) is formed and spontaneous firing of the EMP occurs (as in kindling). Following this, by using a small array of closely-spaced stimulating electrodes out of phase, other MPs are enhanced via the Hebb rule eliminating the dominance of the EMP. We strongly urge that these predictions be tested in the animal models for possible clinical relevance.

Cerebral Cortex↗
PubMed1992

The debrisoquine metabolic phenotype and DNA-based assays: implications of misclassification for the association of lung cancer and the debrisoquine metabolic phenotype.

Debrisoquine is an antihypertensive drug that is metabolized by cytochrome P4502D6. Deficient metabolism is inherited as an autosomal recessive condition. We previously reported in a case-control study that extensive metabolizers of debrisoquine were at greater risk of lung cancer compared to poor and intermediate metabolizers. Cloning of the gene that encodes P4502D6 (CYP2D6) led to the identification of both wild-type and mutant forms of the gene. Subsequently, a DNA-restriction fragment length polymorphism (RFLP) was identified, and a Southern hybridization-based test was developed in an attempt to define the genotype. When the DNA-RFLP test was applied to stored DNA from our study subjects there was neither a significant association with the metabolic phenotype nor an association with lung cancer. Further work has demonstrated that the wild-type gene, which was characterized by a 29-kb allele, can also contain mutations that result in nonfunctional or absent proteins. When these mutations are present, individuals exhibit the poor or intermediate metabolizer phenotype in spite of the presence of the 29-kb putative wild-type allele. Sequence determination of the mutants led to the development of techniques to exploit the polymerase chain reaction, which, together with Southern analysis, have been reported to detect as many as 95% of poor metabolizers. This technique is being used to examine the association of the extensive metabolizer genotype with lung cancer in the subjects from the case-control study. Preliminary results indicate a weak association between the homozygous wild-type genotype and lung cancer; in contrast, the extensive metabolizer phenotype is strongly associated with lung cancer in this subset.(ABSTRACT TRUNCATED AT 250 WORDS)

Case-Control Studies↗
PubMed1991

Lung cancer risk associated with cancer in relatives.

Family history data from an incident case-control study of lung cancer conducted in the Texas Gulf Coast region between 1976 and 1980 were analyzed to evaluate the contribution of cancer in first-degree relatives to lung cancer risk. Odds ratios (OR) increased slightly as the number of relatives with any cancer increased (reaching 1.5 with 4 or more relatives with cancer). Risks were higher for tobacco-related cancers (OR = 1.5 for 2 or more relatives with these tumors) and greatest for first-degree relatives with lung cancer (OR = 2.8 for lung cancer in 2 or more relatives). For cases of squamous cell carcinoma and adenocarcinoma of the lung, risks with 3 or more relatives with any cancer were increased 2-fold (OR = 1.8 and 1.9 respectively), and a significantly elevated risk was found for having a first-degree relative with lung cancer for each histologic type (ORs from 1.7-2.1). Having a spouse with lung cancer increased lung cancer risk (OR = 2.5), and cases with lung cancer reported in a first-degree relative were diagnosed at an earlier age, as were case siblings with lung cancer.

Adenocarcinoma↗
PubMed1991

Problems ascertaining friend controls in a case-control study of lung cancer.

Willingness of newly diagnosed lung cancer patients to volunteer names of friends as potential control subjects was assessed from August through December 1988 in a case-control study at the National Cancer Institute and Naval Hospital, Bethesda, Maryland. Friend controls appeared ideal to examine a genetically determined metabolic characteristic and lung cancer risk, since potentially confounding characteristics could be matched and cooperation should be high. Only 11 of 23 cases named at least one friend. Cases interviewed during the second study month were most likely to volunteer names. Either the recency of the diagnosis of a highly fatal disease or the referral to a tertiary care research hospital may have contributed to the reluctance of cases to volunteer names. No characteristic was identified that might offer a means to increase referral of friend controls.

Adenocarcinoma↗
PubMed1991

Clinical implications of the competitive inhibition of the debrisoquin-metabolizing isozyme by quinidine.

Approximately 10% of western populations are genetically deficient in the enzyme that metabolizes the antihypertensive drug debrisoquin. These "poor metabolizers" process many common medications in an aberrant fashion, resulting in a variety of untoward consequences including exaggerated drug effect, subtherapeutic drug concentrations, or complex drug interactions. A variety of medications, including neuroleptics, antidepressants, beta-blockers, and certain antiarrhythmics, are subject to the influence of this metabolic polymorphism. Quinidine administration changes persons to poor metabolizers of debrisoquin for the duration of therapy. Thus, the use of quinidine with any of the other drugs metabolized by this isozyme may be expected to result in a drug interaction in which a person's response will mimic that of a poor metabolizer. Because no test is commonly available to determine directly the debrisoquin metabolic phenotype, clinicians should be alert to unusual drug reactions in patients receiving quinidine concurrently with the other medications.

Adrenergic beta-Antagonists↗
PubMed1990

Human debrisoquine hydroxylase gene polymorphisms in cancer patients and controls.

The extensive metabolizer phenotype of debrisoquine has been associated with increased risk of lung cancer, and it has been proposed that a molecular test for this phenotype is feasible. DNA restriction fragment length polymorphisms of the human debrisoquine 4-hydroxylase gene locus (CYP2D6), and the metabolic phenotype for debrisoquine have been studied in a group of healthy volunteers, a group of lung cancer patients and two control groups (chronic obstructive pulmonary disease patients and patients with cancers at sites other than the lung). Confirmation of four distinct XbaI allelic fragments (44, 29, 16/9 and 11.5 kb), previously identified among caucasians, was obtained. The 29 kb alleles were the most frequently observed in both poor and extensive metabolizers of debrisoquine. Alleles of 44 kb were found with approximately equal frequency among both poor and extensive metabolizers. The data are consistent with the hypothesis that the 11.5 and 44 kb fragments are associated with mutant alleles of the CYP2D6 gene, but the power of phenotype prediction by these alleles was less than that previously reported for a European (Swiss-German) population. Similarly, the data also show that 8% of 29 kb homozygotes are poor metabolizers (indicating that at least 28% of 29 kb fragments are also associated with mutant alleles) and are not therefore informative for predicting the debrisoquine phenotype. The 16/9 allele may represent either wild-type or mutant alleles. Restriction fragments of 44 kb were found more frequently among cancer patients and chronic obstructive pulmonary disease patients (30%) than among the healthy volunteer group (7%). Genotypes observed were not related to lung tumor histology. Furthermore, at least three EcoRI alleles were found to be in linkage disequilibrium with the 'mutant' 44 kb allele. These data suggest that the 44 kb allele can comprise three distinct haplotypes, in contrast to studies of a European population. These studies indicate that no single mutant CYP2D6 allele as determined by EcoRI appears to be associated with lung cancer, despite the findings that these patients are invariably of the extensive metabolizer phenotype.

Adenocarcinoma↗
PubMed1986

Associative recall properties of the trion model of cortical organization.

We developed a cooperative model of the cortical column incorporating an idealized subunit, the trion (which represents a localized group of neurons), and a discrete time step for firing. We found that networks composed of a small number of trions (with symmetric interactions) supported up to thousands of quasi-stable, periodic firing patterns (MPs) which could be selected out with only small changes in interaction strengths using a Hebb-type algorithm. Here we report a study of the associative recall properties showing striking features: By considering all possible initial firing patterns (for a given set of network connections), we find 1) It takes on the average only 2-5 time steps to recall an MP. 2) Many of the MPs can be individually accessed by thousands of different initial patterns. The variety of examples presented illustrate the rich, general nature of the model.

Action Potentials↗
PubMed1986

Clinical experience with sorbinil--an aldose reductase inhibitor.

A considerable volume of animal pharmacologic data support the view that increased flux through the polyol pathway provides a unifying hypothesis for the major complications of diabetes. An extensive clinical program has been established to verify the extrapolation of the animal pharmacologic findings to man. Clinical data accumulated to date confirm the biochemical and electrophysiologic effects, and encouraging evidence of a drug effect in diabetic neuropathy and retinopathy has already been observed. In the large, controlled safety data base already available, the long-term clinical use of sorbinil is devoid of significant adverse effects in terms of both subjective side effects and laboratory parameters. The only clinically important adverse reaction reported to date has been a hypersensitivity reaction in the early weeks of therapy, which is similar to that seen with other hydantoins.

Aldehyde Reductase↗
PubMed1986

Aldose reductase inhibitors in clinical practice. Preliminary studies on diabetic neuropathy and retinopathy.

Extensive animal data now exist to indicate potential benefit of sorbinil in the treatment of the major complications of diabetes mellitus. A clinical programme has been constructed to explore this therapeutic potential and encouraging evidence of drug effect has already been observed in patients with neuropathy and retinopathy. Two small preliminary studies in patients with painful neuropathy have shown that clinically significant reduction of pain was more frequently achieved with sorbinil than with placebo. A 6-month study of patients with retinopathy, using vitreous fluorophotometry as the criterion of retinal damage, showed significant (p = 0.03) benefit for the sorbinil group compared with the placebo group. Drug evaluation in these areas is complex and difficult but it is anticipated that the accumulation of additional data will further substantiate the efficacy suggested by these early findings. The only clinically important adverse effect of sorbinil is the hypersensitivity reaction. This usually occurs during the initial weeks of therapy and is similar to that seen with phenytoin. The long term use of sorbinil is without significant adverse effects.

Aldehyde Reductase↗
PubMed1985

Model of cortical organization embodying a basis for a theory of information processing and memory recall.

Motivated by V. B. Mountcastle's organizational principle for neocortical function, and by M. E. Fisher's model of physical spin systems, we introduce a cooperative model of the cortical column incorporating an idealized substructure, the trion, which represents a localized group of neurons. Computer studies reveal that typical networks composed of a small number of trions (with symmetric interactions) exhibit striking behavior--e.g., hundreds to thousands of quasistable, periodic firing patterns, any of which can be selected out and enhanced with only small changes in interaction strengths by using a Hebb-type algorithm.

Animals↗
PubMed1983

Processing capability of the primary visual cortex and possible physiologic basis for an apparent motion illusion.

The primary visual cortex is known to process stimuli in a given part of the visual field such that divisions of the cortical column into orientation and ocular dominance minicolumns are present. Applying a model incorporating both the Hebb learning hypothesis and a Mountcastle-like organizational structure to the visual cortex, we predicted that the processing capabilities of the column involve dynamic interactions among minicolumns and are much greater than presently documented. In particular, processing of rotational stimuli in area 17 was suggested by the model. Motivated by this, a psychophysics experiment was conducted that demonstrated a spatial-temporal filling-in process in apparent motion. We have now presented this "human illusion" to cats and recorded from units in area 17 with results which clearly demonstrate striking phenomena not simply understood. The purpose of this note is to present our experimental paradigm with the preliminary results.

Animals↗