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Biomedical subjects

C B Alexander

Publications and source records attributed to C B Alexander.

At least 37 records · Page 2Linked to original sources
PubMed1990

Altered phenotypic expression of immunoglobulin heavy-chain variable-region (VH) genes in Alicia rabbits probably reflects a small deletion in the VH genes closest to the joining region.

Rabbits of the Alicia strain have a mutation (ali) that segregates with the immunoglobulin heavy-chain (lgh) locus and has a cis effect upon the expression of heavy-chain variable-region (VH) genes encoding the a2 allotype. In heterozygous a1/ali or a3/ali rabbits, serum immunoglobulins are almost entirely the products of the normal a1 or a3 allele and only traces of a2 immunoglobulin are detectable. Adult homozygous ali/ali rabbits likewise have normal immunoglobulin levels resulting from increased production of a-negative immunoglobulins and some residual ability to produce the a2 allotype. By contrast, the majority of the immunoglobulins of wild-type a2 rabbits are a2-positive and only a small percentage are a-negative. Genomic DNAs from homozygous mutant and wild-type animals were indistinguishable by Southern analyses using a variety of restriction enzyme digests and lgh probes. However, when digests with infrequently cutting enzymes were analyzed by transverse alternating-field electrophoresis, the ali DNA fragments were 10-15 kilobases smaller than the wild type. These fragments hybridized to probes both for VH and for a region of DNA a few kilobases downstream of the VH genes nearest the joining region. We suggest that this relatively small deletion affects a segment containing 3' VH genes with important regulatory functions, the loss of which leads to the ali phenotype. These results, and the fact that the 3' VH genes rearrange early in B-cell development, indicate that the 3' end of the VH locus probably plays a key role in regulation of VH gene expression.

Animals↗
PubMed1988

Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial.

To test whether changes in folate and vitamin B12 nutrition modify the severity of potentially premalignant lesions identified by cytology in sputum samples of smokers, we conducted a randomized, controlled prospective intervention trial in smokers with bronchial squamous metaplasia. Seventy-three men with a history of 20 or more pack-years of cigarette smoking who had metaplasia on one or more sputum samples were stratified according to smoking level and randomly assigned to four months' treatment with either placebo or 10 mg of folate plus 500 micrograms of hydroxocobalamin. Direct cytological comparison of the two groups after four months showed significantly greater reduction of atypia in the supplemented group. This provides preliminary evidence that atypical bronchial squamous metaplasia may be reduced by supplementation with folate and vitamin B12. However, the significance of these findings is tempered by substantial spontaneous variation in sputum cytologies, the small study population, the short duration of the trial, and the supraphysiological doses of folate and B12 used. The results should not be construed as pointing to a potential way of preventing lung cancer in individuals who continue to smoke or as supporting self-medication with large doses of folate or B12 by smokers.

Bronchi↗
PubMed1988

Neutrophils in reexpansion pulmonary edema.

This study investigated the possible contribution of neutrophils to development of reexpansion pulmonary edema (RPE) in rabbits. Rabbits' right lungs were collapsed for 7 days and then reexpanded with negative intrathoracic pressure for 2 h before study, a model that creates unilateral edema in the reexpanded lungs but not in contralateral left lungs. Two hours after lung reexpansion, significant increases in lavage albumin concentration (17-fold), percent neutrophils (14-fold), and total number of neutrophils (7-fold) recovered occurred in the reexpanded lung but not in the left. After 2 h of reexpansion increased leukotriene B4 was detected in lavage supernatant from right lungs (335 +/- 33 pg/ml) compared with the left (110 +/- 12 pg/mg, P less than 0.01), and right lung lavage acid phosphatase activity similarly increased (6.67 +/- 0.35 U/l) compared with left (4.73 +/- 0.60 U/l, P less than 0.05). Neutropenia induced by nitrogen mustard (17 +/- 14 greater than neutrophils/microliters) did not prevent RPE, because reexpanded lungs from six neutropenic rabbits were edematous (wet-to-dry lung weight ratio 6.34 +/- 0.43) compared with their contralateral lungs (4.97 +/- 0.04, P less than 0.01). An elevated albumin concentration in reexpanded lung lavage from neutropenic rabbits (8-fold) confirmed an increase in permeability. Neutrophil depletion before reexpansion did not prevent unilateral edema, although neutrophils were absent from lung sections and alveolar lavage fluid from neutropenic rabbits.

Acid Phosphatase↗
PubMed1988

Re-expansion pulmonary edema. A potential role for free radicals in its pathogenesis.

Re-expansion pulmonary edema (RPE) has been attributed to decreased lung interstitial pressures from a variety of mechanisms. Because some recent studies have implicated mechanisms that increase microvascular permeability in RPE, we tested whether the edema were due to free radical generation during re-expansion and reoxygenation of the collapsed lung. We used a rabbit model of RPE to test the effects of intracellular (dimethylthiourea) or extracellular (catalase) oxygen metabolite scavengers. Allopurinol was administered separately to determine whether xanthine oxidase was an important source of superoxide in this model. Edema was quantitated both gravimetrically and histologically, and lung xanthine oxidase activity was measured using a sensitive fluorometric assay with pterin as substrate. The results suggest indirectly that OH. or H2O2 (derived from O2-) contribute to the well-documented increase in lung permeability in RPE because dimethylthiourea, dimethylthiourea plus catalase, or catalase alone inhibited the edema to various degrees. Further, we observed histologically that increased numbers of neutrophils were present in re-expanded lungs and that neutrophil infiltration appeared to be diminished by antioxidant administration. Allopurinol did not decrease the edema, because xanthine oxidase activity in rabbit lung tissue is extremely low. We speculate that free radical generation in lung tissue contributes to the pathogenesis of RPE, although reinitiation of lung perfusion and ventilation requires a rapid change in intrathoracic pressure.

Allopurinol↗
PubMed1987

Mineral content of bone: measurement by energy subtraction digital chest radiography.

Several methods are presently available for measuring the mineral content of bone. Those in widespread use include dual-photon absorptiometry and quantitative CT. The feasibility of using dual-energy digital chest radiography for determination of the mineral content of posterior ribs on digital chest images was studied by using a prototype unit. The results showed a significant difference in the mineral density of the posterior ribs of control subjects and those of patients who had osteoporosis (251.1 +/- 36 mg Ca2+/cm2 of rib vs 158.8 +/- 48 mg Ca2+/cm2, p less than or equal to .01) and a close correlation with values obtained by dual-photon absorptiometry of the lumbar spine (r = .77). The results suggest that this technique can provide an accurate assessment of the presence or absence of osteoporosis.

Adult↗
PubMed1986

Calcification in pulmonary nodules: detection with dual-energy digital radiography.

The authors undertook a clinical study to determine the accuracy of dual-energy digital radiography in revealing nodule calcification because calcification in a pulmonary nodule almost excludes the possibility of malignancy. Over a 6-month period, 61 patients with pulmonary nodules (less than or equal to 3 cm) or masses (greater than 3 cm) were examined on a prototype scanned projection unit using a dual-energy detector. In 49 of 61 patients, nodules were noncalcified, and in 12, they were calcified. In 57 patients, the benignancy or malignancy of nodules was established beyond reasonable doubt by pathologic confirmation in 38 and by strong inference in 19 (four patients with noncalcified solitary pulmonary nodules either refused further investigation or surgery or their follow-up was too short to permit exclusion of malignancy). Dual-energy radiography was found to be highly accurate in assessing the presence or absence of calcification in pulmonary nodules and thus in determining their benignancy or possible malignancy.

Adult↗
PubMed1985

Protein phosphorylation and growth control.

Many growth factor receptors and retroviral transforming proteins share the property of phosphorylating proteins on tyrosine. Several substrates for both types of protein-tyrosine kinase have been identified. Treatment of quiescent cells with growth factors such as EGF and PDGF, whose receptors have ligand-stimulated protein-tyrosine kinase activities, induces tyrosine phosphorylation of three proteins, p45, p42 and p41. Two phosphorylated forms of p42 are found, the more basic of which is present in some but not all cells transformed by viral protein-tyrosine kinases. p42 is rapidly (as early as 1 min) but transiently (decreased to baseline by 2h) phosphorylated following PGDF or EGF treatment of quiescent fibroblasts. At saturating levels of mitogen the stoichiometry of p42 phosphorylation is greater than 50%. p42 is a highly conserved, rare (0.002% of total cell protein), soluble cytoplasmic protein. IGF I and insulin, whose receptors also have ligand-stimulated protein-tyrosine kinase activity, induce p42 phosphorylation in appropriate cells. In the case of insulin this effect has been observed in cells with large numbers of insulin receptors. p42 is also phosphorylated in response to mitogens whose receptors lack protein-tyrosine kinase activity, for example 12-O-tetradecanoylphorbol-13-acetate (TPA) and thrombin. For TPA there is evidence that this is an indirect effect due to the activation of a protein-serine/threonine kinase. On the basis of the highly conserved nature of this response and its generality, it seems likely that tyrosine phosphorylation of p42 is important for at least early responses to mitogens.

Animals↗
PubMed1985

Black thyroid: clinical manifestations, ultrastructural findings, and possible mechanisms.

Ultrastructural examination of three black thyroid glands showed lysosomal accumulations of lipofuscin-like pigment and granular electron-dense material in association with 1) a minocycline-associated black thyroid with normal thyroid function; 2) a minocycline-associated black thyroid with a significant inflammatory component, fibrosis, and primary hypothyroidism; and 3) a black thyroid gland with no exposure to minocycline. The deposition of the pigments in the three cases resulted in macroscopically recognizable black thyroid glands. It is speculated that an imbalance in lysosomal function accounts for this abnormality. The glandular hypofunction documented in case 2 is unique and confirms the need to monitor function carefully in patients who are receiving minocycline. In one case electrondense deposits were identified in the thyroid gland interstitium.

Adult↗
PubMed1985

Germline VH genes in an a3 rabbit not typical of any one VHa allotype.

We have undertaken investigations in the rabbit of VH genes that may be responsible for the observations of VHa allotypes unexpected from an animal's pedigree (latent allotypes). A short cDNA probe was prepared and shown to be specific for VHa2 mRNA. Southern analyses with short and large probes were unrevealing but screening of a lambda phage library from a VHa3-expressing animal identified a number of unusual genes. These VH genes are remarkable in that they are far closer to one another in the genome (in one case 3085 bps) than VH genes reported in mouse or man, they are highly homologous over long stretches of sequence, and they encode proteins not typical of any one VHa allotype. Proteins similar to the sort encoded by these genomic V-regions may explain some of the observations of latent allotype. Our data suggest that the allelic behavior of VHa allotypes is not due to allelism of a regulatory mechanism that acts upon identical VH genes in rabbits of different VHa phenotypes.

Animals↗
PubMed1985

Ultrastructural characterization of pulmonary neoplasms. II. The role of electron microscopy in characterization of uncommon epithelial pulmonary neoplasms, metastatic neoplasms to and from lung, and other tumors, including mesenchymal neoplasms.

Ultrastructural analysis through better resolution adds significant information to the evaluation and classification of primary pulmonary neoplasms. Light microscopy is limited in the evaluation of lung neoplasms. In some cases the light microscopic appearance may be entirely misleading, whereas in others it is inconclusive. Immunocytochemistry provides information on cytoplasmic differentiation of various tumors and hence more data on their corresponding phenotypes. The data from immunocytochemistry without corresponding objective electron microscopic evaluation may be very difficult to interpret. Correlation of historical, gross, light, electron microscopic, and immunocytochemical data is essential for a final accurate diagnosis (fig. 20). Fine needle aspiration of pulmonary neoplasms is becoming very fashionable and a diagnosis, including type of neoplasm, is expected on the basis of examination of a limited number of cells which further emphasizes the importance of ultrastructural characterization in helping to establish an accurate diagnosis [63-69]. The current classification of pulmonary neoplasms may need to be modified in the near future to incorporate the newly created data [70-72]. At the present time, there appears to be, at least, a need for a 'double standard', as Sobin [73] has suggested, which would permit the evaluation of the biologic significance of the ultrastructural and immunocytochemical findings (as applied to classification of neoplasms) in an effort to derive meaningful clinicopathologic correlations. Figure 20 emphasizes the additive role which should be played by the various diagnostic modalities to enable a morphologic assessment which would be an accurate predictor of biologic behavior. With an accurate assessment of biologic behavior, a more appropriate and rational approach for therapy is possible. There is also an important role for ultrastructural analysis in metastatic pleural and pulmonary neoplasms, primarily adenocarcinomas, as well as in the differential diagnosis of pulmonary neoplasms versus other tumors that may be similar in histological appearance. The role of ultrastructure in mesenchymal neoplasms is also crucial in defining specific neoplastic cell populations and in some cases in the differentiation from other non-mesenchymal tumors. It seems that routine electron microscopic examination of pulmonary neoplasms provides additional information that may be of great value in the management of patients and in understanding the differentiation, and perhaps histogenesis, of pulmonary neoplasms.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1984

Autonomous cholesterol biosynthesis in murine hepatoma. A receptor defect with normal coated pits.

These studies indicate that autonomous cholesterol biosynthesis by hepatocellular carcinoma may result from absent or defective receptors for chylomicron remnants on the surface of the malignant hepatocytes. In vivo, DAB2 hepatoma or liver were perfused with chylomicron remnants labeled with tritiated palmitic acid. Normal liver had chylomicron remnant uptake/gm tissue that was ten times that of hepatoma. In vitro studies using isolated hepatocytes and cultured DAB2 hepatoma cells showed similar results. Uptake of chylomicron remnants labeled with 3H-palmitic acid by normal hepatocytes during a 4-hour period was ten times that of hepatoma cells. Both in vivo and in vitro differences were statistically highly significant (P less than 0.005). Since many surface receptors are related to the coated pits, the cellular membranes of both neoplastic and normal liver cells were examined by electron microscopy. Coated pits were present in both the hepatoma and normal liver cells and occupied 2.61% and 2.65% of the cell surface, respectively. The defective uptake of chylomicron remnants by DAB2 hepatoma appears to be related to the chylomicron remnant receptor and not to the coated pit-internalization mechanism.

Animals↗
PubMed1984

Genetics and expression of kappa-type light chains in Basilea rabbits.

In contrast to rabbits of b4, b5, b6, and b9 allotypes whose serum immunoglobulins (Igs) are predominantly composed of kappa-type light chains, rabbits of the mutant Basilea strain have serum Igs that are largely of lambda type. We prepared several antisera that recognized a minor K2 (bas) light chain that is produced by Basilea rabbits. With these antisera we identified the K2 (bas) isotype in the serum of the original b9/b9 male rabbit whose offspring displayed the Basilea mutant phenotype. It was present in one half of his nonmutant offspring which inherited b9 from him and another b allotype from their mothers. Breeding was conducted both in Basel and at the NIH to develop and maintain colonies of mutant Basilea strain rabbits. The data obtained during colony development confirm that the trait of expression of the bas allotype maps to the same genetic region (b locus) that is known to control the allelic b allotypes b4, b5, b6 and b9. Homozygotes or heterozygotes of b4, b5 or b6 allotype (bb/bb) were mated with homozygous bbas / bbas rabbits to produce F1s , and then F2s as well as progeny of backcrosses to both homozygous parental types (bb/bb and bbas / bbas ) were produced. The bas allotype segregates as an allele (or pseudoallele ) at the b locus although there was a deficiency in recovery of homozygous bas offspring in both the F2 and backcross matings to bbas / bbas parental type in the NIH colony. This selective deficiency may reflect a deleterious effect on survival of homozygous bas progeny.

Animals↗
PubMed1984

The structural and genetic basis for expression of normal and latent VHa allotypes of the rabbit.

The immunoglobulin heavy chain variable regions of the rabbit are unusual in having genetically controlled, serologically detectable alternative forms, the VHa allotypes, as well as minor VH allotypes of the x, y and w groups. New insights into the probable structural basis for the VHa allotypes have come from re-examination of earlier protein sequence data in the light of newly deduced protein sequences derived from sequencing cloned cDNAs and genomic DNAs encoding VH regions. Here we review this sequence information, and define the allotype-correlated differences at seven positions in framework region 1 and 10 positions in framework region 3 that may lead to the serologically detectable allotypic determinants (allotopes). Most alternative amino acids at allotype-correlated positions can be derived from each other by single-base changes. Thus somatic mutations and/or gene conversion-like events must be considered along with other serological and genetic explanations for various reported observations of the production of latent VHa allotypes. The proximity of rabbit VH genes (approximately 3 kb apart) might enhance the likelihood of conversion-like events in both germline and somatic cells.

Amino Acid Sequence↗
PubMed1984

Small cell carcinoma of the esophagus: evidence for a unified histogenesis.

Four cases of small cell carcinoma of the esophagus, histologically indistinguishable from oat cell carcinoma of the lung, were studied by electron microscopy. Three were composed largely of small cells with neurosecretory granules characteristic of APUD (amine precursor uptake and decarboxylation) cells. Two of these three cases also contained foci of squamous or glandular differentiation, or both. The fourth case was classified as reserve cell carcinoma with squamous differentiation, since the tumor cells were devoid of neurosecretory granules but contained desmosomes and bundles of intracytoplasmic tonofilaments. The evidence provided by these four cases and also by the 48 cases previously reported in the literature supports our hypothesis that a totipotent primitive cell serves as the common precursor for squamous cell, adeno-, and small cell carcinoma of the esophagus. The latter can be subdivided into oat cell and reserve cell carcinomas, both having the propensity for further squamous and glandular differentiation. The hypothesis can also be applied to lung cancer.

Carcinoma, Small Cell↗
PubMed1984

Spontaneous primary dissecting coronary artery aneurysm. Report of two cases.

Two cases of dissecting aneurysm of the left main stem and left anterior descending coronary arteries are presented. Both cases were discovered during routine medicolegal death investigations. Unusual aspects of one of our cases include the history of antecedent trauma and the precise identification of an intimal tear.

Accidents, Traffic↗
PubMed1984

Abnormal lactate dehydrogenase isoenzyme pattern in a critically ill patient.

We have described a patient who had an abnormal isoenzyme of lactate dehydrogenase in both serum and tissue. The presence of LD6 is indicative of a poor prognosis. Some of the biochemical characteristics of the isoenzyme are (1) LD6 is not an artifact, (2) it contains an M subunit but not an H subunit, and (3) it is not an immunoglobulin complex. We believe LD6 may arise during episodes of severe shock as lysosomes rupture and is either a previously sequestered lysosomal LD or is a lysosomal modification of LD5.

Acidosis↗
PubMed1984

Ultrastructural characterization of pulmonary neoplasms. I. The role of electron microscopy in characterization of the most common epithelial neoplasms.

We have attempted to summarize current concepts pertaining to the ultrastructural evaluation of epithelial pulmonary neoplasms, with an emphasis in potential clinicopathological correlations. Routine ultrastructural evaluation of the most commonly encountered pulmonary carcinomas seems to provide, in a significant number of cases, additional information that may be of help in patient management. Immunocytochemistry when employed as an adjunct to electron microscopic evaluation of pulmonary tumors also plays an important role in clarifying morphologic findings. With the advent of specific chemotherapy protocols and future development of monoclonal antibodies in the treatment of neoplasms, accurate tumor classification becomes crucial. The combined use of electron microscopy and immunocytochemistry seems to be extremely useful in providing accurate and reproducible criteria of great potential value in the overall assessment of pulmonary neoplasms. In part II of this study we will address the importance of the ultrastructural evaluation of less common epithelial and mesenchymal pulmonary neoplasms.

Adenocarcinoma↗