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Biomedical subjects

C E Harris

Publications and source records attributed to C E Harris.

At least 19 recordsLinked to original sources
PubMed2001

Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency.

The Rho GTPase, Rac2, is expressed only in hematopoietic cell lineages, suggesting a specific cellular function in these cells. Genetic targeting studies in mice showed that Rac2 is an essential regulator of neutrophil chemotaxis, L-selectin capture and rolling, and superoxide production. Recently, a dominant negative mutation of Rac2, D57N, has been reported to be associated with a human phagocytic immunodeficiency. To understand further the cellular phenotypes associated with this D57N Rac2 mutant we examined its biochemical characteristics and functional effects when expressed in primary murine bone marrow cells. When compared with wild type (WT) Rac2, D57N Rac2 displayed approximately 10% GTP binding ability resulting from a markedly enhanced rate of GTP dissociation and did not respond to the guanine nucleotide exchange factors. These results suggest that D57N Rac2 may act in a dominant negative fashion in cells by sequestering endogenous guanine nucleotide exchange factors. When expressed in hematopoietic cells, D57N Rac2 reduced endogenous activities of not only Rac2, but also Rac1 and decreased cell expansion in vitro in the presence of growth factors due to increased cell apoptosis. Unexpectedly, D57N expression had no effect on proliferation. In contrast, expansion of cells transduced with WT Rac2 and a dominant active mutant, Q61L, was associated with significantly increased proliferation. Transplantation of transduced bone marrow cells into lethally irradiated recipients showed that the percentage of D57N-containing peripheral blood cells decreased markedly from 40% at 1 month to <5% by 3 months postinjection. Neutrophils derived in vitro from the transduced progenitor cells containing D57N demonstrated markedly impaired migration and O(2)(-) responses to formyl-methionyl-leucyl-phenylalanine, reflecting the same cellular phenotype in these differentiated cells as those described previously in patient cells. These data suggest that the phenotypic abnormalities associated with D57N Rac2 may involve not only neutrophil cellular functions, but also abnormal cell survival in other hematopoietic cells and that overexpression of Rac leads to increased proliferation of normal cells in vitro, whereas deficiency of Rac leads to increased apoptosis.

Amino Acid Substitution↗
PubMed2001

Immunosuppressed surfactant protein A-deficient mice have increased susceptibility to Pneumocystis carinii infection.

Immunosuppressed Swiss Black mice deficient in surfactant protein A (SP-A(-/-)) and wild-type control mice (SP-A(+/+)) were exposed to Pneumocystis carinii by environmental exposure, intratracheal inoculation, and direct exposure to other infected animals. The frequency and intensity of P. carinii infection were significantly greater in the SP-A(-/-) mice by all 3 methods of exposure. P. carinii free of SP-A and alveolar macrophages were isolated from SP-A(-/-) mice and were tested in an in vitro attachment assay. Pretreatment of P. carinii with human SP-A resulted in a significant dose-dependent increase of the adherence of P. carinii to the macrophages. Thus, SP-A plays a role in host defense against P. carinii in vivo, perhaps by functioning as a nonimmune opsonin.

Animals↗
PubMed2001

To solve a deadly shortage: economic incentives for human organ donation.

In this article Dr. Harris and attorney Alcorn propose the establishment of a governmentally regulated, posthumous organ market, with economic incentives for the donors, in order to increase the supply of transplantable organs. The authors review transplant technology, provide a short history of donation and sale of organs, tissues, and cells, discuss the various legislative approaches that have been made to increase the supply of organs, and analyze the problems with the open market approach. They conclude with a proposal for a regulated posthumous organ market.

Altruism↗
PubMed2000

A new compound heterozygous mutation of the gonadotropin-releasing hormone receptor (L314X, Q106R) in a woman with complete hypogonadotropic hypogonadism: chronic estrogen administration amplifies the gonadotropin defect.

We describe a woman with complete hypogonadotropic hypogonadism and a new compound heterozygous mutation of the GnRH receptor (GnRHR) gene. A null mutation L314X leading to a partial deletion of the seventh transmembrane domain of the GnRHR is associated with a Q106R mutation previously described. L314X mutant receptor shows neither measurable binding nor inositol phosphate production when transfected in CHO-K1 cells compared to the wild-type receptor. The disease is transmitted as an autosomal recessive trait, as shown by pedigree analysis. Heterozygous patients with GnRHR mutations had normal pubertal development and fertility. The present study shows an absence of LH and FSH response to pulsatile GnRH administration (20 microg/pulse, sc, every 90 min). However, GnRH triggered free alpha-subunit (FAS) pulses of small amplitude, demonstrating partial resistance to pharmacological doses of GnRH. FSH, LH, and FAS concentrations were evaluated under chronic estrogen treatment and repeat administration of GnRH. Not only were plasma FSH, LH, and FAS concentrations decreased, but FAS responsiveness was reduced. This new case emphasizes the implication of the GnRH receptor mutations in the etiology of idiopathic hypogonadotropic hypogonadism. We also have evidence for a direct negative estrogen effect on gonadotropin secretion at the pituitary level, dependent on the GnRHR signaling pathway.

Amino Acid Sequence↗
PubMed1999

Megenteron manteri n. sp. and Steringophorus sp. (Digenea: Fellodistomidae) from Monomitopus agassizzi (Ophidiidae) in the Gulf of Mexico.

During a study of digenean parasites of deep-sea fishes, 81% (17 of 21) of Monomitopus agassizzi (Ophidiidae) from the Gulf of Mexico were infected with Megenteron manteri n. sp. and 10% (2 of 21) were infected with what appears to be a new species of Steringophorus. M. manteri n. sp. differs from M. crassum in having a longer body (3,733-9,394 microns), shorter caeca and a uterus that extends posteriorly beyond the ends of the caeca. The species of Steringophorus differs from other species in the genus in having smaller eggs (19-23 microns long) and caeca that extend into the posterior half of the hindbody.

Animals↗
PubMed1999

A novel heterogeneous nuclear ribonucleoprotein-like protein interacts with NS1 of the minute virus of mice.

NS1, the major nonstructural parvovirus protein of the minute virus of mice, is a multifunctional protein responsible for several aspects of viral replication. NS1 transactivates the P38 promoter (used to express the structural proteins), as well as its own strong promoter, P4. To study the mechanism of activation and to map regions of NS1 responsible for transactivation, NS1 and various deletions of NS1 were cloned in frame with the GAL4DB and cotransfected into COS-7 and LA9 cells with a synthetic GAL4-responsive reporter plasmid. These studies showed NS1 can directly activate transcription through its 129 carboxyl-terminal amino acid residues. Any deletion from this region of the C terminus, even as few as 8 amino acids, completely abolishes transactivation. A yeast two-hybrid system used to identify protein-protein interactions demonstrated that NS1 is able to dimerize when expressed in yeast cells. However, only an almost complete NS11-638 bait was able to interact with the full-length NS1. A two-hybrid screen identified a HeLa cell cDNA clone (NS1-associated protein 1 [NSAP1]) that interacts with NS11-276 and NS11-638. An additional sequence was predicted from human EST (expressed sequence tag) data, and the cDNA was estimated to be at least 2,221 bp long, potentially encoding a 562-amino-acid protein product. A polyclonal antibody raised to a synthetic peptide within NSAP1 recognizes an approximately 65-kDa cellular protein. This NSAP1 cDNA has not previously been characterized, but the predicted protein sequence is 80% identical to the recently identified heterogeneous nuclear ribonucleoprotein (hnRNP) R (W. Hassfeld et al., Nucleic Acids Res. 26:439-445, 1998). NSAP1 contains four ribonucleoprotein domains, as well as a highly repetitive C-terminal region. A closely related mouse cDNA (deduced from murine EST data) encodes a protein with only a single amino acid residue change from the human protein. NSAP1 is predicted to be a 65-kDa polynucleotide binding protein, and it likely functions in the regulation of splicing and/or transport of mRNAs from the nucleus.

Amino Acid Sequence↗
PubMed1999

Development of photosystem-II activity during irradiance of etiolated Helianthus (Asteraceae) seedlings.

Light-induced development of photosystem (PS)-II activity was followed during irradiance of etiolated Helianthus annuus (sunflower) cotyledons using chlorophyll a fluorescence. Cotyledons from seedlings grown in continuous darkness for 6 d were exposed to 100 μmol photons·m(-2)·s(-1) for time periods of 1, 3, 6, and 12 h. Associated with increased time of irradiance exposure were significant: (1) increases in concentration of PS II, (2) increases in quantum efficiency of PS II, (3) decreases in the ratio of PS-II quinone(B) (Q(B))-nonreducing centers to total PS-II centers (PS-II Q(B)-nonreducing centers + PS-II Q(B)-reducing centers), and (4) decreases in the ratio of slow PS-II Q(B)-reducing centers to total PS-II Q(B)-reducing centers (fast PS-II Q(B)-reducing centers + slow PS-II Q(B)-reducing centers). The results support the hypotheses that development of PS II involves assembly of complexes which initially cannot reduce Q(B) and that heterogeneous aspects of PS-II pools during chloroplast maturation may represent different developmental states.

Journal Article↗
PubMed1994

Inhalation-based therapies in the treatment of cystic fibrosis.

As most of the morbidity seen in cystic fibrosis (CF) is related to pulmonary complications, new therapies are being developed that seek to ameliorate these debilitating sequelae. Recently, there has been intense effort into the development of new aerosol-based therapies for CF. This review summarizes much of this recent investigation, with particular emphasis on therapies described in the literature within the past year. Agents that act on the airway epithelium to alter ionic fluxes, namely amiloride and uridine 5'-triphosphate, are outlined. The effects of tobramycin delivered via nebulizer in a cohort of stable CF patients is reported. Recombinant human DNase and distearoyl phosphatidylglycerol liposomes, agents that alter the adhesiveness of CF mucus, are outlined as possible strategies for CF treatment. Finally, antiprotease therapy is considered as a possible addition to the CF armamentarium.

Administration, Inhalation↗
PubMed1993

Receptor-mediated gene transfer to airway epithelial cells in primary culture.

A variety of methods have been utilized for gene transfer to the cells of the airway epithelium. These have included DNA-mediated mechanisms of gene transfer as well as recombinant viral vectors. Despite the availability of these methods, limitations in their utility warrant the development of alternate systems. As an alternative, receptor-mediated endocytosis using transferrin-polylysine conjugates has been shown to transduce immortalized airway epithelial cells efficiently via a physiologic pathway. When transferrin-polylysine conjugates were used to transduce airway epithelial cells grown in primary culture, however, gene transfer occurred inefficiently. Investigation into this relative inefficiency centered on endosomal entrapment of the conjugate-DNA complex. Pretreatment of the cells with chloroquine, which causes vacuolization and disruption of the endosome, or co-delivery of adenoviral particles, which serves to lyse the endosomal membrane, were both associated with greatly improved gene transfer efficiency. These studies established that the relative refractory state of the airway epithelial cells in primary culture was secondary to the retention of the internalized material within the endosome. We thus explored the efficiency of conjugates that possessed a mechanism to escape this endosomal entrapment; adenovirus-polylysine conjugates and transferrin-polylysine/adenovirus-polylysine conjugates were thus employed. Gene transfer efficiency improved significantly with the adenovirus-containing conjugates. These data support the concept that conjugates can be synthesized that mediate highly efficient gene transfer to airway epithelial cells in primary culture via the receptor-mediated endocytosis pathway.

Adenoviridae↗
PubMed1992

Intestinal permeability in the critically ill.

Alterations in intestinal permeability reflect one component of intestinal epithelial barrier function. The objective of this study was to assess the degree of derangement of intestinal permeability in critically ill patients and to investigate the relationship of this to markers of disease severity and sepsis. Sixteen patients admitted to the intensive care unit for a variety of problems were studied with the severity of illness and degree of sepsis recorded daily. A differential sugar absorption test, using lactulose and mannitol as markers, was performed, and in 10 patients this was repeated after an interval of between 4-11 days. The use of the lactulose/mannitol (L/M) ratio corrects for variables unrelated to permeability such as gastric emptying. The L/M ratio was significantly higher in patients (median 0.98) compared to normal controls (median 0.008). The ratios showed no relation to disease severity or sepsis. These results establish that increased intestinal permeability occurs in the general ICU patient but that it is not uniquely related to sepsis. The extent of this abnormality suggests that further study is required to show the various influences on this process.

Adult↗
PubMed1990

Propofol for long-term sedation in the intensive care unit. A comparison with papaveretum and midazolam.

Thirty-seven patients with a wide range of illnesses were studied during mechanical ventilation of the lungs in an intensive care unit. Fifteen were sedated with a continuous propofol infusion, with analgesia provided by bolus doses of papaveretum. Twelve received a continuous infusion of papaveretum, supplemented by bolus doses of midazolam. The level of sedation was assessed every four hours and measurements were made of haemodynamic and respiratory variables. Levels of sedation were generally satisfactory in both groups. Six patients who received propofol required the use of muscle relaxants, because of their strong respiratory drives, to achieve synchronisation with the ventilator. There was no significant difference in respiratory or haemodynamic variables between the groups, but several patients required inotropic support because of their disease. There was no evidence of inhibition of adrenal steroidogenesis in the propofol group. Propofol can be a useful sedative agent in the intensive care unit, but sedative regimens should be tailored to individual patient requirements.

Adolescent↗
PubMed1990

Peripheral blood and bone marrow findings in patients with acquired immune deficiency syndrome.

In 4 years (1984-1987), 183 bone marrow examinations were performed on 155 human immunodeficiency virus (HIV) antibody positive patients. One hundred and fifty three had category IV AIDS. One-third of the marrows yielded specific information. This included opportunistic infection, in particular Mycobacterium Avium Intracellulare Complex (MAI) (24%), malignancy (4%), consistent with ITP (9%) and iron deficiency (1%). In the remaining two thirds of the bone marrows the most frequent non-specific abnormalities were dyserythropoiesis, erythroid hypoplasia, reticuloendothelial iron block, granulomas, lymphoid aggregates, plasmacytosis and histiocytosis. Common peripheral blood findings were anemia, lymphopenia, anisocytosis, rouleaux and atypical lymphocytes. Peripheral blood and bone marrow examinations on 16 patients on AZT are included. These patients have more pronounced blood and bone marrow abnormalities. The causes of these abnormalities are multifactorial and include low T4 levels, severe viral and other infections and therapy with marrow toxic drugs.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Effect of sternotomy and cardiopulmonary bypass on airway pressures and respiratory mechanics during high frequency ventilation.

The airway pressures at ventilatory frequencies of 15, 60, 100, 120 and 150 breaths per minute were measured in eight adult patients undergoing coronary artery bypass grafting. Measurements were made perioperatively at four stages: precardiopulmonary bypass with the chest closed, precardiopulmonary bypass with the chest open, postcardiopulmonary bypass with the chest open and postcardiopulmonary bypass with the chest closed. In five patients thoracic compliance and airways resistance were also measured at these times. Neither sternotomy nor cardiopulmonary bypass made any significant difference to the airway pressures during normal and high frequency ventilation, nor were lung mechanics affected.

Airway Resistance↗
PubMed1988

Effects of thiopentone, etomidate and propofol on the haemodynamic response to tracheal intubation.

The haemodynamic response to tracheal intubation was compared in 303 patients in whom anaesthesia was induced with either thiopentone 4 mg/kg, etomidate 0.3 mg/kg or propofol 2.5 mg/kg, with and without fentanyl 2 micrograms/kg. There was after propofol alone a significant decrease in arterial blood pressure, which did not increase above control values after intubation. Significant increases in arterial pressure followed intubation in patients induced with thiopentone or etomidate alone. Increases in heart rate occurred with all agents after laryngoscopy. The use of fentanyl resulted in arterial pressures lower than those after the induction agent alone, and in an attenuation, but not abolition of the responses to laryngoscopy and intubation.

Adolescent↗
PubMed1988

AIDS and the future.

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Acquired Immunodeficiency Syndrome↗