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C Garner

Publications and source records attributed to C Garner.

At least 37 records · Page 2Linked to original sources
PubMed1998

Aspirin-like molecules that covalently inactivate cyclooxygenase-2.

Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.

Acetylation↗
PubMed1998

[The status of neurologic intensive care in Germany. Current data].

In 1994 this journal published the results of a survey undertaken on behalf of the Working Association for Neurological Intensive Care Medicine (ANIM) in the winter of 1992/93. In the winter of 1996/97 a continuation of this analysis was performed. With the help of a questionnaire the data of 62 intensive care units with a total of 420 beds were established. This is 11 intensive care units and 83 beds more than 1992/93. The intensive care units were again classified into three groups (ventilation units, monitoring units, interdisciplinary units) relating to their equipment and structure. The questions concerned structural organisation, such as the number of beds, type of clinic, number and training of physicians and nurses, technical equipment and availability of large and high-tech apparatus or access to other facilities, such as neurosurgery. Of great interest were data about whether and to what extent special measures of intensive medicine can be taken on the one hand and performance parameter data e.g. days of ventilation and duration of in-patient treatment on the other hand. Detailed data were provided concerning the frequency of each diagnosis of patients treated in those intensive care units. Evaluating the data a positive development in the last four years of the neurological intensive care can be found in most of the areas investigated. It has also been found that neurological intensive care in the new lander has reached equal standard both in quality and quantity. Now a single physician is responsible for 2,3 beds compared to 3,6. Today 78 per cent of the beds in ventilation units are equipped with a ventilator. The overall time of ventilation increased to 48 per cent. Overall there are, however, considerable differences between individual units as well as regions. The data presented can serve as a means to monitor the quality of neurological intensive care.

Equipment and Supplies, Hospital↗
PubMed1998

Influence of 2-(4-aminophenyl)benzothiazoles on growth of human ovarian carcinoma cells in vitro and in vivo.

2-(4-Aminophenyl)benzothiazole molecules substituted in the 3 position of the phenyl ring with a halogen atom or methyl moiety comprise a group of compounds that potently inhibit specific human ovarian carcinoma cell lines. GI50 values fall within the nM range. Inhibition is highly selective -- whereas the GI50 value in IGROV1 cells consistently lies at < 10 nM, SK-OV-3 presents GI50 values > 10 microM. Biphasic dose-response relationships were observed in sensitive cell lines after 48-h drug exposure. COMPARE analyses revealed the very similar profiles of anti-tumour activity of 3-substituted benzothiazoles and 5-(4-dimethylaminophenylazo)quinoline, with Pearson correlation coefficients > 0.65. Anti-tumour activity extended to preliminary in vivo tests. The growth of OVCAR-3 cells in polyvinylidene fluoride (PVDF) hollow fibres implanted in the peritoneal cavity of mice was inhibited by more than 50% after intraperitoneal (i.p.) administration of 2-(4-amino-3-methylphenyl)benzothiazole (10 mg kg(-1)), 2-(4-amino-3-chlorophenyl)benzothiazole (100 mg kg(-1)) or 2-(4-amino-3-bromophenyl)benzothiazole (150 mg kg(-1)). The growth of OVCAR-3 tumours in subcutaneously (s.c.) implanted hollow fibres was retarded by more than 50% after treatment with 2-(4-amino-3-methylphenyl)benzothiazole (6.7 and 10 mg kg(-1)). In addition, the growth of s.c. OVCAR-3 xenografts was delayed after exposure to DF 203. However, the relationship between drug concentration and growth inhibition was inverse.

Animals↗
PubMed1998

Haplotype mapping of a major quantitative-trait locus for fetal hemoglobin production, on chromosome 6q23.

Fetal hemoglobin (Hb F) and fetal cell (FC) levels in adults show considerable variation and are influenced by several genetic variants; the major determinants appear to be unlinked to the beta-globin gene cluster. Recently, a trans-acting locus controlling Hb F and FC production has been mapped to chromosome 6q23 in an Asian Indian kindred that includes individuals with heterocellular hereditary persistence of Hb F (HPFH) associated with beta thalassemia. We have extended the kindred by 57 members, bringing the total studied to 210, and have saturated the region with 26 additional markers. Linkage analysis showed tight linkage of the quantitative-trait locus (QTL) to the anonymous markers D6S976 (LOD score 11.3; recombination fraction .00) and D6S270 (LOD score 7.4; recombination fraction .00). Key recombination events now place this QTL within a 1-2-cM interval spanning approximately 1.5 Mb between D6S270 and D6S1626. Furthermore, haplotype analysis has led to a reevaluation of the genealogy and to the identification of additional relationships in the kindred.

Chromosome Mapping↗
PubMed1997

Cytokine control of PMN phagocytosis: regulatory effects of hypoxemia and hypoxemia-reoxygenation.

We investigated the effects of hypoxemia and hypoxemia-reoxygenation (H/R) on interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), or IL-1beta stimulation of whole blood polymorphonuclear leukocyte (PMN) phagocytosis and bactericidal activity. Whole blood PMN were rendered hypoxemic (venous PO2 < 15 mmHg), normoxic (venous PO2 60-80 mmHg), or reoxygenated after hypoxemia (H/ R = venous PO2 150-200 mmHg) and were incubated with IL-8, TNF-alpha, or IL-1beta before sequential addition of serum-opsonized fluorescent microspheres and fluorescein isothiocyanate-conjugated mouse anti-human CD64, CD32w, CD16, CD35, or CD11b/CD18. Concomitant two-color flow cytometric analyses were then performed measuring mean channel fluorescence and the percentage of PMN positive for phagocytosis, with simultaneous subset receptor analysis on populations of PMN that exceeded control levels of phagocytosis. During hypoxemia, whole blood PMN phagocytosis in the presence of IL-8, TNF-alpha, or IL-1beta was increased compared with normoxia. Northern blot analyses revealed an increase in steady-state mRNA levels for CD32w during hypoxemia + IL-8 and CD64 during hypoxemia + IL-1beta. During reoxygenation, both whole blood PMN phagocytosis and bactericidal activity were reduced in the presence of IL-8, TNF-alpha, or IL-1beta, and in subsets of PMN with reduced phagocytosis H/R reduced CD64, CD32w, CD16, CD35, and CD11b/CD18 expression in the presence of each cytokine. Northern blot analyses revealed that H/R reduced mRNA levels for opsonic receptors primarily for IL-1beta-stimulated PMN. These results demonstrate a direct regulatory effect of hypoxemia and H/R on whole blood PMN phagocytosis, receptor expression, and steady-state mRNA levels of both Fc(gamma) and complement receptors.

Animals↗
PubMed1997

Whole cell Cl- conductances in mouse choroid plexus epithelial cells do not require CFTR expression.

Whole cell patch-clamp studies were performed with tissue isolated from the cystic fibrosis (CF) transgenic Cftrm1cam mouse, to determine whether anion currents in choroid plexus epithelial cells require the expression of cystic fibrosis transmembrane conductance regulator (CFTR). Inclusion of 0.25 mM adenosine 3',5'-cyclic monophosphate (cAMP) and 375 nM protein kinase A (PKA) in the pipette solution caused a significant activation of a Cl(-)-selective, inward-rectifying conductance in cells from wild-type and CF mice. The small, outward currents observed in wild-type and CF animals, however, were not activated by cAMP-PKA. There were no significant differences in the size of currents between wild-type, heterozygote, and CF cells in the presence or absence of cAMP-PKA. A second whole cell conductance was activated when cells from wild-type mice were swollen. These volume-activated currents were Cl- selective and exhibited outward rectification. They were Ca2+ independent and ATP dependent and blocked by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid. The volume-activated channels were also activated in CF mutant cells, and there was no significant difference in the size of the volume-activated currents between wild-type, heterozygote, and CF cells. It is concluded that CFTR neither contributes to the whole cell conductance nor regulates the other anion conductances in choroid plexus epithelial cells.

Animals↗
PubMed1996

Linkage analyses of schizophrenia to chromosome 6p24-p22: an attempt to replicate.

The present study evaluates evidence for linkage of schizophrenia to chromosome 6p24-p22. An independent sample of 211 families ascertained on the basis of having an affected sib-pair diagnosed with schizophrenia or schizoaffective disorder was assessed with seventeen polymorphic markers spanning a 37cM region. Linkage analysis was performed with parametric and non-parametric methods to test for cosegregation using 4 models of inheritance. Neither two-point nor multipoint non-parametric analyses reached significance at a level less than 0.01 for any markers examined in the region and lod score analyses were not suggestive of linkage. Based on initial findings in the present data set and recently published linkage results, two specific areas were densely covered with markers and tested for linkage disequilibrium. After correcting for multiple comparisons within each locus, no significant deviation from expected allele transmission ratios was observed. The present findings together with the published literature fail to find consistent evidence of a linkage for schizophrenia to a single locus on chromosome 6.

Adult↗
PubMed1996

Polymorphonuclear leukocyte opsonic receptor expression after hypoxia/reoxygenation.

We investigated the effects of hypoxia/reoxygenation (H/R) and subsequent stimulation of polymorphonuclear leukocytes (PMNs) with either formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol myristate acetate (PMA) on CD32, CD16, CD35, and CD11b/CD18 expression and on degranulation and superoxide anion production. H/R primed both adherent and fluid-phase PMNs for subsequent up-regulation of CD32 and CD16 (Fcgamma receptors) when stimulated with FMLP and primed both Fcgamma and complement (CD35, CD11b/CD18) receptors when stimulated with PMA. Kinetics assays demonstrated maximal up-regulation of CD32 and CD16 induced by H/R plus FMLP after 30 minutes of reoxygenation, whereas maximal receptor stimulation by H/R plus PMA occurred within 15 minutes of reoxygenation. Neither actinomycin D nor cycloheximide abrogated the effect of H/R with subsequent stimulation of PMNs on receptor expression; however, 10(-5) to 10(-8) mol/L concentrations of either taxol or phalloidin completely abrogated the effect of H/R plus FMLP or PMA on opsonic receptor expression. The effect of H/R plus FMLP on CD32 and CD16 expression was blocked by pertussis toxin, whereas staurosporine, H-7, H-9, and genistein had no effect. Conversely, the effect of H/R plus PMA on CD32, CD16, CD35, and CD11b/CD18 expression was blocked by staurosporine and H-7 but not by H-9, pertussis toxin, or genistein. The up-regulation of CD32, CD16, CD35, and CD11b/CD18 induced by H/R plus FMLP or PMA in the presence or absence of matrix proteins resulted in the increased rosetting of E-anti-CD32, E anti-CD16, E-Con A, EC3b, and EC3bi, respectively. Reduced nicotinamide adenine dinucleotide phosphate oxidase inhibition with diphenyleneiodonium blocked the effect of H/R on receptor expression, degranulation, and superoxide anion production. These results demonstrate that H/R primes PMNs for subsequent receptor up-regulation by divergent intracellular signal transduction pathways and that the receptors induced to the cell surface are biologically active.

Antibodies, Monoclonal↗
PubMed1996

Indication for linkage of the human OB gene region with extreme obesity.

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72-93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

Alleles↗
PubMed1996

Evaluation of TNF-alpha effects on radiation efficacy in a human lung adenocarcinoma model.

This study sought to determine if pretreatment with low-dose tumor necrosis factor-alpha (TNF-alpha) can enhance the effects of radiation in an NCI-H441 human lung tumor xenograft model. In vitro assays were performed on spleen cells, blood leukocytes, and plasma from the animals, as well as on cultured tumor cells. Tumors in animals given only TNF-alpha grew as well as, or better than, tumors in their untreated counterparts at all time-dose regimens employed. In contrast, early treatment with a total radiation dose of 16 Gy resulted in complete tumor inhibition, whereas 8 Gy modestly (but significantly, P < 0.05) slowed tumor progression. However, the administration of TNF-alpha (4 x 10(4) total units/mouse) 16-18 h prior to irradiation (8 Gy total dose) enhanced the antitumor effects of radiation when treatment was initiated early (P < 0.05). Oxygen radical production and response to mitogenic stimulation by splenocytes were greatest in untreated tumor-bearing animals. Total leukocyte counts in mice given radiation or TNF-alpha + radiation were low, and treatment-related changes were found in percentages of neutrophils and lymphocytes. In vitro assays of tumor cells showed that TNF-alpha + radiation resulted in greater suppression of clonogenic survival and incorporation of [3H]TdR and [3H]UdR incorporation than either agent alone. These results suggest that the use of low-dose TNF-alpha together with radiation may be beneficial in the clinical setting and so warrant further investigation.

Animals↗
PubMed1995

Genomic structure of human microtubule-associated protein 2 (MAP-2) and characterization of additional MAP-2 isoforms.

We have determined that the gene for human microtubule-associated protein 2 (MAP-2) spans 19 exons, including 6 exons identified in this study, 1-4, 8, and 13; all six of these exons are transcribed. The alternative splicing of coding exons generates a greater diversity of MAP-2 transcripts and isoforms. The first three exons encode alternate 5' untranslated regions that can be spliced to additional untranslated sequences contained in exons 4 and 5. Exons 8 and 13 are transcribed in human fetal spinal cord, adult brain, MSN cells, and rat brain, and each exon maintains an open reading frame with both high and low molecular weight MAP-2 isoforms. Antibodies generated to synthetic peptides of exons 8 and 13 demonstrate that these exons are translated and MAP-2 isoforms containing these exons are generated.

Alternative Splicing↗
PubMed1995

Enzymatic amplification of specific deoxyribonucleic acid sequences from single cells: evaluation of a simplified and rapid method for use in preimplantation genetic diagnosis.

OBJECTIVE: To develop a simplified polymerase chain reaction (PCR) protocol on single cells for the purpose of preimplantation genetic diagnosis. Also to evaluate a new thermal cycler, RoboCycler 40 (Stratagene, La Jolla, CA), for reducing the time to complete PCR amplification. DESIGN: PCR amplification without DNA purification or reamplification of a 149 base pair (bp) segment of the human Y chromosome was used as a model. The assay was tested in human fetal cells, single lymphocytes and single human blastomeres. RESULTS: Amplification of the 149 bp segment using fetal cells was 100% correct. Results on single lymphocytes were concordant in all but one of the 15 male cases. However, 2 of the 25 female cases were identified as male suggesting the occurrence of DNA contamination. Analysis of 61 blastomeres were concordant in 57 cases (93%); results for male blastomeres showed 12% of false negatives. No false positives were detected for female cells. Amplification using the simplified PCR protocol in combination with the RoboCycler was completed in 2 hours. CONCLUSION: These data show that this PCR assay performed directly, without DNA extraction or purification and without re-amplification is a practical and effective approach for amplification of specific DNA sequences in single cells. Furthermore, the simplified PCR protocol significantly reduced the time to complete DNA amplification. The reduced time is expected to facilitate the management of a routine program for preimplantation genetic diagnosis.

Base Sequence↗
PubMed1995

Hypoxemia up-regulates interleukin-8 stimulated phagocytosis of polymorphonuclear leukocytes by differential regulation of CD32w and CD35 messenger RNA expression.

BACKGROUND: The purpose of these studies was to investigate the effect of hypoxemia on interleukin-8 (IL-8) regulation of phagocytosis and surface opsonic receptor expression of whole blood polymorphonuclear leukocytes (PMNs). METHODS: Whole blood PMNs were rendered hypoxemic (PvO2 less than 15 mm Hg) or normoxic (PvO2 equals 60 to 80 mm Hg) and incubated with IL-8 (50 ng/ml) before the sequential addition of serum-opsonized fluorescent microspheres (emission wavelength, 560 nm) and fluorescein isothiocyanate-conjugated mouse anti-human CD32w or CD35 antibodies (emission wavelength, 513 nm). Concomitant two color flow cytometric analysis was then performed to measure the mean channel fluorescence (MCF) and the percentage of positive PMNs. Steady-state messenger RNA levels for CD32w and CD35 were quantitated by means of Northern blot analysis by using total RNA extracted from purified PMNs from each study group. RESULTS: Hypoxemia increased IL-8 stimulated PMN phagocytosis (percentage of positive PMNs, 38 +/- 1.5 versus 27 +/- 2.0, MCF, 5491 +/- 182 versus 4060 +/- 121 for hypoxemia plus IL-8 versus normoxia plus IL-8, respectively; p < 0.05). Hypoxemia increased IL-8 stimulated PMN expression of CD32w and CD35 (MCF CD32w, 791 +/- 105 versus 336 +/- 81; MCF CD35, 542 +/- 87 versus 254 +/- 41; p < 0.05). Under normoxic conditions IL-8 decreased messenger RNA levels for both CD32w and CD35, but under hypoxemic conditions IL-8 increased messenger RNA levels only for CD32w. CONCLUSIONS: Hypoxemia directly regulates IL-8 control of PMNs by increasing phagocytosis, receptor expression, and messenger RNA for these receptors. Studies investigating cytokine regulation of PMN function need to take into account oxygen tension when establishing the fundamental effects of cytokines on PMN physiology.

Cytokines↗
PubMed1995

[Neurologic rehabilitation in Bavaria. Study of the development of admission capacity of rehabilitation clinics 1992 to 1994].

In order to get information about capacities of neurorehabilitation for patients with acquired brain injuries or stroke in Bavaria, a survey concerning the time interval between registration and admission of the patient (waiting period) was carried out. Structured interviews by telephone were performed and all departments of neurorehabilitation and neurosurgery in Bavaria were included. The waiting period was calculated for the last 3 years and for each phase of rehabilitation using rehabilitation phase model A-D, which was proposed by the Deutscher Verband Rentenversicherungsträger (Association of German social pension Insurancies). As a result, a significant shortening of the waiting period over the last 3 years for almost all phases of rehabilitation has been demonstrated. We therefore conclude that an over capacity may develop in Bavarian neurorehabilitation, at least in certain regions. Quantity seems to be obtained. Next goal required is control of quality.

Brain Damage, Chronic↗
PubMed1994

Uses of GnRH agonists.

Gonadotropin-releasing hormone agonists are a relatively new class of drugs, which, when chronically administered, result in marked reductions in blood levels of testosterone and estrogen. These drugs include leuprolide acetate (Lupron); the first GnRH agonist to be approved in the United States, nafarelin acetate (Synarel); and goserelin acetate (Zoladex). Approved indications for these drugs, depending on the specific agent, include advanced prostate cancer, endometriosis, and precocious puberty. These and other investigational GnRH agonists are also being evaluated in many other diseases, including uterine fibroids, polycystic ovarian disease, breast cancer, fibrocystic breast disease, benign prostatic hypertrophy, and irritable bowel syndrome. Because of their therapeutic potential in many endocrinologic disorders, the GnRH agonists represent one of the most important advances in hormonal therapy in the past few decades. Thus, it appears likely that in the 1990s a greater number of patients will be receiving these agents. This article summarizes the application of GnRH agonist drugs in clinical practice, their side effects, and important information for patient use.

Breast Neoplasms↗
PubMed1994

Human immune response to Pseudomonas aeruginosa mucoid exopolysaccharide (alginate) vaccine.

Chronic lung infection with mucoid Pseudomonas aeruginosa is the major pathologic feature of cystic fibrosis. Previous studies suggested that a failure to produce opsonic antibody to the mucoid exopolysaccharide (MEP; also called alginate) capsule is associated with the maintenance of chronic bacterial infection. Provision of MEP-specific opsonic antibodies has therapeutic potential. To evaluate the ability of MEP to elicit opsonic antibodies, humans were immunized with two lots of MEP vaccine that differed principally in molecular size. Lot 2 had a larger average MEP polymer size. Both vaccines were well tolerated, but lot 1 was poorly immunogenic, inducing long-lived opsonic antibodies in only 2 of 28 vaccinates given doses of 10 to 150 micrograms. In contrast, at the optimal dose of 100 micrograms, lot 2 elicited long-lived opsonic antibodies in 80 to 90% of the vaccinates. The antibodies elicited by both lots enhanced deposition of C3 onto mucoid P. aeruginosa cells and mediated opsonic killing of heterologous mucoid strains expressing distinct MEP antigens. These results indicate that the polymers of MEP with the largest molecular sizes safely elicit opsonic antibodies in a sufficiently large proportion of vaccinates to permit studies of active and passive immunization of cystic fibrosis patients against infection with mucoid P. aeruginosa.

Adult↗