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Biomedical subjects

L Cunningham

Publications and source records attributed to L Cunningham.

At least 37 records · Page 2Linked to original sources
PubMed1995

Evidence for distinct cytokine expression in allergic versus nonallergic chronic sinusitis.

BACKGROUND: The purpose of this study was to characterize the relationship between tissue cytokine expression and the cellular infiltrate present in chronic hyperplastic sinusitis with nasal polyposis (CHS/NP) and to compare the immunopathology and cytokine profile of patients with allergy versus patients without allergy. METHODS: Nasal polyp tissue samples from 12 patients with CHS/NP and nasal turbinate biopsy specimens from 10 normal control patients were examined for the expression of interleukin (IL)-4, IL-2, and interferon (IFN)-gamma cytokine messenger RNA (mRNA) species by in situ hybridization. These data were analyzed in conjunction with data previously reported for the cytokine mRNA species granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, and IL-5 and the immunocytochemical profile of the inflammatory cell infiltrate. Patients with allergy were distinguished from those without allergy on the basis of allergy skin tests. RESULTS: Tissue eosinophilia was a prominent feature of both allergic and nonallergic CHS/NP and correlated in both subgroups with the density of GM-CSF and IL-3 mRNA+ cells. In comparison with normal controls, patients with allergic CHS/NP had significantly higher CHS/NP had significantly higher tissue densities of GM-CSF, IL-3, IL-4, and IL-5 (p < or = 0.025). In contrast, patients with nonallergic CHS/NP had significantly higher tissue densities of GM-CSF, IL-3, and IFN-gamma (p < or = 0.001). The allergic and nonallergic subgroups showed distinct cytokine profiles with the most distinguishing cytokines of the allergic subgroup being IL-4 (p = 0.001) and IL-5 (p = 0.017) and of the nonallergic subgroup being IFN-gamma (p = 0.004). Furthermore, patients with allergic CHS/NP showed an increased density of CD3+ T lymphocytes compared with either controls or patients with nonallergic CHS/NP (p = 0.03). The density of CD3+ T lymphocytes was the only significant difference between patients with allergic and nonallergic CHS/NP. A clinical history of aspirin sensitivity was strongly correlated with nonallergic CHS/NP, as well as the nonallergic CHS/NP profile of cytokines, including IFN-gamma. CONCLUSION: We conclude that distinct mechanisms of eosinophilia exist in patients with allergic versus nonallergic CHS/NP. The allergic mechanism involves production of TH2-type cytokines, including GM-CSF, IL-3, IL-4, and IL-5, by infiltrating T lymphocytes. The nonallergic mechanism remains unknown but does involve production of GM-CSF, IL-3, and IFN-gamma. However, nonallergic eosinophilia is independent of IL-4 and IL-5, cytokines that contribute to tissue eosinophilia in allergic inflammation. Aspirin sensitivity is strongly correlated with nonallergic CHS/NP and production of the nonallergic CHS/NP profile of cytokines, including IFN-gamma.

Adolescent↗
PubMed1995

Isolation and characterization of mutants defective in the cyanide-insensitive respiratory pathway of Pseudomonas aeruginosa.

The branched respiratory chain of Pseudomonas aeruginosa contains at least two terminal oxidases which are active under normal physiological conditions. One of these, cytochrome co, is a cytochrome c oxidase which is completely inhibited by concentrations of the respiratory inhibitor potassium cyanide as low as 100 microM. The second oxidase, the cyanide-insensitive oxidase, is resistant to cyanide concentrations in excess of 1 mM as well as to sodium azide. In this work, we describe the isolation and characterization of a mutant of P. aeruginosa defective in cyanide-insensitive respiration. This insertion mutant was isolated with mini-D171 (a replication-defective derivative of the P. aeruginosa phage D3112) as a mutagen and by screening the resulting tetracycline-resistant transductants for the loss of ability to grow in the presence of 1 mM sodium azide. Polarographic studies on the NADH-mediated respiration rate of the mutant indicated an approximate 50% loss of activity, and titration of this activity against increasing cyanide concentrations gave a monophasic curve clearly showing the complete loss of cyanide-insensitive respiration. The mutated gene for a mutant affected in the cyanide-insensitive, oxidase-terminated respiratory pathway has been designated cio. We have complemented the azide-sensitive phenotype of this mutant with a wild-type copy of the gene by in vivo cloning with another mini-D element, mini-D386, carried on plasmid pADD386. The complemented cio mutant regained the ability to grow on medium containing 1 mM azide, titration of its NADH oxidase activity with cyanide gave a biphasic curve similar to that of the wild-type organism, and the respiration rate returned to normal levels. Spectral analysis of the cytochrome contents of the membranes of the wild type, the cio mutant, and the complemented mutant suggests that the cio mutant is not defective in any membrane-bound cytochromes and that the complementing gene does not encode a heme protein.

Azides↗
PubMed1994

Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy.

BACKGROUND: Enteroviral RNA sequences have been demonstrated in the myocardium of patients with myocarditis or dilated cardiomyopathy from presentation to end-stage disease. The prognosis of heart muscle disease has not previously been evaluated in relation to the detection of enterovirus in myocardial biopsy tissue. METHODS AND RESULTS: We studied 123 consecutive patients with heart muscle disease prospectively. Multiple endomyocardial biopsy samples taken from all patients during diagnostic cardiac catheterization were classified histologically and were examined for enteroviral RNA by use of an enterovirus group-specific hybridization probe. Three enterovirus-negative patients with cardiac amyloidosis were excluded from subsequent analysis. Enteroviral RNA sequences were detectable in 41 (34%) of the remaining 120 patients (group A), while 79 (66%) had no virus detected (group B). The groups did not differ significantly in age, sex, symptomatic presentation, or hemodynamic characteristics; duration of symptoms was significantly shorter in group A (7.8 +/- 9.6 versus 14.9 +/- 19.0 months, P < .05). At follow-up (mean, 25 months; range, 11 to 50 months), patients from group A had an increased mortality compared with those in group B (25% versus 4%, respectively; P = .02). Mortality was also statistically greater in patients with symptomatic cardiac failure (P = .02), those with elevated left ventricular end-diastolic pressures (P = .03), and those in New York Heart Association functional classes III and IV (P = .05). Multivariate regression analysis, however, showed that only the presence of enterovirus RNA and symptomatic heart failure were of independent prognostic value. CONCLUSIONS: These data demonstrate that the detection of enterovirus RNA in the myocardium of patients with heart muscle disease at the time of initial investigation is associated with an adverse prognosis and that the presence of enterovirus RNA is an independent predictor of clinical outcome.

Adolescent↗
PubMed1994

Bupropion in tricyclic antidepressant nonresponders with unipolar major depressive disorder.

Tricyclic antidepressant (TCA) medications are among the most widely used pharmacologic treatments for depression. However, a substantial number of patients fail to respond to these agents. Few standardized trials of pharmacologic treatments for TCA nonresponders are available. Bupropion has an apparently different mechanism of action than TCAs and represents a possible treatment for the TCA nonresponder. Based on positive results from pilot studies, a standardized study evaluating bupropion in TCA nonresponders was conducted. Forty-one depressed outpatients who had failed to respond to adequate documented TCA treatment, defined by specific criteria of dosage, duration, and plasma concentrations, entered a 1-week single-blind placebo phase, followed by an open 8-week bupropion treatment phase utilizing doses of up to the maximum daily dose of 450 mg. Response was measured by change on the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impressions-Severity (CGI-S) and Improvement (CGI-I) Scales, and the Hamilton Anxiety Rating Scale (HAM-A). Bupropion treatment resulted in an improvement in depression on all outcome measures. Forty-nine percent were considered "responders," in that they achieved > or = 50% improvement on the 28-item HAM-D. Fifty-four percent were classified as responders based on a CGI-I rating of much or very much improved. Statistically significant improvement in depressive symptoms, measured by mean scores for the HAM-D, CGI-S, and HAM-A, was achieved at the end of the study (as compared to baseline). Twelve patients (32%) had a HAM-D score of < or = 10 at termination.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Single-channel to multichannel conversions in pediatric cochlear implant recipients.

Speech perception skills were measured in five children who had received a 3M/House single-channel cochlear implant and were subsequently upgraded to a multichannel cochlear implant (Nucleus). A rationale was developed based upon performance with the single-channel device and anticipated performance with the multichannel device. All subjects demonstrated improved acoustic thresholds with the multichannel device. Three of the children demonstrated improvements on identification tasks and two on word recognition tasks.

Adolescent↗
PubMed1993

Attenuation of a reactivated cardiovirulent coxsackievirus B3: The 5'-nontranslated region does not contain major attenuation determinants.

To investigate the molecular basis of pathogenicity of Coxsackieviruses, a virus was reactivated by transfection from a full-length cDNA clone derived from cardiovirulent Coxsackievirus B3 (CVB3). The reactivated virus, rCVB3, was passaged serially in human dermatofibroblasts (HDF). No cytopathic effect was observed up to 12 days after inoculation with rCVB3 or early-passage virus, although disintegration of the monolayers was observed with late-passage virus (10th to 14th passages). Approximately 10% of HDF inoculated with rCVB3 were positive for viral antigens by immunofluorescence using enterovirus- or CVB3-specific monoclonal antibodies. These observations, together with the low infectivity titre of rCVB3 in HDF, suggests that HDF initially support only carrier state infection. After the 14th passage, the cardiovirulence of passaged virus (p14V) in mice was attenuated by a factor of > 10(4). Phenotypic changes of plaque size were also noticed in p14V: An attenuated variant (p14V-1) that produced larger plaques than rCVB3 in Vero cells has been plaque purified. The 5'-terminus of the genome of attenuant p14V-1 was amplified by polymerase chain reaction (PCR) and its sequence determined. Only one point mutation was found within the 5'-nontranslated region (5'NTR) at position 690 (A to U) compared to the viral RNA sequence obtained for rCVB3. An intertypic chimeric virus was reactivated from a cDNA clone after replacing the 5'-terminal 891 nucleotides of the wild-type genome with the corresponding region of the attenuant p14V-1. This chimeric virus, CB3/p14V-1/1, produced wild-type plaques in Vero cells and showed cardiovirulence similar to that of rCVB3 in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Chronic hyperplastic sinusitis: association of tissue eosinophilia with mRNA expression of granulocyte-macrophage colony-stimulating factor and interleukin-3.

BACKGROUND: We investigated the association among tissue eosinophilia, cellular infiltration, and cytokine mRNA expression in chronic hyperplastic sinusitis (CHS). METHODS: Percutaneous biopsies of the maxillary sinuses and nasal polyps were performed in 12 adult patients (six men and six women) of whom seven were nonallergic and 11 were asthmatic. Tissues were compared with biopsy specimens from the inferior and middle turbinates of normal control subjects. RESULTS: Histologically, an eosinophil-predominant inflammatory infiltrate was seen in 10 of 12 patients, whereas a mild to moderate neutrophilic infiltrate was seen in 4 of 12 patients. As determined by immunocytochemistry, diseased tissues and normal control tissues differed significantly in terms of the number of activated (EG2+) eosinophils (p = 0.005) but not in terms of CD3+ or CD4+ T lymphocytes, elastase-positive neutrophils or CD68+ macrophages. The number of eosinophils did not correlate with that of any other cell type. By in situ hybridization, CHS tissues showed significantly higher numbers of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-3 mRNA-positive cells than normal control tissues (p = 0.002 and 0.0005, respectively) per high-powered field. There was a significant correlation between the number of infiltrating EG2+ eosinophils and cells that expressed mRNA for GM-CSF (r = 0.60, p = 0.041) or IL-3 (r = 0.69, p = 0.013). Furthermore, epithelial cells did not show detectable mRNA expression for GM-CSF or IL-3. No significant correlation was found between IL-5 mRNA expression and infiltrating EG2+ eosinophils in diseased tissues. However, the IL-5 density was significantly higher in the five patients with CHS who had positive allergy skin test results than in the seven patients with negative skin test results (p = 0.017) or in normal control subjects. CONCLUSIONS: Our data support a role for GM-CSF and IL-3 in the eosinophilia characteristic of CHS and show that IL-5 mRNA expression is not a prominent feature of nonallergic inflammation. The cellular sources of GM-CSF and IL-3 in CHS remain to be definitely determined.

Adult↗
PubMed1993

Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy.

Molecular hybridization using an enterovirus group specific probe detected virus RNA in muscle biopsy samples from 25 of 96 cases of inflammatory muscle disease and similarly from 41 of 158 cases of postviral fatigue syndrome (PFS). Enterovirus RNA was detected in only two of 152 samples of control muscle. The inflammatory myopathy group comprised patients with polymyositis (PM), juvenile dermatomyositis (JDM) or adult dermatomyositis (DM), and all showed the presence of an inflammatory infiltrate and fiber necrosis on histological examination of a muscle biopsy sample. In contrast, muscle samples from the PFS group were histologically normal except for non-specific changes such as occasional single fiber atrophy. By analogy with enteroviral myocarditis, which can progress to a post-inflammatory disease with persistence of virus in myocardium and disposes to the rapid development of dilated cardiomyopathy, we propose that PFS syndrome may be a sequela of a previous inflammatory viral myopathy.

Biopsy↗
PubMed1991

Cytology of treated and minimal Pneumocystis carinii pneumonia and a pitfall of the Grocott methenamine silver stain.

To clarify the role of foamy alveolar casts (FACs) in the diagnosis of Pneumocystis carinii pneumonia (PCP), we retrospectively reviewed Papanicolaou (Pap)- and Grocott methenamine silver (GMS)-stained slides from 205 bronchial specimens submitted for suspected opportunistic lung infection. FACs containing sporozoites were seen in 86 cases, all with positive GMS. FACs were absent in 119 cases with negative GMS. In patients previously treated for PCP, Pap showed FAC-like material which lacked sporozoites. GMS demonstrated clumped degenerated Pneumocystis carinii (PC) cysts. In 17 GMS-positive cases there were no FACs on Pap due to sampling error and low burden of organisms. Morphologic features of macrophages in these cases can suggest the presence of PC. When FACs are lacking, a special stain is required. When GMS is used, the control must contain PC to avoid a false negative GMS. The inconsistent uptake of GMS by PC is a pitfall which is distinct from sampling error and which to our knowledge has not been previously reported.

Bronchi↗
PubMed1991

Molecular probes for detection of persisting enterovirus infection of human heart and their prognostic value.

Enteroviruses are well recognized in the aetiology of myocarditis. Molecular hybridization using enterovirus group-specific probes shows that virus can be detected in endomyocardial biopsies and persists in myocardium after the inflammation heals. Virus persistence is associated with the subsequent development of dilated cardiomyopathy, progressing to end-stage disease requiring cardiac transplantation. Infectious virus cannot usually be isolated from myocardium nor can virus-specific antigens be detected after the initial inflammatory stage. Patients with healed myocarditis or dilated cardiomyopathy may have no histological evidence of inflammation despite detection of virus-specific RNA sequences by molecular hybridization. Persisting enterovirus RNA in dilated cardiomyopathy is the strongest known predictor of poor prognosis. The molecular mechanism of virus persistence is the selection of defective virus mutants during the initial phase of disease.

Cardiomyopathy, Dilated↗
PubMed1991

Persistent virus infection of muscle in postviral fatigue syndrome.

Nucleic acid was extracted from muscle biopsy samples from a series of highly selected patients suffering from chronic muscle fatiguability following a viral infection (Postviral Fatigue Syndrome: PVFS). Samples were examined for the presence of enteroviral RNA sequences or Epstein-Barr (EBV) virus DNA sequences by molecular hybridisation as these two agents have been implicated by retrospective serology in the aetiology of PVFS. We found enteroviral RNA in 24% of biopsy samples and EBV DNA in a further 9% of biopsy samples: no biopsy was positive for both enteroviral RNA and EBV DNA. In addition, in the case of enteroviruses we found that the persisting virus is defective in control of RNA replication as both strands of enteroviral RNA are present in similar amounts: this is unlike the asymmetric synthesis of genomic RNA seen in a productive, cytolytic enterovirus infection. The implications of these data in relation to mechanisms of viral persistence and muscle dysfunction are discussed.

DNA, Viral↗
PubMed1990

Persistence of enteroviral RNA in chronic fatigue syndrome is associated with the abnormal production of equal amounts of positive and negative strands of enteroviral RNA.

A subgenomic restriction fragment from cDNA prepared from Coxsackie B2 virus (CVB2) RNA was subcloned into a riboprobe vector allowing the production of enteroviral group-specific RNA probes complementary to either the positive (genomic) or negative (template) strand of enteroviral RNA. These riboprobes were used to follow productive infection of cultured cells by CVB2; as expected, positive strand RNA was synthesized in approximately 100-fold excess over negative strand. RNA was extracted from muscle biopsy samples from patients with chronic fatigue syndrome and probed for the presence of enteroviral RNA. In cases where enteroviral RNA was detected the amounts of positive and negative strands of enteroviral RNA were approximately equal, in contrast to the situation in lytic infection of cultured cells. This suggests that enterovirus persistence in muscle is due to a defect in control of viral RNA synthesis.

Animals↗
PubMed1990

Spontaneous decay of oxidized ascorbic acid (dehydro-L-ascorbic acid) evaluated by high-pressure liquid chromatography.

We applied high-pressure liquid chromatography to assess the decomposition of the oxidized form of vitamin C, dehydro-L-ascorbic acid. We selected experimental conditions that might represent a wide variety of clinical and research procedures. Decay of dehydro-L-ascorbic acid proceeded much more rapidly at high pH (7-8) than at low pH (3-5) and was more rapid at 37 or 45 degrees C than at 0 or 23 degrees C. When evaluated at pH 6.6, the percent decay was somewhat more rapid from an initial concentration of 1000 mumol/L than at 5-10 mumol/L. The analytical procedure (HPLC) provided useful information about the rate of decay under various conditions. This may facilitate future biological and clinical studies that require a distinction between the oxidized and reduced forms of vitamin C.

Ascorbic Acid↗
PubMed1989

End-stage dilated cardiomyopathy. Persistence of enterovirus RNA in myocardium at cardiac transplantation and lack of immune response.

Tissue from the explanted hearts of 21 patients with idiopathic dilated cardiomyopathy or 19 patients with other specific heart muscle diseases were investigated for presence of enterovirus-specific RNA with an enterovirus group-specific cDNA probe. This was complementary to coxsackievirus B2 RNA sequences between nucleotide numbers 6,550 and 7,400, which are highly conserved between enteroviruses. Hearts from six patients with dilated cardiomyopathy and one patient with ischemic heart disease were found to contain virus RNA. Serology revealed that only one patient (dilated cardiomyopathy group) was positive for coxsackievirus B-specific IgM but negative for virus RNA in the myocardium. Quantitation of leukocytes and T-lymphocytes in the myocardium and expression of major histocompatibility locus antigens revealed no significant differences associated with persistence of virus RNA. These data demonstrate that enterovirus RNA persists in myocardium of a significant proportion of patients with end-stage dilated cardiomyopathy in the absence of a continuing cell-mediated or humoral immune response.

Adolescent↗
PubMed1989

Treatment of tracheobronchial granular cell myoblastomas with endoscopic bipolar cautery.

Granular cell myoblastomas of the trachea and right upper lobe bronchus were discovered incidentally during therapeutic bronchoscopy. Because of their propensity to cause airway compromise and distal atelectasis, ablation of both lesions was undertaken. This is the first reported case of bipolar cautery of GCM through a flexible fiberoptic bronchoscope. Small tumor size and lack of atelectasis permitted utilization of this technique. Long-term follow-up is necessary to compare this therapy with other nonresectional therapies.

Bronchial Neoplasms↗