Biomedical subjects

K Flynn

Publications and source records attributed to K Flynn.

At least 19 recordsLinked to original sources

PubMed2001

Diagnosis of "ASCUS" in women over age 50 is less likely to be associated with dysplasia.

Many investigators have found that cervical dysplasia is common when follow-up data are obtained from patients with a diagnosis of atypical squamous cells of undetermined significance (ASCUS). This study tests the hypothesis that ASCUS in older women is less likely to predict dysplasia than in younger women, and quantifies the difference. We constructed a retrospective case/control cohort from patients diagnosed with ASCUS by our service in 1997. Follow-up information was obtained on 150 patients over age 50 and a temporally matched control cohort under age 50. In women under 50, our control group, we found that 29.5% of patients had dysplasia on follow-up. This number is similar to that seen in many studies in the literature. In comparison, women over 50 showed only 12.8% of patients with any level of dysplasia. This difference is statistically significant by chi-square analysis, at P = 0.0077. A diagnosis of ASCUS in women over 50 yrs old is 2.3-fold less likely to be associated with dysplasia than that diagnosis in younger patients.

Aged↗

PubMed1998

Cholera toxin stimulates type II pneumocyte proliferation by a cyclic AMP-independent mechanism.

Cholera toxin (CT) stimulated DNA synthesis by low-density primary cultures of adult rat type II pneumocytes (T2P) in a dose-dependent manner, either in the presence or the absence of serum. In the presence of 1% rat serum, 1 microgram/ml CT also stimulated a 50% increase in cell number over 8 days of incubation (P<0.01); this was in addition to a 2-fold increase in cell number induced by the serum alone (P<0.05). The same dose of CT also elevated intracellular cAMP and the total activity of protein kinase A (both P<0.01), suggesting toxin stimulation of T2P proliferation by a cAMP-dependent mechanism. However, the effect of CT on DNA synthesis could not be mimicked by 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo-cAMP), nor by N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl-cAMP), each tested over a wide range of concentrations. l-Isoproterenol stimulated surfactant secretion by over 5-fold (P<0. 01), but neither the beta-agonist, forskolin nor 3-isobutyl-1-methylxanthine had any significant effect on DNA synthesis. The purified B-subunit of CT stimulated DNA synthesis to the same degree as did the holotoxin, either in the presence or the absence of rat serum. In contrast, the purified A-subunit had no significant effect. These data suggest that cholera toxin stimulates type II pneumocyte proliferation through a mechanism that is independent of cAMP, protein kinase A and toxin-catalyzed ADP-ribosylation.

Adenosine Diphosphate Ribose↗

PubMed1998

Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism.

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.

Adenocarcinoma↗

PubMed1997

The generation of memory antigen-specific cytotoxic T cell responses by CD28/CD80 interactions in the absence of antigen.

The interaction of co-stimulatory molecules CD80/CD86 on antigen-presenting cells with CD28 on naive CD8+ cytotoxic T (Tc) cells is understood to be critical in the induction of Tc effectors. CD80 is capable of providing signal 2 for the activation of Tc cells, but has no effect if encountered in the absence of specific peptide/MHC complexes (signal 1). We have found that CD80 presented in vitro to resting memory viral-immune or alloimmune Tc cells can provide sufficient stimulus for the generation of effector Tc cells in the absence of specific antigen, the peptide/MHC class I complex. Effector Tc cells generated in vitro from influenza- or class I alloantigen-primed mice by co-stimulation in the absence of antigen require exogenous interleukin (IL)-2 signaling via the cell surface-expressed IL-2 receptor or, under conditions of IL-2 blockade, exogenous IL-7. Activation of memory Tc cells by signal 1 and 2 is independent of IL-2 and IL-7. Although memory influenza-immune Tc cells did respond to CD80 in the absence of antigen, the presence of antigen +CD80 enabled an earlier induction of these Tc cells and they retained their lytic activity in vitro over a longer time period. The capacity of memory Tc cells to be activated by signal 2 alone provides one explanation for the observed heterogeneity of phenotype of memory T cells in vivo and a possible mechanism for the maintenence of memory in the absence of persisting antigen.

Animals↗

PubMed1997

Minor physical anomalies in older patients with late-onset schizophrenia, early-onset schizophrenia, depression, and Alzheimer's disease.

The authors assessed five groups of older subjects (age > 45) for evidence of minor physical anomalies. The groups were patients with early-onset schizophrenia (onset at age < 45; n = 15), late-onset schizophrenia (onset at age > 45; n = 8), Alzheimer's disease (AD; n = 11), and unipolar depression (n = 11), and normal comparison (NC) subjects (n = 15). Patients with late- and early-onset schizophrenia, and unipolar depression were found to have significantly more anomalies than NC subjects. Patients with AD did not have significantly more anomalies than NC subjects, although the patients with AD were significantly older than the NC subjects. The authors discuss implications of these findings on the pathophysiology of schizophrenia.

Aged↗

PubMed1997

Transferring managed care principles to VA.

The Under Secretary for Health asked the Health Services Research and Development (HSR&D) service to identify the managed care principles that would enable The Department of Veterans Affairs (VA) to most improve its efficiency and effectiveness while retaining its unique mission. In response to this request, HSR&D's Management Decision & Research Center (MDRC) prepared this article. This article represents the initial work done by the MDRC to determine the extent to which readily available published evidence on implementing managed care principles meets the Under Secretary's information needs and to outline potential areas for further work. It provides an overview and synthesis of existing literature. The document was prepared by the MDRC Technology Assessment Program, which took responsibility because of its expertise in systematic reviews and syntheses of the literature, with contributions from the MDRC's programs in information dissemination and management research.

Community Health Planning↗

PubMed1996

Widespread eruptive dermal and atypical melanocytic nevi in association with chronic myelocytic leukemia: case report and review of the literature.

Eruptive nevi have been associated with local skin trauma and immunosuppression, and atypical eruptive nevi preceding melanoma have been reported in immunocompromised transplant patients. We describe a 25-year-old man with widespread eruptive atypical and dermal melanocytic nevi in association with chronic myelocytic leukemia. Our patient's disease differs from earlier reports of eruptive nevi because his nevi appeared before induction chemotherapy. Eruptive nevi may have been a prodrome to leukemia in this patient. His nevi were histologically similar to eruptive atypical nevi observed in AIDS patients and may imply a link between systemic immunosuppression and melanocyte proliferation. We suggest that patients in whom eruptive nevi develop in association with immunosuppression should be carefully observed for the development of melanoma skin cancer.

Adult↗

PubMed1996

Memory alloreactive cytotoxic T cells do not require costimulation for activation in vitro.

We have studied the costimulation requirements for the generation of cytotoxic T (Tc) cells in an in vitro recall response to alloantigens. Firstly, we demonstrate that recombinant vaccinia viruses encoding class I MHC can stimulate primary in vivo responses and prime for secondary in vitro responses specific for the immunizing alloantigen. The secondary in vitro response comprises both naive and memory components that are distinguishable kinetically. Naive alloreactive Tc cell precursors are dependent upon the presence of CD80 on the in vitro stimulating population for activation and generation of effector function, as described previously. However, Tc cells from animals primed in vivo with vaccinia virus (VV) encoding allo-MHC do not require CD28-CD80 interactions to respond to the alloantigen presented in vitro. This finding provides further evidence that memory Tc cells have less stringent activation requirements in vitro than naive cells. From limiting dilution analysis of the relative contribution of naive and memory Tc cell precursors in 'primary' responses, to MHC class I alloantigen, memory alloreactive Tc cell precursors, possibly primed by cross-reactive environmental antigens, contribute approximately one-fifth of the precursors. Memory responses exhibit similar precursor frequencies as primary responses. Thus, we conclude that memory is largely a result of qualitative rather than quantitative changes in Tc cell precursors.

Animals↗

PubMed1996

Aspects of cytotoxic T cell memory.

Immunological T cell memory manifest itself in an accelerated second-set graft, or allogeneic tumour cell, rejection. Memory viral-immune cytotoxic T cells have shortened kinetics of induction in vivo and differentiate into more potent effector cells in vitro. The requirements for induction of memory T cells are less stringent than for naive T cells. Memory T cells can be activated by antigen (signal 1) or interaction with co-stimulatory molecules (CD28/CD80, signal 2) alone. Memory T cells are phenotypically distinguishable from naive T cells by a number of cell surface markers, but not from activated T cells. Persistence of antigen is not required for the maintenance of long-lived memory. Continuous stimulation by signal 2 alone and or longevity is sufficient to explain life-long persistence of T cell memory. All available data on memory T cells are consistent with a deterministic model of T cell memory formation, following a precise pathway of T cell differentiation.

Animals↗

PubMed1995

Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma.

BACKGROUND: The Epstein-Barr virus (EBV) is consistently detected in patients with nasopharyngeal carcinoma. To determine whether EBV infection is an early, initiating event in the development of this malignant tumor, we screened nasopharyngeal-biopsy samples, most of which were archival, for preinvasive lesions, including dysplasia and carcinoma in situ. Preinvasive lesions were found in 11 samples, which were tested for the presence of EBV. METHODS: EBV infection was detected with in situ hybridization for EBV-encoded RNAs (EBERs) and by immunohistochemical staining for latent membrane protein 1 (LMP-1). The larger samples were also tested for the EBV genome with the use of Southern blotting. The expression of specific EBV RNAs was determined by the amplification of complementary DNA with the polymerase chain reaction. RESULTS: Evidence of EBV infection was detected in all 11 tissue samples with dysplasia or carcinoma in situ. EBERs were identified in all eight samples tested, and LMP-1 was detected in all six of the tested samples. Six of the seven samples tested for the EBV termini contained clonal EBV DNA: Transcription of the latent EBV gene products, EBV nuclear antigen 1, LMP-1, LMP-2A, and the BamHI-A fragment, was detected in most of the samples. Viral proteins characteristic of lytic lesions were not detected. CONCLUSIONS: Preinvasive lesions of the nasopharynx are infected with EBV. The EBV DNA is clonal, indicating that the lesions represent a focal cellular growth that arose from a single EBV-infected cell and that EBV infection is an early, possibly initiating event in the development of nasopharyngeal carcinoma. Preinvasive lesions contain EBV RNAs that are characteristic of latent infection but not the viral proteins that are characteristic of lytic infection. The detection of the EBV-transforming gene, LMP-1, in all the neoplastic cells suggests that its expression is essential for preinvasive epithelial proliferations associated with nasopharyngeal carcinoma.

Antigens, Viral↗

PubMed1995

Undifferentiated, nonkeratinizing, and squamous cell carcinoma of the nasopharynx. Variants of Epstein-Barr virus-infected neoplasia.

Nasopharyngeal carcinoma (NPC) samples of distinct histological types, including squamous cell carcinoma (WHO type 1), nonkeratinizing carcinoma (WHO type 2), and undifferentiated carcinoma (WHO type 3), were analyzed for Epstein-Barr virus (EBV) infection and gene expression by using in situ and biochemical techniques. The EBV-encoded RNAs (EBER) were detected in situ in most tumor cells of all three WHO types of NPC. In foci of squamous differentiation and keratinization within less differentiated NPC and throughout the expanse of well differentiated squamous cell carcinoma, EBER expression was less abundant. Latent membrane protein, an EBV-encoded membrane protein, was detected in 72% (36/50) of all NPC and 67% (6/9) of the cases of squamous cell carcinoma. The EBV genomes were present as clonal episomal forms, without detectable linear viral DNA, in all cases of squamous cell carcinoma analyzed. Polymerase chain reaction amplification of cDNA detected EBV transcription for Epstein-Barr nuclear antigen 1, latent membrane proteins 1 and 2, and BamHI A in all samples, indicating that all forms of NPC express the same EBV genes. These results reveal that EBER expression is significantly decreased in areas with squamous differentiation and confirm that all types of NPC, regardless of histological type or differentiation contain clonal episomal EBV genomes, express specific EBV genes and are a clonal expansion of EBV-infected cells.

Base Sequence↗

PubMed1993

Effect of secobarbital and morphine on arterial blood gases in healthy human volunteers.

Secobarbital is still widely used as a hypnotic and morphine as an analgesic perioperatively in surgical patients. Their combination is often used as a preanesthetic medication. Although their ventilatory depressant effect is recognized, the resulting blood gas changes have not been studied as yet adequately in a sufficiently large population of healthy volunteers. Therefore this study was undertaken. Thirty healthy volunteers who gave valid written consent were studied. Secobarbital 2.0 mg/kg intravenously caused a significant (P < .05) decrease in arterial oxygen pressure (PaO2), peaking at 10 minutes (n = 10; mean age, 23.4 years). Morphine, 0.2 mg/kg intravenously also caused a significant decrease in PaO2 at 5 minutes (n = 10; mean age, 26.3 years). The combination of the same doses of morphine and secobarbital caused a significantly (P < .01) greater decrease in PaO2 at 5 and 10 minutes than the sole administration of either drug (n = 10; mean age, 23.5 years). Arterial oxygen pressure remained significantly (P < .05) reduced for 30 minutes. Although the PaCO2 increases after secobarbital and morphine did not reach statistical significance, their combination caused a significant (P < .05) increase in PaCO2. Both secobarbital and morphine alone caused significant (P < .05) decrease in pHa at 30 minutes. Their combination caused a significant (P < .01) reduction in pHa from 5 minutes until 60 minutes. In conclusion, both secobarbital and morphine alone caused ventilatory depression. The duration of ventilatory depression was greater with the intravenous combination than with either drug alone.

Adult↗

PubMed1993

Minor physical anomalies in schizophrenia and mood disorders.

The Waldrop Physical Anomaly Scale was used to assess the prevalence of minor physical anomalies in three groups: schizophrenia patients (n = 118), patients with mood disorders (n = 33), and normal controls (n = 31). Patients with schizophrenia had significantly more anomalies than controls. Patients with mood disorders did not have significantly different anomaly scores than schizophrenia patients or controls. Patients with tardive dyskinesia (TD) had significantly more anomalies than those without TD. Physical anomalies in the schizophrenia group were not found to be related to severity of psychopathology, age of onset, positive or negative schizophrenic symptoms, or socioeconomic status.

Abnormalities, Multiple↗

PubMed1993

Alpha interferon and hepatitis B and C. An integrated approach using practice guidelines.

Utilizing the techniques of total quality management, a team designed a clinical guideline for the use of alpha interferon as a treatment for patients with chronic hepatitis. The team included TEMINEX staff, a primary care physician, the plan's internal gastroenterologist, and its university-based consultant gastroenterologists. A synopsis of the available published research data and clinical opinion (a draft TEMINEX report) was used to focus discussions. The final TEMINEX report represented consensus on patient selection criteria and treatment regimens. All members of the team agreed to a review and approval process. Although quantitative data concerning the effects of guideline implementation are not yet available, it appears that the concerns of all members of the team have been satisfied. Patient selection criteria supported by the results of well-designed research are in place. Appropriate candidates for alpha-interferon therapy receive expedited treatment and the plan's internal monitoring processes are more efficient. Primary care physicians and consultant gastroenterologists feel that they made positive contributions both to the quality of care and to the consensus development process.

Health Maintenance Organizations↗

PubMed1993

Effect of hydroxyzine and meperidine on arterial blood gases in patients with chronic obstructive pulmonary disease.

Hydroxyzine is frequently used to tranquilize chronic obstructive pulmonary disease patients, who may be concomitantly receiving narcotic analgesics. Therefore, its effect alone and in combination with meperidine on arterial blood gases and ventilation at rest were evaluated in 44 patient volunteers, who gave informed consent. Hydroxyzine, 1.5 mg/kg i.v. caused no significant decrease in PaO2 and pH, no increase in PaCO2 at 5, 10, 20, 30 and 60 min post-infusion (n = 13, mean age = 63.4 years). Meperidine, 1.5 mg/kg i.v. caused a significant (p < 0.001) reduction in PaO2 for 20 min with concomitant increase in PaCO2 (n = 14; mean age = 49.4 years). The combination of the same doses of hydroxyzine with meperidine i.v. caused no greater decrease in PaO2 or in pH or increase in PaCO2 than did meperidine alone (n = 17; mean age = 52.6 years), indicating no greater ventilatory depression with the combination than with meperidine alone. The lack of significant pH decreases at 30 and 60 min further corroborates no potentiation of meperidine by hydroxyzine. In conclusion, hydroxyzine, even when given through the i.v. route in excess of the maximum i.m. therapeutic dose, caused no changes in PaO2, PaCO2 or pH in chronic obstructive pulmonary disease patients. Therefore, its i.m. administration resulting in lower blood levels than i.v., is not likely to cause ventilatory depression. Furthermore, hydroxyzine caused no potentiation of the ventilatory depression induced by meperidine, hence hydroxyzine may be safely employed in combination with meperidine.

Aged↗

PubMed1992

Smoking and schizophrenia.

Several studies have shown that patients with schizophrenia have an extremely high prevalence of smoking, almost 90%, compared to only 33% in the general population and 45-70% in patients with other psychiatric diagnoses. The reasons for the high prevalence of smoking among schizophrenics is unknown, but it is likely that smoking behavior in schizophrenia may be a complex process, related to numerous interrelationships between the psychopathological, biochemical, and neuropharmacological aspects of smoking and of schizophrenia.

Antipsychotic Agents↗

PubMed1992

Alterations of the p53 gene in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignancy which is consistently associated with the Epstein-Barr virus (EBV). The structure of the EBV genome in NPC suggests that NPC is a clonal proliferation of epithelial cells which emerges after EBV infection. The disease develops with high incidence in specific populations in discrete geographic locations, implicating possible genetic or environmental cofactors. Mutations of the p53 gene are among the most frequent genetic changes found in a large variety of human tumors. Mutations in p53 have been shown to abrogate the suppressor function of wild-type p53 and thus contribute to the transformed phenotype. To determine if mutation in p53 participates in the development of the malignant clone in NPC, the structure and sequence of p53 in 42 primary, metastatic, and nude mouse-passaged NPC specimens was analyzed. A high frequency (6 of 9) of mutations was detected in the nude mouse-passaged tumors, while only 2 of 15 metastatic and 0 of the 18 primary tumors harbored mutant p53. The p53 mutations included single-point mutations and more extensive changes such as frame shifts, deletion, duplication, or complete loss of coding sequences. These data indicate that alterations of the p53 gene are unlikely to be involved in the initial genetic events leading to the clonal outgrowth in NPC. However, although it is a rare NPC which can be established in nude mice, this growth advantage appears to be conferred on tumors bearing a mutant p53.

Animals↗

PubMed1992

Technology management information exchange (TEMINEX). Applied technology assessment for HMOs.

In an effort to obtain timely, comprehensive and valid information, The HMO Group medical directors have pooled resources to facilitate decision-making on the appropriate use of new or unfamiliar technologies. The HMO Group has responded to over 175 requests for information on topics such as organ transplants, testing and screening procedures, drugs and devices.

Health Maintenance Organizations↗