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Biomedical subjects

C Lynch

Publications and source records attributed to C Lynch.

At least 55 records · Page 3Linked to original sources
PubMed1999

Volatile anesthetic sensitivity of T-type calcium currents in various cell types.

UNLABELLED: We evaluated the effects of volatile anesthetics on T-type calcium current (ICa,T) present in four different cell types using the whole cell version of the patch clamp technique. In dorsal root ganglion neurons and in two neuroendocrine cells--adrenal glomerulosa cells (AG) and thyroid C-cells--ICa,T was reversibly decreased by volatile anesthetics at clinically relevant concentrations, with isoflurane and enflurane being more potent that halothane. In AG cells, the most sensitive cell type tested, ICa,T was reduced 47%+/-4% (n = 6) by isoflurane (0.7 mM) and 56%+/-2% (n = 5) by enflurane (1.2 mM), but by only 24%+/-1% (n = 5; P < 0.05) by halothane (0.7 mM). Isoflurane caused a significant increase in the rate of deactivation of ICa,T in AG cells. In ventricular myocytes, however, ICa,T was much less sensitive to both isoflurane and halothane. The differential sensitivity of ICa,T in various cell types to the anesthetics may reflect differences in the channels expressed in these tissues or differences in the cellular intermediates involved in anesthetic action. Depression of ICa,T in neuronal cells may contribute to anesthetic action through decreases in cellular excitability. IMPLICATIONS: Using the patch clamp technique, we showed that T-type calcium channels, which promote cellular excitability, are inhibited by volatile anesthetics in neuronal and neuroendocrine cells, but not in ventricular myocytes. Inhibition of neuronal T-type channels may contribute to the mechanism of action of volatile anesthetics.

Anesthetics, Inhalation↗
PubMed1999

Searching for the evidence in pre-hospital care: a review of randomised controlled trials. On behalf of the Ambulance Response Time Sub-Group of the National Ambulance Advisory Committee.

OBJECTIVES: To identify randomised controlled trials (RCTs) which evaluate aspects of pre-hospital care; to perform categorisation by theme; to compare the sensitivity and precision of the search databases. DATA SOURCES: August 1997 updates of MEDLINE and EMBASE databases, using the Datastar online system. Papers published in 1987 or later were included, with no language restrictions. STUDY SELECTION: A trial was eligible for inclusion if it was judged, by two independent and blinded assessors, that participants followed up in the trial were definitely or possibly assigned prospectively to one of two or more alternative forms of healthcare with random allocation or a quasi-random method of allocation. RESULTS: The literature search retrieved 849 papers, of which 569 (67%) were in MEDLINE and 486 (57%) in EMBASE. Forty one (5%) were confirmed as reports of RCTs or quasi-RCTs, and the total number of individual trials was 38. Ten of these trials dealt with thrombolytic drugs; 14 were concerned with other drugs, 12 with equipment, and two with other interventions. Four trials were based on a sample size of more than 1000, and seven reported a statistically significant effect on mortality. All 41 papers were in EMBASE, and all but one were also in MEDLINE. CONCLUSIONS: Evidence based policy making with respect to the organisation of pre-hospital services cannot depend on RCTs. In the current relative absence of such evidence, practitioners and decision makers must use alternative information sources. A future review could examine a broader range of literature and be based on a wider search of published and unpublished material.

Abstracting and Indexing↗
PubMed1999

Medical libraries, bioinformatics, and networked information: a coming convergence?

Libraries will be changed by technological and social developments that are fueled by information technology, bioinformatics, and networked information. Libraries in highly focused settings such as the health sciences are at a pivotal point in their development as the synthesis of historically diverse and independent information sources transforms health care institutions. Boundaries are breaking down between published literature and research data, between research databases and clinical patient data, and between consumer health information and professional literature. This paper focuses on the dynamics that are occurring with networked information sources and the roles that libraries will need to play in the world of medical informatics in the early twenty-first century.

Databases, Factual↗
PubMed1998

Multiple ionic mechanisms mediate inhibition of rat motoneurones by inhalation anaesthetics.

1. We studied the effects of inhalation anaesthetics on the membrane properties of hypoglossal motoneurones in a neonatal rat brainstem slice preparation. 2. In current clamp, halothane caused a membrane hyperpolarization that was invariably associated with decreased input resistance; in voltage clamp, halothane induced an outward current and increased input conductance. Qualitatively similar results were obtained with isoflurane and sevoflurane. 3. The halothane current reversed near the predicted K+ equilibrium potential (EK) and was reduced in elevated extracellular K+ and in the presence of Ba2+ (2 mM). Moreover, the Ba2+-sensitive component of halothane current was linear and reversed near EK. The halothane current was not sensitive to glibenclamide or thyrotropin-releasing hormone (TRH). Therefore, the halothane current was mediated, in part, by activation of a Ba2+-sensitive K+ current distinct from the ATP- and neurotransmitter-sensitive K+ currents in hypoglossal motoneurones. 4. Halothane also inhibited Ih, a hyperpolarization-activated cationic current; this was primarily due to a decrease in the absolute amount of current, although halothane also caused a small, but statistically significant, shift in the voltage dependence of Ih activation. Extracellular Cs+ (3 mM) blocked Ih and a component of halothane-sensitive current with properties reminiscent of Ih. 5. A small component of halothane current, resistant to Ba2+ and Cs+, was observed in TTX-containing solutions at potentials depolarized to approximately -70 mV. Partial Na+ substitution by N-methyl-D-glucamine completely abolished this residual current, indicating that halothane also inhibited a TTX-resistant Na+ current active near rest potentials. 6. Thus, halothane activates a Ba2+-sensitive, relatively voltage-independent K+ current and inhibits both Ih and a TTX-insensitive persistent Na+ current in hypoglossal motoneurones. These effects of halothane decrease motoneuronal excitability and may contribute to the immobilization that accompanies inhalation anaesthesia.

Anesthetics, Inhalation↗
PubMed1998

Thiopental and methohexital depress Ca2+ entry into and glutamate release from cultured neurons.

BACKGROUND: Although barbiturates activate alpha-aminobutyric acid type A receptors as part of their hypnotic effect, these drugs also inhibit voltage-gated calcium channels. The authors determined if barbiturates could decrease neuronal intracellular Ca2+ transients and the resulting glutamate release. METHODS: Neonatal rat cerebellar granule neurons were isolated and cultured on coverslips and studied at 37 degrees C. Spectrofluorometric assays were used during identical conditions to monitor intracellular Ca2+ with the Ca2+ -sensitive fluorophore fura-2 and glutamate release by a glutamate dehydrogenase-coupled assay, which produced the reduced form of nicotinamide-adenine dinucleotide phosphate in proportion to the amount of glutamate released. Neurons were depolarized by a rapid increase in external [K+] from 5 to 55 mM. Control responses were compared with those in the presence of 10, 30, and 100 microM thiopental; 3, 10, and 30 microM methohexital; decreased external [Ca2+]; or voltage-gated calcium channel blockers. RESULTS: Thiopental and methohexital depressed the intracellular Ca2+ transient peak and plateau in a dose-dependent manner, as did decreased Ca2+. The intermediate dose of either drug caused approximately 50% decrease in peak intracellular Ca2+ and 60% decrease in glutamate release. In the presence of specific L- and/or N-type voltage-gated calcium channel blockade by nicardipine or omega-conotoxin-GVIA, respectively, 30 microM thiopental further decreased the intracellular Ca2+ transient. Thiopental caused a dose-dependent decrease in glutamate release, which was proportional to the decreased peak intracellular Ca2+. CONCLUSIONS: Thiopental and methohexital depress the depolarization-induced increase in intracellular Ca2+ and the accompanying glutamate release, actions which can contribute to the anesthetic and neuronal protective effects of these drugs.

Anesthetics, Intravenous↗
PubMed1998

High-dose multimodality therapy with autologous stem-cell support for stage IIIB breast carcinoma.

PURPOSE: Women with locally unresectable and inflammatory breast carcinoma (IBC) have an approximately 30% 5-year disease-free survival (DFS) rate with conventional multimodality therapy. A short but dose-intensive multimodality phase II trial was designed in an attempt to improve outcome in stage IIIB disease. Mastectomy was performed after high-dose therapy to evaluate pathologic response to treatment. METHODS: Women with newly diagnosed disease received four 2-week cycles of doxorubicin 90 mg/m2 with granulocyte colony-stimulating factor (G-CSF), followed by cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) with marrow and peripheral-blood progenitor cell (PBPC) support. Local therapy consisted of mastectomy and radiotherapy. Tamoxifen (5 years) was begun if the patient was estrogen receptor-positive (ER+). RESULTS: Fifty women (46 stage IIIB [91% IBC], four stage IIIA) entered the study and 47 are assessable. Ten had mastectomy before any systemic therapy (seven with pathologic IBC, three with residual tumor after mastectomy). Eighty percent received full-dose doxorubicin with 60% on schedule. Clinical response rates to induction were 15% complete response (CR), 5% very good partial response (VGPR), 59% partial response (PR), and 21% minor response (MR)/stable disease (SD). Mastectomy after CTCb in 37 patients showed a 14% pathologic CR rate, 29% microscopic foci in breast and/or axilla, and 57% gross tumor. Fifteen (32%) patients have relapsed (median, 17 months post-CTCb). The 30-month DFS is estimated at 64%. For those in pathologic CR, with microscopic, or with gross disease remaining after CTCb, the 30-month DFS is estimated at 100%, 70%, and 38%, respectively. Those with zero, one to three, or > or = four positive nodes at axillary dissection had a median DFS of 31, 18, and 13 months, respectively. CONCLUSION: This short but dose-intensive multimodality approach for stage IIIB breast carcinoma is feasible with encouraging results to date.

Adult↗
PubMed1998

Inhibition of neuronal Na+ channels by antidepressant drugs.

Although tricyclic antidepressant (TCA) blockade of cardiac Na+ channels is appreciated, actions on neuronal Na+ channels are less clear. Therefore, the effects of TCAs (amitriptyline, doxepin and desipramine) as well as trazdone and fluoxetine on voltage-gated Na+ current (INa) were examined in bovine adrenal chromaffin cells using the whole-cell patch-clamp method. Amitriptyline produced concentration-dependent depression of peak INa evoked from a holding potential of -80 mV with KD value of 20.2 microM and a Hill coefficient of 1.2. Although 20 microM amitriptyline induced no change in the rate or voltage dependence of INa activation, steady-state inactivation demonstrated a 15-mV hyperpolarizing shift. Similar results were observed for doxepin and desipramine. This shift in steady-state inactivation was associated with a slowed rate of recovery from the inactivated state. Contrasting results were observed with the atypical antidepressants: while 20 microM fluoxetine depressed peak INa by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 microM trazodone decreased peak INa by only 19% and caused only a 3-mV shift. Although the magnitude of fluoxetine effects was similar to those of the TCAs, the onset of fluoxetine effects was substantially slower than for amitriptyline. In voltage-clamp and current-clamp measurements from neonatal rat dorsal root ganglion neurons, 20 microM amitriptyline decreased INa by 52% and depressed action potential dynamics consistent with enhanced Na+ channel inactivation. The effects of the TCAs on INa are similar to local anesthetic behavior and could contribute to certain analgesic actions.

Amitriptyline↗
PubMed1997

Active efflux of antimicrobial agents in wild-type strains of enterococci.

Enterococci are intrinsically resistant to numerous antimicrobial agents. We examined the energy-dependent efflux of radiolabeled drugs from four reference strains of Enterococcus faecalis and a strain of Enterococcus faecium and found that most strains pumped out norfloxacin and chloramphenicol. Efflux of tetracycline was detected only in certain strains.

Anti-Bacterial Agents↗
PubMed1997

Ifosfamide/carboplatin/etoposide/paclitaxel in advanced lung cancer: update and preliminary survival analysis.

The primary objective of this study was to define the maximum tolerated dose and toxicity profile of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), given as a 24-hour infusion, in conjunction with ifosfamide/carboplatin/etoposide (ICE) chemotherapy in patients with advanced lung cancer. Paclitaxel was escalated from 75 to 225 mg/m2 in 25-mg/m2 increments. All patients received granulocyte colony-stimulating factor 5 microg/kg/d from day 4 until the neutrophil count was > or = 10,000/microL. The study population consisted of 41 patients with a median age of 60 years and a median follow-up of 20.7 months. Stage distribution included 5% stage IIIA, 46% stage IIIB, and 49% stage IV. Histology consisted of 61% adenocarcinoma, 12% squamous cell carcinoma, 10% large cell carcinoma, 15% small cell carcinoma, and 2% mixed. The predominant toxicity was hematologic; 63% of patients experienced grade 4 neutropenia and 49% developed grade 4 thrombocytopenia. Fever and neutropenia occurred in 34% of patients. Hematologic toxicity was, in all cases, short-term and reversible and was not dose related. With few exceptions, nonhematologic toxicity was not clinically important. Among 39 patients evaluable for response, 36% achieved a remission (8% complete, 28% partial, 41% had stable disease, and 23% experienced disease progression). Among 33 patients with non-small cell lung cancer, the response rate was 27% (one complete response, eight partial responses, 15 had stable disease, and nine had progressive disease). Among six patients with small cell carcinoma, the response rate was 83% (two complete responses, three partial responses, and one had stable disease). The median survival of all 41 patients was 13.6 months. Survival was almost identical between stage IIIA and stage IV subsets. We conclude that it is possible to safely administer full-dose single-agent paclitaxel with granulocyte colony-stimulating factor support in conjunction with full-dose ifosfamide/carboplatin/etoposide chemotherapy. While response rates observed were not particularly notable, median survival is considerably longer than that usually achieved with combination chemotherapy in advanced lung cancer.

Adult↗
PubMed1996

Multiple synchronous primaries of the gastrointestinal tract: a molecular case report.

Six synchronous gastrointestinal primaries were identified in a 70 year old male with no known cancer predisposition syndrome or recognized risk factors except alcohol abuse. These specimens appeared to be independent and unrelated by gross and histopathological examination. In order to further evaluate the six tumors, we analyzed selected DNA sequences for alterations in the K-ras oncogene and p53 tumor suppressor gene. In addition, three loci were analyzed to determine microsatellite instability. Using the polymerase chain reaction, single stranded conformational polymorphism, and DNA sequencing, we demonstrated that each primary manifests genetic characteristics typical of the tissue of origin. In addition, one primary, a moderately differentiated colon adenocarcinoma, exhibited mutations not detected in the other specimens. This study suggests that these synchronous primaries arose independently and progressed along different carcinogenic pathways.

Adenocarcinoma↗
PubMed1996

Cancer incidence among alachlor manufacturing workers.

A historical cohort study was conducted to evaluate cancer incidence among chemical workers with occupational and environmental exposure to alachlor, the active ingredient in a family of pre-emergent acetanilide herbicides. The study followed 943 workers with at least 1 year of cumulative employment at the Monsanto plant in Muscatine, Iowa, from startup of the alachlor manufacturing process in March 1968 through December 1990. Approximately 96% of all workers were successfully traced to determine their last known residence and cancer status. Eighteen workers were diagnosed with cancer during the follow-up period, based on pathology information from the statewide cancer registry maintained by the State Health Registry of Iowa. The standardized incidence ratio for all cancers was 1.5 (95% CI 0.9-2.4) for all workers exposed to alachlor, which was due primarily to elevated rates for colorectal cancer and chronic myeloid leukemia. Workers with 5 or more years in estimated high alachlor exposure jobs had elevated rates of colorectal cancer (3 cases, SIR = 5.2, 95% CI 1.1-15.1). Interpretation of the study results is limited by the small size of the study population, minimal length of follow-up, and current information concerning alachlor metabolism in primates and humans. Nonetheless, the findings suggest the need for continued evaluation of this and other alachlor-exposed cohorts.

Acetamides↗
PubMed1996

The local repressor AcrR plays a modulating role in the regulation of acrAB genes of Escherichia coli by global stress signals.

Genes acrAB encode a multidrug efflux pump in Escherichia coli. We have previously reported that transcription of acrAB is increased under general stress conditions (i.e. 4% ethanol, 0.5 M NaCl, and the stationary phase in Luria-Bertani medium). In this study, lacZ transcriptional fusions and an in vitro gel mobility shift assay have been utilized to study the mechanisms governing the regulation of acrAB. We found that a closely linked gene, acrR, encoded a repressor of acrAB. Nevertheless, the general stress conditions increased transcription of acrAB in the absence of functional AcrR, and such conditions surprisingly increased the transcription of acrR even more strongly than that of acrAB. These results suggest that the general-stress-induced transcription of acrAB is primarily mediated by global regulatory pathway(s), and that one major role of AcrR is to function as a specific secondary modulator to fine tune the level of acrAB transcription and to prevent the unwanted overexpression of acrAB. To our knowledge, this represents a novel mechanism of regulating gene expression in E. coli. Evidence also suggests that the up-regulation of acrAB expression under general stress conditions is not likely to be mediated by the known global regulators, such as MarA or SoxS, although elevated levels of these proteins were shown to increase the transcription of acrAB.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Myocardial depressant effects of sevoflurane. Mechanical and electrophysiologic actions in vitro.

BACKGROUND: The effects of anesthetic concentrations of sevoflurane were studied in isolated myocardial tissue to delineate the mechanisms by which cardiac function is altered. METHODS: Isometric force of isolated guinea pig ventricular papillary muscle was studied at 37 degrees C in normal and 26 mM K+ Tyrode's solution at various stimulation rates. Normal and slow action potentials were evaluated using conventional microelectrodes. Effects of sevoflurane on sarcoplasmic reticulum function in situ were also evaluated by its effect on rapid cooling contractures, which are known to activate Ca2+ release from the sarcoplasmic reticulum, and on concentrations of rat papillary muscle. Finally, Ca2+ and K+ currents of isolated guinea pig ventricular myocytes were examined using the whole-cell patch clamp technique. RESULTS: Sevoflurane equivalent to 1.4% and 2.8% depressed guinea pig myocardial contractions to approximately 85 and approximately 65% of control, respectively, although the maximum rate of force development at 2 or 3 Hz and force in rat myocardium after rest showed less depression. In the partially depolarized, beta-adrenergically stimulated myocardium, sevoflurane selectively depressed late peak force without changing early peak force, whereas it virtually abolished rapid cooling contractures. Sevoflurane did not alter the peak amplitude or maximum depolarization rate of normal and slow action potentials, but action potential duration was significantly prolonged. In isolated guinea pig myocytes at room temperature, 0.7 mM sevoflurane (equivalent to 3.4%) depressed peak Ca2+ current by approximately 25% and increased the apparent rate of inactivation. The delayed outward K+ current was markedly depressed, but the inwardly rectifying K+ current was only slightly affected by 0.35 mM sevoflurane. CONCLUSIONS: These results suggest that the direct myocardial depressant effects of sevoflurane are similar to those previously described for isoflurane. The rapid initial release of Ca2+ from the sarcoplasmic reticulum is not markedly decreased, although certain release pathway, specifically those induced by rapid cooling, appear to be depressed. Contractile depression may be partly related to the depression of Ca2+ influx through the cardiac membrane. The major electrophysiologic effect of sevoflurane seems to be a depression of the delayed outward K+ current, which appears to underlie the increased action potential duration.

Anesthetics, Inhalation↗