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C Lynch

Publications and source records attributed to C Lynch.

At least 19 recordsLinked to original sources
PubMed2001

Calmodulin signals capacitation and triggers the agonist-induced acrosome reaction in mouse spermatozoa.

Capacitated acrosome-intact spermatozoa interact with specific sugar residues on neoglycoproteins (ngps) or solubilized zona pellucida (ZP), the egg's extracellular glycocalyx, prior to the initiation of a signal transduction cascade that results in the fenestration and fusion of the sperm plasma membrane and the outer acrosomal membrane at multiple sites and exocytosis of acrosomal contents (i.e., induction of the acrosome reaction (AR)). The AR releases acrosomal contents at the site of sperm-zona binding and is thought to be a prerequisite event that allows spermatozoa to penetrate the ZP and fertilize the egg. Since Ca(2+)/calmodulin (CaM) plays a significant role in several cell signaling pathways and membrane fusion events, we have used a pharmacological approach to examine the role of CaM, a calcium-binding protein, in sperm capacitation and agonist-induced AR. Inclusion of CaM antagonists (calmodulin binding domain, calmidazolium, compound 48/80, ophiobolin A, W5, W7, and W13), either in in vitro capacitation medium or after sperm capacitation blocked the npg-/ZP-induced AR. Purified CaM largely reversed the AR blocking effects of antagonists during capacitation. Our results demonstrate that CaM plays an important role in priming (i.e., capacitation) of mouse spermatozoa as well as in the agonist-induced AR. These data allow us to propose that CaM regulates these events by modulating sperm membrane component(s).

Acrosome Reaction↗
PubMed2001

Prospective study of correlations between biopsy-detected high grade prostatic intraepithelial neoplasia, serum prostate specific antigen concentration, and race.

BACKGROUND: High grade prostatic intraepithelial neoplasia (HGPIN), a premalignant lesion of the prostate gland, is more common in black men than in white men. The influence of HGPIN on the serum prostate specific antigen (PSA) concentration is controversial, and correlations between HGPIN and PSA in black men and white men have not been investigated. METHODS: Between January 1992 and December 1998, 411 black men and 639 white men with suspected prostate carcinoma underwent an initial benign prostate biopsy at a single medical center. The presence or absence of HGPIN in the biopsy specimens was determined by one uropathologist. RESULTS: HGPIN was identified in 8.9% of the specimens. When stratified by PSA concentration (< 4.0 ng/mL, 4.0-9.9 ng/mL, and > or = 10.0 ng/mL), HGPIN was associated with an increased PSA concentration only among men with PSA concentrations < 4.0 ng/mL (P = 0.01). The prevalence of HGPIN in the black and white patients was 13.4% and 5.9%, respectively (P < 0.0001), and was significantly greater in black men than in white men with PSA concentrations < 4.0 ng/mL (P = 0.002). Among the patients with PSA concentrations < 4.0 ng/mL, black race was an independent predictor of an increased PSA concentration when adjusted for patient age, prostate volume, and the presence or absence of HGPIN (P = 0.03). CONCLUSIONS: HGPIN is more common in black men than in white men and may produce an increase in the PSA concentration. However, racial differences in the prevalence of HGPIN may not contribute to racial differences in PSA concentrations among men with no clinical or histologic evidence of carcinoma.

Adult↗
PubMed2001

Surgery for cervical radiculomyelopathy.

BACKGROUND: Cervical spondylosis causes pain and disability by compressing the spinal cord or roots. Surgery to relieve the compression may reduce the pain and disability, but is associated with a small but definite risk. We sought to assess the balance of risk and benefit from surgery. OBJECTIVES: To determine whether: 1) surgical treatment of cervical radiculopathy or myelopathy is associated with improved outcome, compared with conservative management and 2) timing of surgery (immediate or delayed upon persistence/progression of relevant symptoms and signs) has an impact on outcome. SEARCH STRATEGY: We searched Medline (between 1966 and 1998), Embase (between 1980 and 1998) and the Cochrane Controlled Trials Register. Authors of the identified randomised controlled trials were contacted to detect any additional published or unpublished data. SELECTION CRITERIA: All unconfounded truly or quasi-randomised controlled trials allocating patients with cervical radiculopathy or myelopathy to 1) "best medical management" or "decompressive surgery (with or without some form of fusion) plus best medical management" 2) "early decompressive surgery" or "delayed decompressive surgery". DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data. MAIN RESULTS: Two trials involving a total of 130 patients were included. One trial with 81 patients compared surgical decompression with either physiotherapy or cervical collar immobilization in patients with cervical radiculopathy. The short-term effects of surgery, in terms of pain, weakness or sensory loss were superior, however, at one year no significant differences between groups were present. One trial with 49 patients compared the effects of surgery with those of conservative treatment in patients with mild functional deficit associated with cervical myelopathy. No significant differences were observed between groups, up to two years following treatment.

Cervical Vertebrae↗
PubMed2001

Gemcitabine and vinorelbine in patients with advanced lung cancer: preclinical studies and report of a phase I trial.

PURPOSE: This study was designed to assess the efficacy of gemcitabine plus vinorelbine using the mouse Lewis lung carcinoma model and to translate this regimen to a phase I clinical study of these two agents in patients with advanced lung cancer. MATERIALS AND METHODS: Using the mouse Lewis lung cancer model, employing growth delay and isobologram analysis, we demonstrated that gemcitabine, in combination with vinorelbine, produced additive activity with little increased toxicity over a wide range of doses. At the highest dose level studied, antagonism was observed. Based on these results, we initiated a phase IGemcitabine and vinorelbine in patients with advanced lung cancer: preclinical studies and report of a phase I trial study of this combination at the Dana Farber Cancer Institute (DFCI) in patients with untreated or once pretreated non-small-cell lung cancer (NSCLC) or once pretreated small-cell lung cancer (SCLC). Vinorelbine (given in an intravenous bolus) and gemcitabine (given in a 30-min infusion) were initially administered to patients at a dose of 15 mg/m2 and 500 mg/m2, respectively, on days 1, 8, and 15 of a 28-day cycle. Seven dose levels were subsequently explored over the course of the study. There was no intrapatient dose escalation. RESULTS: From November 1996 to March 1998, 40 patients were enrolled: 32 had NSCLC, 5 had SCLC and 3 had mixed disease (both SCLC and NSCLC). The patients were evenly divided by gender, the median age was 58 years (range 38 to 73 years), and the median ECOG performance status was 1 (range 0 to 2). All patients had normal renal and hepatic function and none had previously received gemcitabine or vinorelbine. Toxic reactions included mild to moderate fatigue, nausea, constipation, and, most significantly, neutropenia and thrombocytopenia. Phlebitis was a major problem when central venous lines were not used with 15% grade 1/2 events. The day-15 dose was held in 43% of patients at the expanded dose. No true maximum tolerated dose was reached after completion of seven dose levels. Dose level 4 (22.5 mg/m2 vinorelbine and 1,000 mg/m2 gemcitabine) was chosen for expansion and future study due to the potential increased ability of patients to receive the full doses on time. CONCLUSIONS: We conclude that this drug combination and dosage are feasible and have potential as either a front- or second-line chemotherapeutic regimen for advanced lung cancer, and phase II/III trials should be performed. However, hematologic toxicities, as found in this study, could probably be reduced with treatment on days 1 and 8 every 21 days, and current literature would suggest this to be the preferred schedule.

Adult↗
PubMed2001

Intravesical pressure and the TUR syndrome.

Intravesical pressure was measured continuously during 35 transurethral prostate resections using a fine suprapubic catheter. Absorption of irrigating fluid was detected by tagging it with ethanol and sampling the expired breath using an alcohol meter. Higher mean (SD) intravesical pressure was demonstrated in those patients who absorbed irrigating fluid (19.1 (7.7) mmHg) than in those who did not (12.4 (6.5) mmHg; p = 0.00004). Higher peak pressures were also demonstrated among absorbing patients. Traditional risk factors for fluid absorption, such as operator experience and resectate mass, were found to correlate with pressure exposure over time. Exposure to supranormal bladder pressure over time is the final common path for all causes of absorption. Vesical pressure monitoring may be a valuable feedback tool during difficult resections or operator training.

Absorption↗
PubMed2001

Role of calcium in acute hyperthermic myocardial injury.

INTRODUCTION: We hypothesized that intracellular calcium overload may play an important role in heat-induced myocardial injury. This postulate was investigated using a model of isolated guinea pig papillary muscle in which resting tension was measured as an indirect indicator of cytosolic free-calcium concentration and the fluorescence changes of Fluo-3 AM dye was measured as a direct indicator of cytosolic free-calcium concentration. METHODS AND RESULTS: Excised guinea pig right ventricular papillary muscles were attached to a force transducer in a high-flow tissue bath and superfused with Tyrode's solution at 37 degrees +/- 0.5 degrees C. The temperature was rapidly changed to between 38.0 degrees and 56.0 degrees C for 60 seconds and then returned to 37.0 degrees C. Hyperthermia caused a reversible increase in resting tension at temperatures between 45 degrees and 50 degrees C and irreversible contracture at > or =50 degrees C. Rapid cooling contracture experiments and experiments measuring fluorescence of myocytes loaded with 5 microM Fluo-3 AM dye demonstrated that the hyperthermia-induced rise in resting tension was likely due to an increase in intracellular calcium content. Inhibition of the sarcoplasmic reticulum calcium pump with 20 microM thapsigargin resulted in irreversible contracture of the papillary muscles at temperatures between 45 degrees and 50 degrees C and significant increases in Fluo-3 fluorescence at 48 degrees C. Blockade of sarcolemmal calcium channels with 0.5 mM cadmium or 40 microM verapamil did not attenuate the heat-induced increase in resting tension and Fluo-3 fluorescence. CONCLUSION: Hyperthermia causes an increase in resting tension of cardiac muscle that most likely is mediated by a calcium channel-independent increase in calcium permeability of the sarcolemmal membrane and/or release of stored intracellular calcium.

Acute Disease↗
PubMed2001

Speech processing strategy preferences among 55 European CLARION cochlear implant users.

This multicentre study investigates the preference and performance of a group of 55 adult CLARION cochlear implant users with the choice of simultaneous analogue stimulation (SAS) and continuous interleaved sampler (CIS) strategies during the first 3 months of implant use. Subjects were programmed with both strategies and instructed to use each of the two strategies in daily life to ascertain preference. Subjects were tested in both strategies with open-set sentence materials, auditory alone, at 2, 6 and 12 weeks after the initial programming session. Questionnaires were completed with preference ratings being recorded for the two strategies: 25% of subjects preferred SAS and 75% CIS. Subjects performed better in their strategy of choice. Preferences were set very early on in the process and did not change. Factors influencing preference are discussed. Offering the choice of fundamentally different strategies improves both individual and group performance.

Acoustic Stimulation↗
PubMed2001

Differential sensitivity of expressed L-type calcium channels and muscarinic M(1) receptors to volatile anesthetics in Xenopus oocytes.

Since volatile anesthetics inhibited high voltage-gated calcium channels and G-protein-coupled M(1) muscarinic signaling, their effects upon M(1) receptor-induced modulation of L-type (alpha1C) calcium channel was investigated. Voltage-clamped Ba(2+) currents (I(Ba)) were measured in Xenopus oocytes coexpressed with L-type channels and M(1) muscarinic receptors. M(1) receptor agonist, acetyl-beta-methylcholine (MCh) inhibited the peak and late components of I(Ba) in a dose-dependent manner. Analysis of I(Ba) after the treatment with MCh or volatile anesthetics revealed that the inactivating component, its time constant, and the noninactivating current were all decreased by these agents. MCh-induced inhibition followed a second messenger pathway that included G-proteins, phospholipase C, inositol-1,4,5-trisphosphate, and intracellular calcium [Ca(2+)](i). Although halothane or isoflurane inhibited I(Ba,) their effect was not mediated through these intracellular second messengers. By using volatile anesthetics and MCh sequentially, and in various combinations, the susceptibility of L-type currents and their modulation by M(1) receptors to volatile anesthetics were investigated. When MCh and volatile anesthetics were administered together simultaneously, a pronounced inhibition that was approximately equal to the sum of their individual effects was seen. Halothane or isoflurane further inhibited the I(Ba) when either volatile anesthetic was administered following the inhibition produced by prior administration of MCh. However, when MCh was administered following either volatile anesthetic, its effect was significantly reduced. Thus, whereas volatile anesthetics appear to directly inhibit L-type channels, they also interfere with channel modulation by G-protein-coupled receptors, which may have functional implications for both neuronal and cardiovascular tissues.

Anesthetics, Inhalation↗
PubMed2001

A phase II trial of the cyclin-dependent kinase inhibitor flavopiridol in patients with previously untreated stage IV non-small cell lung cancer.

PURPOSE: Flavopiridol is a potent cyclin-dependent kinase inhibitor with preclinical activity against non-small cell lung cancer (NSCLC), inhibiting tumor growth in vitro and in vivo by cytostatic and cytotoxic mechanisms. A Phase II trial was conducted to determine the activity and toxicity of flavopiridol in untreated patients with metastatic NSCLC. EXPERIMENTAL DESIGN: A total of 20 patients were treated with a 72-h continuous infusion of flavopiridol every 14 days at a dose of 50 mg/m(2)/day and a concentration of 0.1-0.2 mg/ml. Dose escalation to 60 mg/m(2)/day was permitted if no significant toxicity occurred. Response was initially assessed after every two infusions; patients treated longer than 8 weeks were then assessed after every four infusions. Plasma levels of flavopiridol were measured daily during the first two infusions to determine steady-state concentrations. RESULTS: This study was designed to evaluate a total of 45 patients in two stages. However, because no objective responses were seen in the first 20 patients, the early-stopping rule was invoked, and patient accrual was halted. In four patients who received eight infusions, progression was documented at 15, 20, 40, and 65 weeks, respectively. The most common toxicities included grade 1 or 2 diarrhea in 11 patients, asthenia in 10 patients, and venous thromboses in 7 patients. The mean +/- SD steady-state concentration of drug during the first infusion was 200 +/- 89.9 nM, sufficient for cytostatic effects in in vitro models. CONCLUSIONS: At the current doses and schedule, flavopiridol does not have cytotoxic activity in NSCLC, although protracted periods of disease stability were observed with an acceptable degree of toxicity.

Aged↗
PubMed2001

Effect of tetrandrine on cellular electrophysiology and calcium uptake of myocardium in guinea pigs and dogs.

OBJECTIVE: To study the effects of tetrandrine, a Chinese herbal medicine, on the action potential (AP), contraction as well as sarcoplasmic reticulum (SR) calcium uptake of myocardium in guinea-pigs and dogs. METHODS: Changes in AP, dV/dt, peak tension (PT) and dT/dt of myocardial cells were studied using the technique of glass electrode. Changes of the calcium uptake rate by sarcoplasmic reticulum and release of inorganic phosphate from sarcoplasmic reticulum were assessed with biochemical techniques. RESULTS: Tetrandrine exerts a concentration-dependent and frequency-dependent negative inotropic effect and shortens action potential duration. Tetrandrine depresses both dT(E)/dt and dT(L)/dt as well as the tension of myocardium, and reduces dV/dt and amplitude only in the slow action potential, thus implying that tetrandrine blocks the slow calcium channel. In addition, compared with thapsigargin, a specific inhibitor of Ca(2+)-ATPase on SR, tetrandrine more apparently suppresses the contraction of the myocardium. CONCLUSIONS: Tetrandrine is a wide-range calcium antagonist of plant origin. Not only it blocks the voltage-operated calcium channels as other authors reported, but also may play an important role in affecting the function of Ca(2+)-ATPase and calcium release channels on SR. From this study, we also suggest that the calcium channel appears to be more critical than SR for the contraction of myocardium.

Action Potentials↗
PubMed2000

Reliability of reporting on lifestyle and agricultural factors by a sample of participants in the agricultural health study from iowa.

PURPOSE: Information on agricultural practices has been obtained by questionnaire in several epidemiologic investigations. This project evaluated the reliability of self-reported information on pesticide use and various demographic and lifestyle factors among a group of farmers from Iowa.METHODS: 2,921 Iowa farmers participating in the Agricultural Health Study completed enrollment questionnaires approximately one year apart. Responses on the two questionnaires were compared for percent agreement and by Kappa statistics to evaluate reliability.RESULTS: Percent agreement for ever/never use of specific pesticides and application practices was quite high and generally ranged from 70% to over 90% and did not vary by age or educational level. Kappas were typically in the 0.50 to 0.60 range. Agreement was lower (typically 50% to 60%) for duration or frequency of use of specific pesticides. Agreement on lifestyle and non-agricultural factors was comparable to that reported in other studies.CONCLUSIONS: Level of agreement regarding pesticide use in this population is similar to that found for diet, physical activity, and medical conditions, which have been successfully evaluated in many epidemiologic studies. Information on agricultural practices from self-completed questionnaires has sufficient reliability for use in epidemiologic investigations.

Journal Article↗
PubMed2000

Self-report of smoking, obesity and hypertension history and survival among a cohort of iowa renal cell carcinoma cases.

PURPOSE: Smoking, obesity and hypertension are well-established risk factors for the development of renal cell carcinoma (RCC). However, little is known regarding the ability of RCC patient history regarding these characteristics to predict future survival.METHODS: To evaluate this question, we conducted follow-up on a cohort of incident RCC cases first assembled in Iowa from 1986-1989 for case-control analysis. We report data on 364 cases aged 40-86 years who reported detailed anthropometric and lifestyle history on a mailed questionnaire. Mortality experiences through 1998 were determined by linkage to the Iowa Cancer Registry and other databases; 233 deaths were identified during the 2,470 total years of follow-up, with 145 of those having RCC listed as the underlying cause of death on the death certificate. The Cox Proportional Hazards model was used to estimate the risk associated with each potential prognostic characteristic.RESULTS: After adjustment for age, a suggestion of an association with survival was noted for history of hypertension [Relative Risk (RR) = 0.8; 95% Confidence Interval (CI) 0.5-1.1] but no association was noted for either smoking or weight history. After further adjustment for tumor stage at diagnosis, evidence of an association for either smoking or obesity remained absent. However, after similar adjustment, the protective effect of history of hypertension actually strengthened slightly (RR = 0.7; CI 0.5-0.9).CONCLUSIONS: Data from this follow-up study of incident RCC cases in Iowa suggests that after adjustment for the strongest independent predictor of survival, a reported history of hypertension is associated with better survival.

Journal Article↗
PubMed2000

Long-term outcome of surgery for dogs with cranial cruciate ligament deficiency.

Fifty-eight dogs with cranial cruciate ligament deficiency were assessed and treated surgically. At an average of 50 months postoperatively, the functional outcome was assessed by means of an owner-based clinical assessment and a clinical examination. Client-based data were available for 26 dogs and 20 dogs were reassessed after 50 months. The results were compared with the initial values and with data from an assessment 13 months postoperatively. The level of disability at 50 months was judged to be significantly less than initially. However, there were no differences between the initial assessments and those made after 50 months for the perceived 'effect of cold weather' and the dogs' 'ability to jump', despite both measures having improved after 13 months. Age and meniscal injury were identified as poor prognostic indicators for the long-term outcome. The equivalent joint on the contralateral limb deteriorated significantly during the study.

Animals↗
PubMed2000

The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics.

Despite widespread use of volatile general anesthetics for well over a century, the mechanisms by which they alter specific CNS functions remain unclear. Here, we present evidence implicating the two-pore domain, pH-sensitive TASK-1 channel as a target for specific, clinically important anesthetic effects in mammalian neurons. In rat somatic motoneurons and locus coeruleus cells, two populations of neurons that express TASK-1 mRNA, inhalation anesthetics activated a neuronal K(+) conductance, causing membrane hyperpolarization and suppressing action potential discharge. These membrane effects occurred at clinically relevant anesthetic levels, with precisely the steep concentration dependence expected for anesthetic effects of these compounds. The native neuronal K(+) current displayed voltage- and time-dependent properties that were identical to those mediated by the open-rectifier TASK-1 channel. Moreover, the neuronal K(+) channel and heterologously expressed TASK-1 were similarly modulated by extracellular pH. The decreased cellular excitability associated with TASK-1 activation in these cell groups probably accounts for specific CNS effects of anesthetics: in motoneurons, it likely contributes to anesthetic-induced immobilization, whereas in the locus coeruleus, it may support analgesic and hypnotic actions attributed to inhibition of those neurons.

Action Potentials↗
PubMed2000

The effects of growth hormone and IGF-1 deficiency on cerebrovascular and brain ageing.

Research studies clearly indicate that age-related changes in cellular and tissue function are linked to decreases in the anabolic hormones, growth hormone and insulin-like growth factor (IGF)-1. Although there has been extensive research on the effects of these hormones on bone and muscle mass, their effect on cerebrovascular and brain ageing has received little attention. We have also observed that in response to moderate calorie restriction (a treatment that increases mean and maximal lifespan by 30-40%), age-related decreases in growth hormone secretion are ameliorated (despite a decline in plasma levels of IGF-1) suggesting that some of the effects of calorie restriction are mediated by modifying the regulation of the growth hormone/IGF-1 axis. Recently, we have observed that microvascular density on the surface of the brain decreases with age and that these vascular changes are ameliorated by moderate calorie restriction. Analysis of cerebral blood flow paralleled the changes in vasculature in both groups. Administration of growth hormone for 28 d was also found to increase microvascular density in aged animals and further analysis indicated that the cerebral vasculature is an important paracrine source of IGF-1 for the brain. In subsequent studies, administration of GHRH (to increase endogenous release of growth hormone) or direct administration of IGF-I was shown to reverse the age-related decline in spatial working and reference memory. Similarly, antagonism of IGF-1 action in the brains of young animals impaired both learning and reference memory. Investigation of the mechanisms of action of IGF-1 suggested that this hormone regulates age-related alterations in NMDA receptor subtypes (e.g. NMDAR2A and R2B). The beneficial role of growth hormone and IGF-1 in ameliorating vascular and brain ageing are counterbalanced by their well-recognised roles in age-related pathogenesis. Although research in this area is still evolving, our results suggest that decreases in growth hormone and IGF-1 with age have both beneficial and deleterious effects. Furthermore, part of the actions of moderate calorie restriction on tissue function and lifespan may be mediated through alterations in the growth hormone/IGF-1 axis.

Aging↗
PubMed2000

Xenon anesthesia.

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Anesthesia, Inhalation↗