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Biomedical subjects

G Kelly

Publications and source records attributed to G Kelly.

At least 73 records · Page 4Linked to original sources
PubMed1995

Ability of some K+ channel blockers to reverse inhibition of electrically evoked contractions of longitudinal muscle-myenteric plexus.

Blockers selective for different potassium (K+) channels were examined for their ability to reverse inhibition of electrically evoked contractions of longitudinal muscle-myenteric plexus (lm-mp) by adenosine analogs. Cyclohexyl adenosine (CHA) was selected for these studies, since it effectively inhibited contraction (EC50 33 nM). 4-aminopyridine (4-AP) antagonized the inhibition by the adenosine analog, but also stimulated contraction by itself. alpha- and gamma-dendrotoxin produced the most profound reversal of CHA-induced inhibition, while producing a minimal contraction alone. Other blockers produced only nominal reversal of the CHA-induced inhibition. These results suggest that inhibition by CHA is mediated via activation of an alpha- and gamma-dendrotoxin-sensitive K+ channel.

4-Aminopyridine↗
PubMed1995

Interleukin-1 beta enhances spinal cord blood flow after intrathecal administration in the normal rat.

The effects of acute intrathecal recombinant human interleukin-1 beta (rhIL-1 beta) administration on spinal cord blood flow (SCBF), volume, and velocity were determined by laser-Doppler flowmetry in normal anesthetized rats with the use of a randomized and blinded protocol. The intrathecal administration of rhIL-1 beta (0.16-16 ng) produced a dose-dependent increase in SCBF that was not related to changes in blood pressure; arterial pH, PO2, PCO2; or spinal cord temperature. The IL-1 beta-induced enhancement of SCBF was directly proportional to the resultant elevation of spinal cord rhIL-1 beta content and was significantly correlated with an elevated blood velocity. The IL-1 receptor antagonist (IL-1ra) in concentrations 50- and 200-fold higher than IL-1 beta completely blocked the IL-1 beta-induced increase in SCBF when both compounds were administered concomitantly, but when administered alone, IL-1ra did not affect SCBF or other parameters. This suggests that IL-1 beta action was mediated by a specific interaction with an IL-1 membrane receptor site. The results suggest a role of IL-1 beta in the regulation of spinal cord hemodynamics. A potential pharmacological approach using IL-1 agonists for the treatment of the delayed appearance of posttraumatic spinal ischemia is proposed.

Animals↗
PubMed1995

p53 alterations in plutonium-induced F344 rat lung tumors.

The tumor suppressor gene p53 plays a critical role in the cellular response to genetic damage caused by radiation. In addition, mutations in this gene are often encountered in cells in lung tumors resected from uranium miners whose exposure to radon daughters exceeded 450 working level months. However, most of these miners also smoked tobacco products. Thus whether this gene is of specific importance in lung cancer is unclear. In this study, aberrations in the p53 gene were investigated using an immunohistochemical assay on 38 lung tumors (26 squamous cell carcinomas, 9 adenocarcinomas and 3 adenosquamous carcinomas) from rats that had inhaled 239PuO2 aerosols. Only 2 tumors exhibited detectable levels of staining of p53 products; both were large, well-differentiated squamous cell carcinomas that had invaded the pleural cavity or mediastinum. Direct DNA sequence analysis was used to characterize the mutations in these two tumors, and both exhibited G-->A transition mutations. One tumor was mutated in the first position of codon 283, resulting in a lysine for glutamine substitution; the other tumor was mutated at the second position of codon 280, resulting in a histidine to arginine substitution. No alterations in exons 5-7 of the p53 gene were found in a representative sample of tumors that did not exhibit elevated levels of the protein by immunohistochemistry. Further, no detectable polymorphisms or deletions were observed within the rat p53 gene after Southern blot analysis of 18 randomly selected 239Pu-induced tumors. These results suggest that p53 mutations are relatively unimportant in the development of lung tumors induced in the rat by high-linear energy transfer radiation.

Adenocarcinoma↗
PubMed1994

Micturition patterns after spinal trauma as a measure of autonomic functional recovery.

The purpose of these experiments was to determine whether experimental spinal trauma would result in urological dysfunction similar to that seen clinically and whether recovery of normal micturition can be correlated with motor functional recovery. A standard rat model of spinal impact trauma was employed. Neurologic evaluation included a modified 7 point hindlimb Tarlov scale applied weekly for 4 weeks after injury. Micturition measurement was accomplished by placing the animal in a metabolic cage for 24-hour periods and collecting urine on an electronic scale connected to Lotus Measure data acquisition software. All assessments were performed in a blinded fashion. Animals were categorized as normal control (N = 10), sham injured (N = 11), spinal cord injury (SCI) without (N = 11) and with locomotor recovery (N = 11). There were no differences in total micturition volume among the 4 groups, while the number of micturitions per 24 hours was significantly less for SCI without locomotor recovery (10.4 +/- 5.9) than for control (21.3 +/- 4.5). The volume per micturition was significantly greater for SCI (2.0 +/- 0.7 ml.) than for control (0.8 +/- 0.2 ml.). There were no differences among groups in the ratio of number of micturitions night/day. The SCI group had significantly greater largest and smallest micturitional volumes. Results clearly show alterations in micturition patterns induced by SCI. These were proportional to, but did not correlate fully with, the severity of injury and degree of motor recovery. Thus, recovery of a normal micturition pattern did not occur to the same extent as did motor functional recovery. This difference underscores the potential value of autonomic measures of SCI for distinguishing outcome categories after experimental SCI.

Analysis of Variance↗
PubMed1994

The natural history of HIV infection in women attending a sexually transmitted disease clinic in Dublin.

OBJECTIVE: To determine the progression rates to AIDS in women in Dublin. SUBJECTS AND METHODS: 109 HIV-1 seropositive women who presented to the Department of Genitourinary Medicine, St. James's Hospital, Dublin, were included in a retrospective analysis. Of these 101 (93%) were intravenous drug users (IVDUs), 7 were heterosexual partners of IVDUs and one had a hetero-sexual partner of no known risk group. Forty-four women (40%) had had 57 children since the time of their first known HIV seropositive test. Progression rates from CDC Stage 11/111 to AIDS are computed. Progression curves are generated according to the Kaplan-Meier method using the Statistical Analysis Software (SAS). RESULTS: The estimated cumulative progression rate at 5 years was 24% (SE 6.6%). 17 out of 109 (15.6%) developed AIDS. The mean follow up time was 2.8 years (SE 0.2). The prevalence of oesophageal candidiasis taking development of AIDS as the point in time was 9 out of 17 (53%), of Mycobacterium hominis infection (TB) 5 (29%) and of Pneumocystis carcinii pneumonia (PCP) 2 (12%). There was no statistical difference in progression rates to AIDS between those women who had children after becoming infected versus those who had none. CONCLUSIONS: Progression rates to AIDS in Irish women is higher than reported in other studies of homosexual/bisexual men, but is similar to rates estimated for both male and female IVDUs. Oesophageal candidiasis is the commonest presenting AIDS diagnosis followed by TB, while PCP is rare, contrary to the findings of similar studies in the USA.

AIDS-Related Opportunistic Infections↗
PubMed1994

Effects of acute and chronic cocaine on breathing and chemosensitivity in awake rats.

The barometric method was used to study effects of acute (AC) and chronic cocaine (CC) on breathing and chemosensitivity in awake rats. Effects of AC were evaluated 15 min after daily intraperitoneal injections, and effects of CC were measured at each week of the 4-wk treatment. Sham rats (group 1, n = 10) were injected with NaCl (0.2 ml). Cocaine HCl was given daily in groups 2 (20 mg/kg, n = 5) and 3 (40 mg/kg, n = 10). Effects of AC on the respiratory responses to 10% O2 in N2 and 5% CO2 in 21% O2 were studied 15 min after the first injection of cocaine. Effects of CC on chemosensitivity were studied at weekly intervals. NaCl had no effects on the breathing pattern or chemosensitivity. During normoxia, AC caused an increase in respiratory rate in group 2 and rapid and shallow respiration in group 3. The effects were similar from the first to the last injection at week 4. Haloperidol, a dopamine (DA) receptor blocker, abolished (group 4, n = 8) or prevented (group 5, n = 9) effects of AC. CC had no effects in all normoxic rats. During exposure to either low O2 or high CO2 the AC-induced polypnea was replaced by deep and slow respiration. CC had no effects on CO2 response in all rats. In contrast, 10% O2 response of tidal volume in group 2 and minute ventilation in group 3 were attenuated at weeks 3 and 4 compared with control.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of imposed postfeedback delays in programmed instruction.

Imposed postfeedback delays promote discrimination training; the present experiments determined whether they also improve performance in programmed instruction. In two experiments, college students completed 45 sets of Holland and Skinner's (1961) programmed text on behavior analysis in a computerized format in a three-component multiple schedule. In Experiment 1, the conditions were (a) no delay between questions, (b) a 10-s delay after each question (noncontingent delay), and (c) a 10-s delay after each question answered incorrectly (contingent delay). Noncontingent delay produced better performance than no delay and contingent delay. To determine whether performance increased in the noncontingent delay condition because subjects studied the material during delay periods, Experiment 2 tested three conditions: (a) no delay between questions, (b) a 10-s delay after each question (noncontingent delay), and (c) a 10-s delay after each question with the screen blank during the delay period. Noncontingent delay produced better performance than no delay, but there was no difference in performance between no delay and noncontingent delay with blank screen. Hence, noncontingent delay improved performance because students used delay periods to study. Furthermore, subjects preferred noncontingent delay to the other conditions, and session time increased only slightly.

Journal Article↗
PubMed1994

Expression of transforming growth factor alpha and epidermal growth factor receptor in rat lung neoplasms induced by plutonium-239.

Ninety-two rat lung proliferative lesions and neoplasms induced by inhaled 239PuO2 were evaluated for aberrant expression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor receptor (EGFR). Expression of TGF-alpha protein, measured by immunohistochemistry, was higher in 94% of the squamous cell carcinomas and 87% of the foci of alveolar epithelial squamous metaplasia than that exhibited by the normal-appearing, adjacent lung parenchyma. In contrast, only 20% of adenocarcinomas and foci of epithelial hyperplasia expressed elevated levels of TGF-alpha. Many neoplasms expressing TGF-alpha also expressed excessive levels of EGFR mRNA. Southern and DNA slot blot analyses showed that the elevated EGFR expression was not due to amplification of the EGFR gene. These data suggest that increased amounts of TGF-alpha were early alterations in the progression of plutonium-induced squamous cell carcinoma, and these increases may occur in parallel with overexpression of the receptor for this growth factor. Together, these alterations create a potential autocrine loop for sustaining clonal expansion of cells initiated by high-LET radiation.

Animals↗
PubMed1994

Characterization of mianserin neuroprotection in experimental spinal trauma: dose/route response and late treatment.

The neuroprotective action of the 5-hydroxytryptamine (5-HT2/5-HT1C) antagonist mianserin was examined with respect to optimal dosage, route of administration and time of treatment after a moderate spinal impact trauma (50 g.cm by the weight-drop method) to the thoracic region of the rat. In a previous study (Salzman et al., 1991b) a single 1-mg/kg i.v. dose of mianserin improved multiple measures of functional outcome when given 15 min after injury, whereas higher doses (5 and 10 mg/kg i.v.) displayed lesser therapeutic actions as well as pulmonary depressant effects. In these studies, lower dosages of minanserin (0.5 and 0.1 mg/kg i.v.) also were not associated with neuroprotection. Although the 1-mg/kg i.v. dosage again displayed significant efficacy when administered at 15 min delaying treatment to 30 min resulted in only marginal therapeutic actions. Nonetheless, i.p. dosage of 10 mg/kg (but not 2.5 mg/kg) at 15 min retained therapeutic efficacy, suggesting a pharmacodynamic influence. In support of this conclusion, the intrathecal administration of a 50-fold lower dose of minanserin (0.006 mg) at 15 min after injury resulted in neuroprotection that was superior to that of peripheral doses and was retained when this intrathecal dosage was administered at 1 hr after trauma. These results suggest a central mechanism of action for mianserin. Consistent with this was the lack of effect of mianserin (1 mg/kg i.v. at 15 min) upon post-traumatic spinal edema but its ability to reverse the decrease in central 5-HT oxidative metabolism after injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Losartan improves the natriuretic response to ANF in rats with high-output heart failure.

During severe congestive heart failure (CHF), a number of sodium-retaining and vasoconstricting mechanisms are activated, including the renin-angiotensin-aldosterone system. In CHF, the renal effects of atrial natriuretic factor (ANF) are attenuated. The interaction of these endocrine factors is a major determinant of the clinical course of CHF. This study was designed to evaluate the role of the renin-angiotensin-aldosterone system in the development of avid sodium retention in CHF, induced in rats by creation of an aorto-caval fistula. Rats with aorto-caval fistula either compensate and maintain a normal sodium balance (UNaV > 1400 microEq/day) or decompensate and develop severe sodium retention (UNaV < 200 microEq/day), which leads to severe CHF. Chronic treatment with losartan, an angiotensin II receptor blocker, 10 mg/day, resulted in dramatic natriuresis (UNaV > 1000 microEQ/day) in decompensated rats, but not in compensated rats or controls. ANF infusion (50 micrograms/kg/hr) increased fractional sodium excretion 46-fold in compensated rats, but only 18-fold in decompensated rats. A similar pattern of responsiveness to ANF was observed in urinary cyclic GMP excretion. Chronic losartan treatment restored the natriuretic and urinary cyclic GMP excretion responses of decompensated rats to ANF. The improvement in the natriuretic response after losartan treatment was associated with a suppression of the previously elevated plasma aldosterone. These results demonstrate the pivotal role of angiotensin II in the development of sodium retention and of the blunted renal response to ANF in CHF, and indicate why losartan is useful therapy for cardiac edema.

Angiotensin Receptor Antagonists↗
PubMed1993

Serum albumin: a marker for morbidity in peritoneal dialysis patients.

This study was designed to determine if the serum albumin is a marker for morbidity or mortality in peritoneal dialysis (PD) patients. The impact of a low serum albumin on the risk of hospitalization, peritonitis, or death was examined in 71 patients. Blood urea nitrogen (BUN), cholesterol, age, and the presence or absence of diabetes were also examined. In independent analyses, the serum albumin was lower (32.7 +/- 5.6 v 36.3 +/- 4.3 g/L, P < 0.01), the diagnosis of diabetes was more frequent (41% v 7%, P < 0.01), and the number of episodes of peritonitis were greater (2.0 +/- 1.6 v 0.7 +/- 1.3, P < 0.01) in the group of patients hospitalized compared with those not hospitalized. When diabetics were excluded from analysis, the serum albumin remained significantly lower in hospitalized patients. Stepwise logistic regression analysis, excluding the 10 patients hospitalized only for treatment of peritonitis, confirmed that only a low serum albumin and the diagnosis of diabetes were independent predictors of increased morbidity as evident by the increased frequency of hospitalization. Every 10 g/L decrease in the serum albumin increased the odds ratio for hospitalization by 5.2. The diagnosis of diabetes resulted in a 10-fold increase in the odds ratio. We conclude that a low serum albumin serves as a marker of morbidity in PD patients, primarily as a marker of increased risk for hospitalization. The diagnosis of diabetes also greatly increases the likelihood of hospitalization. Peritonitis is a cause for hospitalization, but not an independent risk factor.

Adult↗
PubMed1993

Choroidoretinal neovascularisation following radon seed treatment of retinoblastoma in two patients.

Two patients who developed localised radiation retinopathy many years after brachytherapy for retinoblastoma are described. In both patients extracapsular cataract extraction and YAG laser capsulotomy were followed by preretinal and vitreous haemorrhage and in one patient there was deterioration of existing radiation retinopathy with macular oedema. Premacular and vitreous haemorrhage occurred from focal, preretinal neovascular membranes which appeared to originate from residual choroidal vascular radicals. Laser photocoagulation was successful in ablating preretinal neovascular membranes and limiting the extent of macular oedema from incompetent retinal capillaries adjacent to the atrophic macular scars.

Brachytherapy↗
PubMed1993

Characterization of the K-ras gene of the marsupial Monodelphis domestica.

A cDNA clone isolated from a plasmid library contains the complete coding sequence for the K-ras gene of the marsupial Monodelphis domestica, a South American opossum. The nucleotide sequence of the coding region of the opossum K-ras gene is very similar to the K-ras coding sequences of placental mammals. The coding region of the opossum gene is 95% identical to the human gene at the nucleotide level; the human and opossum genes are 99% identical at the level of encoded amino acids. Transcribed but untranslated regions of the opossum gene 3' and 5' to the coding region are similar to corresponding regions of the human and mouse genes, but are less highly conserved than translated sequences. Based on the nucleotide sequence of the opossum K-ras cDNA clone, primers were designed that allowed amplification of exons 1 and 2 of the gene from opossum genomic DNA by the polymerase chain reaction. When exons 1 and 2 of K-ras were amplified from DNA isolated from an ultraviolet radiation-induced eye tumor of M. domestica and the nucleotide sequence of amplified material was determined, a heterozygous mutation in codon 61 of the gene was detected. This T to A transversion resulted in a change in the amino acid encoded by the codon. The tumor from which DNA was isolated had previously been shown to contain a transforming K-ras oncogene. Thus, the opossum K-ras gene can be mutationally activated in a manner similar to the K-ras genes of placental mammals.

Animals↗
PubMed1993

Halothane anesthesia is neuroprotective in experimental spinal cord injury: early hemodynamic mechanisms of action.

The neuroprotective potential of halothane anesthesia was explored in a weight-drop model of spinal trauma in the rat (N = 252). In initial experiments, animals were subjected to 25, 50 or 100 g cm impact injuries at T10 during pentobarbital or halothane anesthesia and their outcomes determined using somatosensory-evoked potentials, blinded neurologic evaluations for two weeks, and post-mortem analysis of spinal serotonin levels. Subsequently, halothane anesthesia was combined with either pentobarbital or nitrous oxide or given as a late treatment to pentobarbital anesthetized rats subjected to 50 g cm injuries. A series of acute studies were then performed in order to assess the hemodynamic and respiratory concomitants of halothane vs. pentobarbital, as well as the effect of mechanical ventilation and bicarbonate treatment upon halothane neuroprotection. Finally, the effect of a 50 g cm impact upon local white matter spinal cord blood flow was measured during halothane or pentobarbital anesthesia using laser-Doppler flowmetry. Results demonstrate an active neuroprotective action for halothane anesthesia that is not altered by the presence of other anesthetics and is most prominent at severe injury levels. The data suggest the importance of immediate injury responses in this action. Late halothane treatment was ineffective when given as early as 10 minutes postinjury while both the electrophysiological and hemodynamic effects of halothane vs. pentobarbital were apparent during this 10 minute period. Thus, halothane was associated with the prevention of spinal ischemia during the first 10 minutes after trauma in comparison to pentobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia, Inhalation↗
PubMed1992

Expression of epidermal growth factor receptor in plutonium-239-induced lung neoplasms in dogs.

The expression of epidermal growth factor receptor (EGF-R) was examined in canine lung tumors and in proliferative epithelial foci induced by plutonium-239 to determine if EGF-R was associated with specific neoplastic phenotypes or putative preneoplastic lesions. Seventeen (47%) of 36 canine lung tumors expressed EGF-R. Of these 17 tumors, three tumors hybridized with an erb-B RNA probe, which identified activated cell oncogenes. The expression of EGF-R was not correlated with tumor etiology, e.g., spontaneous versus radiation induced, but did correlate with specific histologic phenotypes. Nineteen (15%) of 127 proliferative epithelial foci in the canine lungs also expressed EGF-R. The phenotypic specificity demonstrated for EGF-R in canine lung tumors parallels that previously shown in human lung tumors. This finding, in addition to the identification of EGF-R in nonneoplastic proliferative lung lesions, indicates that radiation-induced lung tumors in the dog may be a useful animal model to investigate the role of EGF-R in lung carcinogenesis.

Adenocarcinoma↗
PubMed1991

Chemical carcinogen-induced damage to the c-neu and c-myc protooncogenes in rat lung epithelial cells: possible mechanisms for differential repair in transcriptionally active genes.

N-methyl-N'-nitro-N-nitrosoguanidine (M-NNG)-induced damage to two transcriptionally active genes, c-neu and c-myc, was studied in rat lung epithelial cells in vitro. MNNG, a direct acting alkylating agent that produces alkalilabile sites in DNA, caused damage to both protooncogenes. DNA damage was determined by monitoring the disappearance of specific fragments generated by restriction enzyme digestion in Southern blots. DNA repair in the c-neu and c-myc protooncogenes was examined in confluent cells by measuring the reappearance of these same bands. While the c-neu gene exhibited repair in 24 h, none was detected in the c-myc gene. These results imply that the promutagenic DNA lesions caused by MNNG are differentially repaired in two transcriptionally active genes.

Animals↗