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Biomedical subjects

K Mason

Publications and source records attributed to K Mason.

At least 19 recordsLinked to original sources
PubMed1999

Enhancement of tumor radioresponse in vivo by gemcitabine.

Gemcitabine, 2'2'-difluoro-2'-deoxycytidine, is an inhibitor of DNA synthesis and has been shown previously in vitro and in vivo to enhance the cytotoxic activity of radiation as well as some chemotherapeutic agents. Because gemcitabine has shown clinical activity on its own in several solid tumors traditionally treated with radiotherapy, it was of interest to optimize the combination of gemcitabine and radiation. To determine the optimal gemcitabine dose to combine with irradiation and to determine the effect of gemcitabine on tumor growth, mice bearing SA-NH tumors were treated with 2.5 to 600 mg/kg gemcitabine, and subsequent tumor growth was determined. At low doses, gemcitabine induced transient growth delay, whereas higher doses showed both cytotoxic and cytostatic activity. Flow cytometric, histological, and mitotic analyses of irradiated tumors showed that gemcitabine induced a dose-dependent inhibition of DNA synthesis and induction of apoptosis of cells in S phase. DNA synthesis recovered in cells at the G1-S boundary of the cell cycle in a dose-dependent manner, and a parasynchronous movement of cells through the cell cycle ensued. To determine the optimal schedule for gemcitabine administration in relation to irradiation, tumor-bearing mice were given a single 50 mg/kg dose of gemcitabine at various times before or after irradiation. Gemcitabine enhanced radioresponse in a time-dependent fashion. The highest enhancement factors for tumor growth delay (1.68-2.03) were observed when gemcitabine was administered 24-60 h before irradiation. Although gemcitabine reduced the radiation tumor control dose at all administration times used, the greatest enhancement of tumor radiocurability occurred when gemcitabine was administered 24 h before irradiation (dose modification factor of 1.54). Moreover, gemcitabine decreased the lung metastatic rate in mice with local tumor control from 73% in mice receiving radiation alone to 40% in mice receiving the combination (all combination times included). These results suggest that gemcitabine has strong radioenhancing properties and that the greatest interaction occurs when gemcitabine administration precedes irradiation by 24-72 h. Preliminary studies indicate that normal tissues recover more quickly than tumor tissues from gemcitabine treatment; thus, optimized scheduling of gemcitabine and irradiation may serve to improve the therapeutic ratio of the combination.

Animals↗
PubMed1998

Selective uncoupling of RGS action by a single point mutation in the G protein alpha-subunit.

Heterotrimeric G proteins function as molecular relays, shuttling between cell surface receptors and intracellular effectors that propagate a signal. G protein signaling is governed by the rates of GTP binding (catalyzed by the receptor) and GTP hydrolysis. RGS proteins (regulators of G protein signaling) were identified as potent negative regulators of G protein signaling pathways in simple eukaryotes and are now known to act as GTPase-activating proteins (GAPs) for G protein alpha-subunits in vitro. It is not known, however, if Galpha GAP activity is responsible for the regulatory action of RGS proteins in vivo. We describe here a Galpha mutant in yeast (gpa1(sst)) that phenotypically mimics the loss of its cognate RGS protein (SST2). The gpa1(sst) mutant is resistant to an activated allele of SST2 in vivo and is unresponsive to RGS GAP activity in vitro. The analogous mutation in a mammalian Gqalpha is also resistant to RGS action in transfected cells. These mutants demonstrate that RGS proteins act through Galpha and that RGS-GAP activity is responsible for their desensitizing activity in cells. The Galphasst mutant will be useful for uncoupling RGS-mediated regulation from other modes of signal regulation in whole cells and animals.

Animals↗
PubMed1998

Multiplex display polymerase chain reaction amplifies and resolves related sequences sharing a single moderately conserved domain.

We present a technique, multiplex display polymerase chain reaction (MD-PCR), that amplifies and resolves coding sequences from messenger RNAs sharing only a single moderately conserved domain encoding eight or nine amino acids. The technique, a form of single-sided PCR, allows detection of known and novel genes in a family by using one degenerate primer complementary to a gene family-specific domain. A second common primer is complementary to an oligonucleotide ligated to a nearby restriction enzyme cleavage site. Uniquely, restriction enzyme digestion of single-stranded cDNA, a technique never previously performed to useful advantage, is used to increase the specificity and sensitivity of the technique. Up to several hundred bases of coding sequence are amplified simultaneously from many (potentially from all) genes in a specific family, yielding products of different sizes from different genes, and allowing amplified products to be resolved electrophoretically. Typically, more than 50% of the amplified sequences are from the targeted gene family and many of the amplified products are novel sequences. mRNAs representing less than 1 in 100,000 messages can be detected. The method allows the focused yet open-ended examination of genes in families known to be important in both normal cellular homeostasis and the etiology of many diseases.

Animals↗
PubMed1998

The anxiogenic agents, yohimbine and FG 7142, disrupt the noradrenergic response to novelty.

Whether or not abnormal noradrenergic transmission can be a causal factor in anxiety is controversial. The present experiments examined this question by comparing the effects of two anxiogenic agents on noradrenaline efflux in the frontal cortex of freely moving rats. A single anxiogenic dose of either yohimbine (2.5 or 5 mg/kg) or FG 7142 (10 or 20 mg/kg) was administered to rats by i.p. injection. Yohimbine increased spontaneous efflux of noradrenaline, but FG 7142 had no effect. However, subsequent exposure of rats to a novel environment increased noradrenaline efflux in vehicle-, but not drug-treated rats. Calculation of the net change in noradrenaline efflux caused by transfer to the novel environment showed that this was reduced by yohimbine, whereas FG 7142 increased it. These two compounds also had different effects on locomotor activity in the novel environment. The results suggest that anxiety is unlikely to be invariably associated with increased noradrenergic transmission, in the frontal cortex at least. However, it remains possible that any disruption of the noradrenergic response to stress could be an underlying feature of anxiety.

Adrenergic alpha-Agonists↗
PubMed1998

Expression of novel potassium channels in the chick basilar papilla.

Ionic currents are critical for the functioning of the inner ear auditory sensory epithelium. We set out to identify and molecularly clone the genes encoding the channels responsible for several currents in the chick basilar papilla. Here we describe an inward-rectifying K+ channel, cKir2.3, present in both hair cells and support cells in the apical end of the chick basilar papilla. The biophysical properties of the human ortholog, hKir2.3, are similar to those of an inward-rectifying channel found in the apical end of the chick basilar papilla, suggesting that this channel may contribute to the corresponding current. Additionally, we describe two new members of the Kv6 subfamily of putative regulatory voltage-gated K channels, cKv6.2 and cKv6.3. Both are expressed in hair cells in the apical end of the chick basilar papilla; cKv6.2 is also strongly expressed in support cells and in the brain.

Amino Acid Sequence↗
PubMed1997

A prospective, randomized study of open vs laparoscopic inguinal hernia repair. An assessment of postoperative pain.

OBJECTIVE: To compare postoperative pain after laparoscopic hernia repair and conventional open hernia repair. DESIGN: Prospective, randomized study. SETTING: Veterans Affairs Medical Center. PATIENTS: Sixty-two patients scheduled for elective inguinal hernia repair. INTERVENTIONS: Patients were randomized in the operating room to have a laparoscopic hernia repair (30 patients) or a conventional open hernia repair (32 patients). All operations were performed while the patient was under general anesthesia to avoid anesthesia as a confounding variable. MEASURES: Postoperative pain following laparoscopic hernia repair and open hernia repair were compared using the McGill Pain Score, the McGill Visual Analogue Pain Scale score, and the number of acetaminophen with 30-mg codeine sulfate (Tylenol 3) tablets needed for pain during the first and second 24-hour periods postoperatively. All of the patients were interviewed and the postoperative pain was evaluated by a special study nurse (P.M.L.) who was blinded to the repair technique. RESULTS: At 24 hours, the patients with laparoscopic hernia repair had 26% less pain by the McGill Pain Score (P = .02) and 31% less pain by the McGill Visual Analogue Scale (P = .006) than those who underwent an open hernia repair. At 48 hours the patients who underwent laparoscopic hernia repair had 28% less pain by the McGill Pain Score (P = .03), 42% less pain by the McGill Visual Analogue Scale (P = .002), and used 42% fewer analgesic tablets (P = .004). CONCLUSION: Patients with a laparoscopic hernia repair had significantly less pain postoperatively than those with standard open hernia repairs.

Aged↗
PubMed1997

Effects of chronic ethanol exposure on GABA receptors and GABAB receptor modulation of 3H-GABA release in the hippocampus.

Chronic ethanol treatment (CET), sufficient for decreasing long-term potentiation (LTP) in rats, also enhances 3H-GABA release from hippocampal slices in these same animals. The mechanism for an increase in GABA release may involve changes in presynaptic receptors. Therefore, we characterized presynaptic autoreceptor modulation of 3H-GABA release in hippocampal slices from control and CET rats. The effects of a GABAB receptor agonist (baclofen) and antagonist [2-hydroxy (OH)-saclofen] were tested for their ability to modulate electrically stimulated 3H-GABA release from superfused hippocampal slices. Baclofen decreased stimulated release in a dose-dependent manner and 2-OH-saclofen increased release consistent with the existence of presynaptic GABAB autoreceptors in hippocampus. The GABAA antagonist bicuculline did not significantly modulate basal or stimulated release. When the effects of baclofen and 2-OH-saclofen were measured in animals 48 hr after withdrawal from CET, presynaptic modulation of release by baclofen and 2-OH-saclofen was decreased. In addition, we examined the density of 3H-baclofen and 3H-bicuculline binding in the hippocampal formation using quantitative autoradiographic techniques. We found that the density of 3H-baclofen binding sites was not affected by CET, whereas the density of 3H-bicuculline binding sites was increased by 28% in ethanol-treated rats. These data may explain how CET increases presynaptic regulation of GABA release from hippocampus that may contribute to the decrease in LTP seen in rats after CET.

Alcoholism↗
PubMed1996

Increased levels of extracellular noradrenaline in the frontal cortex of rats exposed to naturalistic environmental stimuli: modulation by acute systemic administration of diazepam or buspirone.

In vivo microdialysis was used to investigate the effects of an IP injection of diazepam or buspirone (each at 3 mg/kg) on spontaneous efflux of noradrenaline in rat frontal cortex, and on changes in efflux induced by naturalistic stress. After drug administration, rats either remained in their home cages or were transferred individually to a novel cage, 1 h later. The novel cage was brightly lit (1500 lux) and contained another, unfamiliar rat. After transfer to the novel cage, noradrenaline efflux was lower in diazepam-injected rats than in their vehicle-injected counterparts. However, in both cases, stress caused a significant increase in efflux and the net increase was not affected by diazepam. Similarly, buspirone, which increased spontaneous efflux of noradrenaline, did not affect the net increase in efflux during stress. Neither compound modified locomotor activity in the novel cage. This suggests that any changes in noradrenaline efflux are unrelated to drug effects on non-specific arousal. It is concluded that generically unrelated anxiolytic agents can have different effects on spontaneous efflux of noradrenaline but do not modify the noradrenergic response to naturalistic stimuli.

Animals↗
PubMed1995

Kinetics of the reaction of a myelin basic protein peptide with soluble IAu.

The kinetics of formation and dissociation of IAu-peptide complexes have been examined in the absence of detergent, using a glycosylphosphatidylinositol (GPI)-linked form of IAu. The GPI-linked form contains a lipid membrane anchor which can be specifically cleaved by phosphatidylinositol-specific phospholipase C to yield a water-soluble form of IAu. We find rapid binding of the myelin basic protein (MBP) peptide analogue Ac(1-14)A4C15 to IAu, as well as rapid dissociation of IAu-MBP peptide complexes at neutral pH in the absence of detergent. The reaction kinetics of the water-soluble and detergent-solubilized complexes are the same to within experiment error. In the presence of this MBP peptide, Ac(1-14)A4C15, cells transfected with native IAu as well as cells transfected with a GPI-linked form of IAu are functional in stimulating T-helper hybridoma cells.

Amino Acid Sequence↗
PubMed1995

Myelin basic protein peptide complexes with the class II MHC molecules I-Au and I-Ak form and dissociate rapidly at neutral pH.

The acetylated N-terminal peptide of myelin basic protein (MBP) is the immunodominant T cell epitope in the induction of experimental autoimmune encephalomyelitis in the I-Au- and I-Ak-expressing mouse strains. We used a direct binding assay to examine the kinetics of binding and dissociation of a series of MBP peptide analogues with the affinity-purified class II MHC molecules I-Au and I-Ak. We observe much faster in vitro rates of binding and dissociation than has been reported previously for other immunogenic peptides at neutral pH. The kinetics also reveal inactivation of the peptide-free class II MHC molecules. These results are consistent with previously proposed mechanisms for tolerance escape and autoimmune disease.

Amino Acid Sequence↗
PubMed1995

You can tell by the nose--judging sex from an isolated facial feature.

Measurements taken from the nose are among the most important physical variables which discriminate statistically between male and female faces, yet several investigators have claimed that it is difficult to judge sex on the basis of noses presented in isolation. Previous work on the isolated nose has, however, involved the use of frontal views only, which may have obscured important physical differences between the noses of males and females. An investigation of the accuracy of judgments of the sex of isolated noses observed in frontal, profile, and three-quarter views by male and female subjects is reported. Judgment of sex was performed significantly more accurately than chance in all cases except for frontal views of female noses, where judgment was significantly less accurate than chance. Analysis of variance demonstrated a significant interaction of sex of nose and view of nose, such that male noses were identified better in frontal and in profile views, but female noses better in the three-quarter view. It is suggested that one possible reason for the seemingly contradictory role of the nose in previous studies of sex judgment is that all noses look more male in frontal views. For a nose to be perceived as female, its distinctive shape must be made available to the perceiver; this is most likely from the three-quarter view.

Adolescent↗
PubMed1995

Kinetics of the reactions between the invariant chain (85-99) peptide and proteins of the murine class II MHC.

The region comprising residues 83-107 of the extracytoplasmic domain of the class II MHC-associated invariant chain protein is essential for its functional interaction with MHC proteins. A nested set of peptides that encompass this region, designated the class II invariant chain-derived peptides (CLIP), bind to many MHC proteins and inhibit the binding of antigenic peptides. The kinetics of the reactions between CLIP and five different murine class II MHC proteins have been determined. Specificity of CLIP binding was confirmed by competition with antigenic peptides. Large differences in the reaction rates were observed. For example, half-times of dissociation ranged from 4.4 min to 17.5 h, a > 200-fold difference. These results demonstrate that CLIP bind to MHC heterodimers at a site that involves the polymorphic residues. These data support the hypothesis that the CLIP binding site is within the peptide binding groove. It is further suggested that these differences in kinetic stabilities of CLIP-MHC protein complexes might affect the diversity of endogenous peptides bound to class II MHC proteins.

Amino Acid Sequence↗
PubMed1994

Short-lived complexes between myelin basic protein peptides and IAk.

Kinetic rate constants and the equilibrium dissociation constant have been determined for the reaction between an affinity-purified class II major histocompatibility complex molecule IAk and a myelin basic protein analogue peptide, fluorescein-labeled Ac(1-14)A4C15. Under the experimental conditions used, the lifetime of the peptide-free IAk molecule with respect to inactivation is 3.1 hr. The equilibrium dissociation constant, 3.3 +/- 1.7 microM, is determined from measurements of the kinetics of peptide inhibition of IAk inactivation. The measured peptide dissociation halftime is relatively short, 30 min, and the deduced association rate is 100 M-1.s-1. The rate constants and the equilibrium constant are similar to those characteristic of kinetic intermediates in reactions of peptides and class II proteins that lead to long-lived terminal complexes.

Amino Acid Sequence↗
PubMed1994

The value of routine chest roentgenograms on admission for rehabilitation after traumatic spinal cord injury.

The value of routine chest roentgenograms has come under increasing scrutiny in the medical literature. In this retrospective study we investigated the value of routine chest radiographs obtained on admission to a rehabilitation unit after an acute spinal cord injury. The charts of all patients admitted for rehabilitation after a traumatic spinal cord injury during a 1-year period were reviewed and 79 patients fulfilled criteria for inclusion into the study. Of the 79 patients, 12 had findings on routine admission films, 9 of which were felt to be significant (11.4%). All 9 patients with abnormal admission films had experienced cardiopulmonary complications during their acute hospitalization (P < 0.001). Fourteen patients with normal chest roentgenograms on admission had repeat films performed during their rehabilitation stay, 4 of which were abnormal. All 4 had experienced cardiopulmonary complications during their acute hospitalizations (P < 0.01). Our findings would support the selective use of admission chest roentgenograms in spinal cord-injured patients with clinical indications or a history of cardiopulmonary complications during their acute care stay.

Adult↗
PubMed1994

A cladistic analysis of the evolutionary relationships of the members of the tyrosinase gene family using sequence data.

Recently, DNA sequence data have been published on tyrosinase and tyrosinase-related proteins (TRPs) in a wide variety of vertebrates ranging from Rana to Homo. These proteins are in turn members of a larger family of binuclear copper-binding proteins, which all contain two highly conserved copper-binding domains. This gene family also includes tyrosinases from fungi and bacteria as well as arthropodan and molluscan hemocyanins. Parsimony-based alignment and tree construction algorithms (Malign, v1.85 and PAUP, 3.1.1) were used to analyze the diversification of both the evolutionarily conserved copper-binding domains in copper-binding proteins in general as well as the diversification of the vertebrate tyrosinase gene family more specifically. These analyses show that the diversification of the vertebrate tyrosinase gene family minimally predates the diversification of vertebrates. Vertebrate tyrosinases proper first diverged from an ancestral tyrosinase-related protein (TRP) that then subsequently diverged to form tyrosinase-related protein-1s (TRP-1s) and tyrosinase-related protein-2s (TRP-2s).

Algorithms↗
PubMed1993

Reliability of notification data for childhood bacterial meningitis.

This study reports the notification rates over ten years (1980-1989) for 232 children with documented bacterial meningitis in Nottingham District Health Authority. The average notification rate was approximately 50 per cent of known cases. It was higher for meningococcal infections (57/84, 68 per cent) than for any other type (45/148, 30 per cent), and lower in neonates (1/29, 3 per cent) than in any other age group (101/203, 50 per cent). The results show that the notification rates required to be adjusted during the decade of the study (1980-1989). The achievement of better notification rates may now be more feasible since implementation of the recommendations of the Committee of Inquiry into the Future Development of the Public Health Function for the control of communicable diseases. This paper provides a baseline upon which to measure the impact of such changes.

Adolescent↗