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Biomedical subjects

L Marsh

Publications and source records attributed to L Marsh.

At least 55 records · Page 3Linked to original sources
PubMed1995

Novel antagonist to agonist switch in chimeric G protein-coupled alpha-factor peptide receptors.

The alpha-factor analog desTrp1,Ala3 alpha-factor (dTA-alpha-factor) acts as an antagonist for both the S. cerevisiae alpha-factor receptor (c-alpha-FR) and the S. kluyveri alpha-factor receptor (k-alpha FR). Chimeric alpha-factor receptors in which a portion (residues 250-303) of the seven hydrophobic segments were derived from the k-alpha FR and the rest from c-alpha FR conferred potent activation of cellular responses by dTA-alpha-factor including induction of FUS1 expression without significantly affecting binding. Chimeric receptors with all hydrophobic segments derived from one receptor did not express sensitivity. We propose that dTA-alpha-factor represents an antagonist that that has an activation energy barrier to activating c-alpha FR and k-alpha FR but which retains a latent potential to act as an agonist.

Binding, Competitive↗
PubMed1995

Anterior hippocampal volume deficits in nonamnesic, aging chronic alcoholics.

Magnetic resonance imaging was used to quantify the volume of the hippocampus in 47 men with chronic alcoholism and 72 healthy male control subjects. The subjects ranged in age from 21 to 70 years, thus permitting a test of whether older alcoholics suffer greater brain tissue volume reduction than do younger ones. Comparison brain regions included temporal lobe gray matter, white matter, and cerebrospinal fluid, as well as measures of the lateral ventricles, third ventricle, and temporal horns. The results of this cross-sectional study showed that the anterior, but not the posterior, portions of the hippocampus in both hemispheres were significantly smaller in the alcoholic than the healthy control group. Furthermore, the bilateral anterior hippocampal volume loss was greater in older than younger alcoholics. Despite the hippocampal volume deficit, these alcoholics did not demonstrate an explicit memory impairment; furthermore, memory test scores did not correlate significantly with hippocampal volumes. In the alcoholics, the age-related volume loss, which was over and above that expected in normal aging, was also evident in the temporal cortex and white matter. Likewise, alcoholic ventricular enlargement was age-related. Analysis of covariance revealed that the anterior hippocampal deficit persisted after accounting for the temporal lobe gray matter volume deficit. Multiple regression analysis revealed that the age-related brain volume abnormalities observed in the alcoholics could not be attributed to duration of alcoholism or total lifetime consumption of alcohol.

Adult↗
PubMed1995

Structural brain imaging in schizophrenia.

In vivo neuroimaging techniques have characterized the global features of brain dysmorphology in schizophrenia. These features include ventriculomegaly and widespread sulcal dilation, which particularly affect the frontal and temporal lobes and involve cortical gray matter rather than white matter. Dysmorphology of specific brain structures such as the basal ganglia and hippocampus, which have been implicated in the pathophysiology of schizophrenia by pharmacological manipulations and post mortem investigations, have not been consistently observed in vivo, perhaps because of differences in imaging and analysis techniques, methods used to control for variance due to age and head size, and sample characteristics. The epidemiology of the observed widespread brain dysmorphology supports a developmental origin, perhaps with limited progressive change beyond that expected in normal aging. Establishing the clinical significance of relatively static structural brain dysmorphologies remains a major challenge that may be best met by use of combined cross-sectional and longitudinal study designs.

Aging↗
PubMed1994

Volumetric MRI assessment of temporal lobe structures in schizophrenia.

This magnetic resonance imaging (MRI) study was designed to investigate whether patients with schizophrenia have focal or lateralized deficits in the volumes of temporal lobe structures. Estimated volumes of the temporal lobes, hippocampi, superior temporal gyri, lateral ventricles, third ventricle, temporal horns of the lateral ventricles, and a frontal-parietal reference area (FPRA) were quantified for each hemisphere. The schizophrenic group had less gray matter (GM) in the temporal lobes and the FPRA relative to controls. Ventricular volumes were significantly larger in the schizophrenic group, as was cerebrospinal fluid (CSF) volume for temporal lobe sulci. No significant differences in hippocampal volumes emerged between groups. The magnitude of GM deficit was not greater in the temporal lobes relative to the FPRA. These results confirm the presence of bilateral GM volume deficits of the temporal lobes in schizophrenia but do not support the hypothesis that structural changes preferentially affect the temporal lobes or the left cerebral hemisphere.

Adult↗
PubMed1994

Noncontiguous domains of the alpha-factor receptor of yeasts confer ligand specificity.

The Saccharomyces cerevisiae alpha-factor receptor has a 3400-fold higher affinity for the S. cerevisiae alpha-factor peptide (c-alpha-f) than for the Saccharomyces kluyveri alpha-factor peptide (k-alpha-f) as determined by competition for [3H] c-alpha-f binding. The S. kluyveri alpha-factor receptor has an approximately 2-fold higher affinity for k-alpha-f than for c-alpha-f. The S. kluyveri receptor gene (k-STE2) is incompletely regulated by S. cerevisiae mating type and poorly expressed on the surface of an S. cerevisiae mating type a strain. A chimeric receptor (c/k1) with amino acid residues 1-45 derived from S. cerevisiae and amino acid residues 46-427 from S. kluyveri exhibits the binding specificity of the S. kluyveri receptor. However, chimeric receptors containing residues 1-168 (c/k2) or 1-250 (c/k3) from S. cerevisiae and the remainder from the S. kluyveri receptor exhibit specificities similar to one another, but intermediate between the parent S. cerevisiae and S. kluyveri receptors. The relative ability of c-alpha-f and k-alpha-f to induce growth arrest in strains expressing chimeric receptors parallels relative affinity. Thus, two noncontiguous domains that include putative extracellular loops 1 and 3 and associated transmembrane segments, but exclude the extracellular NH2 terminus and loop 2, appear to contribute to alpha-factor receptor ligand specificity. COOH-terminal regions of the S. kluyveri receptor appear to confer a desensitization defect when expressed in S. cerevisiae. The S. cerevisiae receptor truncated at residue 296 retains ligand specificity for growth arrest.

Amino Acid Sequence↗
PubMed1994

The relationship between P300 amplitude and regional gray matter volumes depends upon the attentional system engaged.

Event-related potentials (ERPs) and brain magnetic resonance images (MRIs) were acquired from 28 normal men, age 21-60 years. ERPs were recorded during 3 paradigms designed to elicit automatic or effortful attention, and a combination of both. MRI-derived measures of brain gray matter, white matter and cerebral spinal fluid (CSF) volumes were computed from frontal, parietal and temporal lobes. P300 amplitude correlated significantly with gray matter volumes but not with white matter or CSF volumes. Furthermore, the relationships between P300 amplitude and gray matter volumes reflected functional rather than direct topographical relationships: P300 recorded at Pz during automatically elicited attention correlated significantly with frontal but not parietal lobe gray matter volumes, P300 recorded during effortful attention correlated significantly with parietal but not frontal lobe gray matter volumes, and P300 recorded when both types of attention were invoked correlated significantly with both frontal and parietal gray matter volumes. Startle blinks, also elicited during automatic attention-engaging paradigms, were significantly correlated with frontal but not parietal lobe gray matter volumes. There was no evidence for a direct spatial relationship between P300 amplitude and the gray matter volumes underlying the recording electrode.

Adult↗
PubMed1994

Medial temporal lobe structures in schizophrenia: relationship of size to duration of illness.

Reductions in the size of medial temporal lobe structures in schizophrenia have been demonstrated using magnetic resonance imaging. It is not clear whether these neuropathological changes are present premorbidly or if they reflect an adult-onset progressive process. In this study, quantitative measures were made of the lateral ventricles, third ventricle, amygdala, hippocampus, and cerebral hemispheres from coronal MRI images on 33 patients with schizophrenia and 41 normal controls. Images were selected a priori from the region of the temporal lobe in which we had previously demonstrated reduced volume of temporal lobe gray matter in a separate sample of patients. Results showed a decrease in amygdala, hippocampal, and amygdala-hippocampal size bilaterally and an increase in third and lateral ventricular volume. Advancing age in normals was associated with a decrease in the size of medial temporal structures and an increase in lateral ventricular size. In schizophrenia, there was a correlation between age and lateral ventricle size, but duration of illness was not associated with reductions in medial temporal tissue or ventricular enlargement. These results are consistent with prior evidence from neuroimaging and postmortem studies of medial temporal pathology in schizophrenia and support hypotheses that neuropathological changes in schizophrenia are not progressive.

Adult↗
PubMed1993

Preservation of parotid function after external beam irradiation in head and neck cancer patients: a feasibility study using 3-dimensional treatment planning.

PURPOSE: Radiation-induced xerostomia is a frequent complication and major cause of morbidity in head and neck cancer patients. The severity of xerostomia is related to radiation dose and the amount of parotid tissue included in the irradiated volume. To reduce this side-effect and preserve salivary function, we have evaluated the use of 3-dimensional (3-D) treatment planning to spare the contralateral parotid gland in twelve patients undergoing radiation therapy for head and neck cancers. METHODS AND MATERIALS: In each case, beam's eye view displays were used to design beam and blocking arrangements that excluded the contralateral parotid. Ten patients were treated with 2 nonopposing oblique fields in the axial and non-axial plane while two patients required a non-axial, non-coplanar 3-field arrangement. These 3-D treatment plans were also compared with conventional 2-dimensional (2-D) plans. The 2-dimensional plans were designed independently of the 3-D treatment planning information using the orthogonal radiographs and hard copies of the computed tomography scans. RESULTS: An average of 1.8% (range, 0-7%) of the target volume was underdosed with the 95% isodose level for the 3-D plans compared with 18.8% (range, 2.0-36.6%) for the 2-D plans. This was due to improved identification of the target volumes and better design of blocked fields with beam's eye view treatment planning. Furthermore, the mean dose to the opposite parotid was 3.9 Gy for the 3-D plans vs 28.9 Gy for the conventional plans. With a minimum follow-up of 4 months, only 2 of 12 patients have complained of a dry mouth. CONCLUSION: These encouraging results suggest that this approach is feasible in many cases. 3-D treatment planning may allow the use of parotid sparing techniques in patients who otherwise would not have been considered candidates using conventional radiotherapy techniques.

Adult↗
PubMed1992

The clinical application of a non-axial treatment plan for pancreatic and biliary malignancies.

Standard radiation therapy for adenocarcinoma of the pancreas treats a substantial portion of the renal parenchyma. It was hypothesized that rotating the plane of treatment to a non-axial orientation, with the anterior field entering the patient from an inferior oblique direction, would decrease the renal dose of radiation without increasing the liver dose or compromising the target dose. To test this hypothesis, patients referred for radical radiation treatment for tumors of the pancreas or distal common bile duct were prospectively evaluated by performing treatment planning using axial and non-axial field arrangements. Treatment plans were compared using dose volume histograms (DVHs) of both kidneys and the liver. In all 15 cases analyzed, the non-axial plan was superior to the axial plan with respect to renal dose, without significantly increasing the hepatic dose and was used for treatment. Treatment was not significantly more complex nor was gastrointestinal toxicity increased. These findings show that non-axial field arrangements can be used on a routine basis to decrease the renal dose of radiation for the treatment of pancreatic and biliary malignancies. It is anticipated that in the future, a combination of DVH-guided treatment planning and sophisticated renal function studies will be necessary to permit a more accurate prediction of the probability of renal complications resulting from radiation therapy.

Aged↗
PubMed1992

Extensive allelic variation in Cryptococcus neoformans.

The orotidine monophosphate pyrophosphorylase (OMPPase) gene locus of the DNA of 13 Cryptococcus neoformans var. neoformans strains, including 10 recent clinical isolates, was studied by using restriction fragment length polymorphisms and nucleotide sequence analysis. The OMPPase locus (URA5) is highly polymorphic, and at least six alleles were identified. The nucleotide sequences of some alleles differed by up to 5%. The majority of the nucleotide polymorphisms in the protein-coding region occurred at the third codon position and were silent. The low frequency of replacement nucleotide substitutions relative to silent nucleotide substitutions implied that there is strong selection against amino acid changes in OMPPase. The allelic variation suggested that there is extensive genomic diversity among C. neoformans clinical isolates from one geographic area. The various alleles are potentially useful markers in the study of the population structure, epidemiology, and pathogenesis of C. neoformans strains.

Alleles↗
PubMed1992

Substitutions in the hydrophobic core of the alpha-factor receptor of Saccharomyces cerevisiae permit response to Saccharomyces kluyveri alpha-factor and to antagonist.

Mutations in the Saccharomyces cerevisiae alpha-factor receptor that lead to improved response to Saccharomyces kluyveri alpha-factor were identified and sequenced. Mutants were isolated from cells bearing randomly mutagenized receptor gene (STE2) plasmids by an in vivo screen. Five mutations lead to substitutions in hydrophobic segments in the core of the receptor (M54I, S145L, S145L-S219L, A229V, L255S-S288P). Remarkably, strains expressing these mutant receptors exhibited positive pheromone responses to desTrp1,Ala3-alpha-factor, an analog that normally blocks these responses. The M54I mutation appeared to affect only ligand specificity. The other mutations conferred additional effects on signaling or recovery. Two mutants were more sensitive to alpha-factor than wild type (S145L, A229V). One mutant was more sensitive to alpha-factor-induced cell cycle arrest initially, but then recovered more efficiently (S145L-S219L). One mutant (L255S-S288P) conferred positive pheromone responses to alpha-factor as assayed by FUS1-lacZ reporter induction, but did not display growth arrest. The hydrophobic receptor core thus appears to control activation by some ligands and to play roles in aspects of signal transduction and recovery.

Amino Acid Sequence↗
PubMed1991

The influence of linguistic context on young children's understanding of homophonic words.

This study investigates young children's understanding of homophones in two different linguistic contexts. Research has shown that children interpret homophones according to their 'primary' sense even though this is inappropriate to the linguistic context. The present study investigates the influence of different contexts on their interpretations of homophones. A picture test, similar to the British Picture Vocabulary Scale (BPVS), was devised, depicting ten homophones in both their primary and secondary senses. Forty-eight children who were in matched pairs following the BPVS pre-test and whose ages ranged from three to six were asked to select the picture which showed the homophone, first when the homophone was in no linguistic context, and secondly following one of two conditions of the same story which differed according to the richness of context provided. Results showed that those children assigned to story B, the expanded version with full linguistic details and explanations of the words it contained, were more able to identify correctly the secondary meanings of the homophones intended than those children given story A, the unexpanded version. Analyses of variance showed both a significant age trend and a story-type effect. These results are interpreted as showing that the linguistic context is an important factor in young children's understanding of word meaning.

Attention↗
PubMed1988

Vocal quality 10 years after radiotherapy for early glottic cancer.

The voices of 12 patients who had been treated by radiotherapy for Stage I squamous carcinoma of the glottis at least 10 years previously, and who had shown no signs of recurrent disease, were assessed. A speech therapist detected significant abnormalities in all patients, but these did not detract from the overall high satisfaction of the patients with their voice quality.

Aged↗
PubMed1988

STE2 protein of Saccharomyces kluyveri is a member of the rhodopsin/beta-adrenergic receptor family and is responsible for recognition of the peptide ligand alpha factor.

We have cloned the gene for the alpha-factor receptor of the yeast Saccharomyces kluyveri by using the Saccharomyces cerevisiae receptor gene (c-STE2) as a probe. The nucleotide sequence of the S. kluyveri gene (k-STE2) shows that its predicted polypeptide contains seven hydrophobic segments capable of spanning a lipid bilayer and thus that, like c-STE2, it appears to be a member of the rhodopsin/beta-adrenergic receptor family. The k-STE2 polypeptide is 50% identical to that coded by c-STE2, with high conservation (greater than 67%) in the putative membrane-spanning domains. The carboxyl-terminal amino acid sequences are not similar, but both are very hydrophilic and rich in serine and threonine residues. The k-STE2 gene is functional in S. cerevisiae: it reverses the mating defect of an S. cerevisiae mutant defective in its STE2 gene. S. cerevisiae strains expressing k-STE2 rather than c-STE2 exhibit the mating-factor selectivity characteristic of S. kluyveri: better response to S. kluyveri alpha factor than to S. cerevisiae alpha factor. (S. cerevisiae normally responds much better to its own alpha-factor peptide than to the related alpha-factor peptide of S. kluyveri.) This observation demonstrates that the STE2 gene is responsible for ligand selectivity and provides additional evidence that the STE2 protein is the receptor for alpha factor.

Amino Acid Sequence↗
PubMed1988

The early results from a randomised study of radiotherapy versus Nolvadex (tamoxifen) as initial treatment for stage III breast cancer.

Eighty-seven postmenopausal patients have been randomised to receive either radiotherapy or Nolvadex (tamoxifen) as first line treatment for locally advanced (stage III) breast cancer. After a median follow-up of two years no significant differences have been found in the rate of progression of local disease, the time to development of overt metastases or survival.

Breast Neoplasms↗