Biomedical subjects

J S Morris

Publications and source records attributed to J S Morris.

At least 55 records · Page 3Linked to original sources

PubMed2000

Evaluation of 24-color multifluor-fluorescence in-situ hybridization (M-FISH) karyotyping by comparison with reverse chromosome painting of the human breast cancer cell line T-47D.

Multifluor-fluorescence in-situ hybridization (M-FISH) chromosome paints for all the chromosomes in the human complement labeled with different combinations of fluorochromes is a recent technological development enabling assignment of chromosomal material to rearranged chromosomes. Little data is available on the accuracy and limitations of the approach to the analysis of complex karyotypes, which are characteristic of many malignant diseases. Here we compare M-FISH analysis of the breast-cancer-derived cell line T-47D with a previous analysis by reverse chromosome painting analysis of flow-sorted chromosomes from the same material. This demonstrated a high degree of concordance. It also illustrated the limitations of M-FISH analysis, including difficulties identifying small regions of chromosomal material and intrachromosomal rearrangements. Confirmation of selected aberrations using less-complex mixtures of painting probes and further definition of abnormalities using single copy markers may be required. The detailed karyotype description possible by M-FISH analysis contrasts with the definition in the original G-banding analysis. This and the level of concordance with reverse FISH painting supports the utility of the approach in the definition of complex karyotypes.

Breast Neoplasms↗

PubMed2000

Effects of selenium deficiency on tissue selenium content, deiodinase activity, and thyroid hormone economy in the rat during development.

The iodothyronine deiodinases, D1, D2, and D3, all contain selenium (Se) in the form of selenocysteine at their active sites, and they play crucial roles in determining the circulating and intracellular levels of the active thyroid hormone (TH), T3. However, not only are serum T3 levels normal in Se-deficient rats but phenotypic and reproductive abnormalities are minimal, and it has been suggested that regulatory mechanisms exist to conserve Se in critical tissues. The present study was designed to determine, in rats: 1) whether the effects of Se-deficiency are greater in the fetus and neonate than in the adult; 2) whether there are tissues other than brain and thyroid in which deiodinase activities are maintained; 3) whether the maintenance of deiodinase activity in a specific tissue is associated with a concomitant preservation of Se level in that tissue; and 4) whether TH economy and general health is maintained over several generations. The tissues studied included liver, cerebrum, thyroid, pituitary, skin, brown adipose tissue, uterus, ovary, testis, placenta, and the implantation site (uterus plus contents) at E9. The results have revealed that, with the exception of liver, skin, and nonpregnant uterus, all of the tissues studied maintained substantial deiodinase activity (>50%) during prolonged Se-deficiency. Second, although the ability of a tissue to maintain deiodinase activity in the face of dietary Se deprivation was associated in some tissues with a concomitant local preservation of Se concentration, this was not the case for all tissues. Only when Se levels were decreased by more than 80% was deiodinase activity markedly decreased. Third, the effects of Se-deficiency were no greater in the fetus than in the adult; and fourth, at the level of Se-deficiency employed in this study, TH economy and general health were successfully maintained over six generations of Se-deficient rats. How Se levels are maintained in specific tissues, whether Se is sequestered in specific cells of a tissue or organ during dietary Se deprivation, and the precise mechanisms by which plasma T3 levels are maintained in Se-deficient animals remain unanswered. Further insights may be gained by using diets that are even lower in Se than those that were used herein and/or by conducting studies using radioactive forms of Se and thyroid hormones.

Aging↗

PubMed2000

Morphodensitometric analysis of protein kinase C beta(II) expression in rat colon: modulation by diet and relation to in situ cell proliferation and apoptosis.

We have recently demonstrated that overexpression of PKC beta(II) renders transgenic mice more susceptible to carcinogen-induced colonic hyperproliferation and aberrant crypt foci formation. In order to further investigate the ability of PKC beta(II) to modulate colonocyte cytokinetics, we determined the localization of PKC beta(II) with respect to cell proliferation and apoptosis along the entire colonic crypt axis following carcinogen and diet manipulation. Rats were provided diets containing either corn oil [containing n-6 polyunsaturated fatty acids (PUFA)] or fish oil (containing n-3 PUFA), cellulose (non-fermentable fiber) or pectin (fermentable fiber) and injected with azoxymethane (AOM) or saline. After 16 weeks, an intermediate time point when no macroscopic tumors are detected, colonic sections were utilized for immunohistochemical image analysis and immunoblotting. Cell proliferation was measured by incorporation of bromodeoxyuridine into DNA and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling. In the distal colon, PKC beta(II) staining was localized to the upper portion of the crypt. In comparison, proximal crypts had more (P < 0.05) staining in the lower tertile. AOM enhanced (P < 0.05) PKC beta(II) expression in all regions of the distal colonic crypt (upper, middle and lower tertiles). There was also an interaction (P < 0.05) between dietary fat and fiber on PKC beta(II) expression (corn/pectin > fish/cellulose, fish/pectin > corn/cellulose) in all regions of the distal colonic crypt. With respect to colonic cell kinetics, proliferation paralleled the increase in PKC beta(II) expression in carcinogen-treated animals. In contrast, apoptosis at the lumenal surface was inversely proportional to PKC beta(II) expression in the upper tertile. These results suggest that an elevation in PKC beta(II) expression along the crypt axis in the distal colon is linked to enhancement of cell proliferation and suppression of apoptosis, predictive intermediate biomarkers of tumor development. Therefore, select dietary factors may confer protection against colon carcinogenesis in part by blocking carcinogen-induced PKC beta(II) expression.

Animals↗

PubMed2000

Dietary fish oil reduces O6-methylguanine DNA adduct levels in rat colon in part by increasing apoptosis during tumor initiation.

There is epidemiological, clinical, and experimental evidence that dietary fish oil, containing n-3 polyunsaturated fatty acids, protects against colon tumor development. However, its effects on colonocytes in vivo remain poorly understood. Therefore, we investigated the ability of fish oil to modulate colonic methylation-induced DNA damage, repair, and deletion. Sprague Dawley rats were provided with complete diets containing either corn oil or fish oil (15% by weight). Animals were injected with azoxymethane, and the distal colon was removed 3, 6, 9, or 12 h later. Targeted apoptosis and DNA damage were assessed by cell position within the crypt using the terminal deoxynucleotidyl transferase-mediated nick end labeling assay and quantitative immunohistochemical analysis of O6-methylguanine adducts, respectively. Localization and expression of the alkyl group acceptor, O6-methylguanine-DNA-methyltransferase, was also determined. Lower levels of adducts were detected at 6, 9, and 12 h in fish oil- versus corn oil-fed animals (P < 0.05). In addition, fish oil supplementation had the greatest effect on apoptosis in the top one-third of the crypt, increasing the apoptotic index compared with corn oil-fed rats (P < 0.05). In the top one-third of the crypt, fish oil feeding caused an incremental stimulation of apoptosis as adduct level increased. In contrast, a negative correlation between apoptosis and adduct incidence occurred with corn oil feeding (P < 0.05). Diet had no main effect (all tertiles combined) on O6-methylguanine-DNA-methyltransferase expression over the time frame of the experiment. The enhancement of targeted apoptosis combined with the reduced formation of O6-methylguanine adducts may account, in part, for the observed protective effect of n-3 polyunsaturated fatty acids against experimentally induced colon cancer.

Analysis of Variance↗

PubMed1999

A subcortical pathway to the right amygdala mediating "unseen" fear.

Neuroimaging studies have shown differential amygdala responses to masked ("unseen") emotional stimuli. How visual signals related to such unseen stimuli access the amygdala is unknown. A possible pathway, involving the superior colliculus and pulvinar, is suggested by observations of patients with striate cortex lesions who show preserved abilities to localize and discriminate visual stimuli that are not consciously perceived ("blindsight"). We used measures of right amygdala neural activity acquired from volunteer subjects viewing masked fear-conditioned faces to determine whether a colliculo-pulvinar pathway was engaged during processing of these unseen target stimuli. Increased connectivity between right amygdala, pulvinar, and superior colliculus was evident when fear-conditioned faces were unseen rather than seen. Right amygdala connectivity with fusiform and orbitofrontal cortices decreased in the same condition. By contrast, the left amygdala, whose activity did not discriminate seen and unseen fear-conditioned targets, showed no masking-dependent changes in connectivity with superior colliculus or pulvinar. These results suggest that a subcortical pathway to the right amygdala, via midbrain and thalamus, provides a route for processing behaviorally relevant unseen visual events in parallel to a cortical route necessary for conscious identification.

Adult↗

PubMed1999

Covariation of activity in habenula and dorsal raphé nuclei following tryptophan depletion.

Abnormal serotonergic function is implicated in the pathogenesis of affective disorders. We induced transient depressive relapses in volunteer patients by rapidly depleting plasma tryptophan, the precursor of serotonin (5-HT), and measured neural activity during different cognitive tasks using positron emission tomography (PET). Neural activity in several 5-HT-related brain areas, e.g., dorsal raphé, habenula, septal region, amygdala, and orbitofrontal cortex, covaried significantly with plasma levels of tryptophan and ratings of depressed mood. Task-specific responses in left amygdala and left anterior cingulate were attenuated by tryptophan depletion. We used these PET data to test the hypothesis that projections from the habenula modulate dorsal raphé activity and that this modulation is enhanced in patients experiencing a profound mood change following serotonergic challenge. A strong linear correlation (r(2) > 0.5) between habenula and raphé activity was observed in subjects with postdepletion ratings >/=10 on a modified Hamilton depression scale, whereas subjects experiencing milder changes in mood had weaker habenula-raphé coupling (r(2) < 0.5). These data support a model of the serotonergic system in which the habenula projection to the raphé represents a convergent feedback pathway that controls the release of 5-HT throughout the brain. In our experiment we were able to engage this system in patients who were sensitive to tryptophan depletion.

Adult↗

PubMed1999

Saying it with feeling: neural responses to emotional vocalizations.

To determine how vocally expressed emotion is processed in the brain, we measured neural activity in healthy volunteers listening to fearful, sad, happy and neutral non-verbal vocalizations. Enhanced responses to emotional vocalizations were seen in the caudate nucleus, as well as anterior insular, temporal and prefrontal cortices. The right amygdala exhibited decreased responses to fearful vocalizations as well as fear-specific inhibitory interactions with left anterior insula. A region of the pons, implicated in acoustic startle responses also showed fear-specific interactions with the amygdala. The data demonstrate: firstly, that processing of vocal emotion involves a bilaterally distributed network of brain regions; and secondly, that processing of fear-related auditory stimuli involves context-specific interactions between the amygdala and other cortical and brainstem regions implicated in fear processing.

Adult↗

PubMed1999

Dissociable neural responses to facial expressions of sadness and anger.

Previous neuroimaging and neuropsychological studies have investigated the neural substrates which mediate responses to fearful, disgusted and happy expressions. No previous studies have investigated the neural substrates which mediate responses to sad and angry expressions. Using functional neuroimaging, we tested two hypotheses. First, we tested whether the amygdala has a neural response to sad and/or angry facial expressions. Secondly, we tested whether the orbitofrontal cortex has a specific neural response to angry facial expressions. Volunteer subjects were scanned, using PET, while they performed a sex discrimination task involving static grey-scale images of faces expressing varying degrees of sadness and anger. We found that increasing intensity of sad facial expression was associated with enhanced activity in the left amygdala and right temporal pole. In addition, we found that increasing intensity of angry facial expression was associated with enhanced activity in the orbitofrontal and anterior cingulate cortex. We found no support for the suggestion that angry expressions generate a signal in the amygdala. The results provide evidence for dissociable, but interlocking, systems for the processing of distinct categories of negative facial expression.

Adult↗

PubMed1999

Brain mechanisms associated with depressive relapse and associated cognitive impairment following acute tryptophan depletion.

BACKGROUND: Acute tryptophan depletion lowers brain serotonin synthesis and results in a transient, but striking, clinical relapse in recovered depressed patients. AIMS: To identify brain regions which change their activity as an acute depressive relapse evolves and to determine how pathological mood might modulate neural activity during a cognitive task. METHOD: We used H2(15)O positron-emission tomography (PET) to study eight recovered depressed men after tryptophan depletion and after a control procedure. During both PET scan sessions, subjects performed a paced verbal fluency task which alternated with a control verbal repetition task. RESULTS: Increasing levels of depression after tryptophan depletion were associated with diminished neural activity in the ventral anterior cingulate, orbitofrontal cortex and caudate nucleus regions. In addition, depressive relapse attenuated cognitive task-related activation in the anterior cingulate cortex. CONCLUSIONS: Our data indicate that changes in neural activity in distinct brain regions mediate the clinical phenomena of depression and depression-related cognitive impairment following acute tryptophan depletion. These changes could be associated with the widespread distribution of serotonin neurons in brain pathways associated with the expression of affect and cognitive performance.

Adult↗

PubMed1999

Relationship between DNA adduct levels, repair enzyme, and apoptosis as a function of DNA methylation by azoxymethane.

DNA alkylating agent exposure results in the formation of a number of DNA adducts, with O6-methyl-deoxyguanosine (O6-medG) being the major mutagenic and cytotoxic DNA lesion. Critical to the prevention of colon cancer is the removal of O6-medG DNA adducts, either through repair, for example, by O6-alkylguanine-DNA alkyltransferase (ATase) or targeted apoptosis. We report how rat colonocytes respond to administration of azoxymethane (a well-characterized experimental colon carcinogen and DNA-methylating agent) in terms of O6-medG DNA adduct formation and adduct removal by ATase and apoptosis. Our results are: (a) DNA damage is greater in actively proliferating cells than in the differentiated cell compartment; (b) expression of the DNA repair enzyme ATase was not targeted to the proliferating cells or stem cells but rather is confined primarily to the upper portion of the crypt; (c) apoptosis is primarily targeted to the stem cell and proliferative compartments; and (d) the increase in DNA repair enzyme expression over time in the bottom one-third of the crypt corresponds with the decrease in apoptosis in this same crypt region.

Alkyl and Aryl Transferases↗

PubMed1998

Effect of ovariohysterectomy in bitches with mammary neoplasms.

Ninety bitches with mammary tumours were studied for two years after the surgical removal of the primary tumour(s). Twenty-nine of the bitches had been spayed before the development of the mammary tumour, 22 were spayed when the tumours were removed and 39 were left entire. Fifty-eight of the bitches (64 per cent) had benign tumours and, of these, 15 (26 per cent) developed a new mammary tumour within two years, irrespective of whether the bitch was spayed. The other 32 bitches had malignant tumours which were grouped into 'invasive' and 'well defined' carcinomas. Sixty-three per cent of the spayed bitches and 57 per cent of the entire bitches, with invasive carcinoma were dead within two years of surgery as a result of their mammary tumours. For those with well defined carcinomas the tumour-related death rates were 18 per cent and 33 per cent respectively for the spayed and entire bitches. These findings suggest that ovariohysterectomy when mammary tumours are removed does not have a significant effect on the progression of malignant disease, and that about one in four bitches with a benign mammary tumour is likely to develop a further tumour in another gland.

Animals↗

PubMed1998

Conscious and unconscious emotional learning in the human amygdala.

If subjects are shown an angry face as a target visual stimulus for less than forty milliseconds and are then immediately shown an expressionless mask, these subjects report seeing the mask but not the target. However, an aversively conditioned masked target can elicit an emotional response from subjects without being consciously perceived. Here we study the mechanism of this unconsciously mediated emotional learning. We measured neural activity in volunteer subjects who were presented with two angry faces, one of which, through previous classical conditioning, was associated with a burst of white noise. In half of the trials, the subjects' awareness of the angry faces was prevented by backward masking with a neutral face. A significant neural response was elicited in the right, but not left, amygdala to masked presentations of the conditioned angry face. Unmasked presentations of the same face produced enhanced neural activity in the left, but not right, amygdala. Our results indicate that, first, the human amygdala can discriminate between stimuli solely on the basis of their acquired behavioural significance, and second, this response is lateralized according to the subjects' level of awareness of the stimuli.

Adult↗

PubMed1998

Experience-dependent modulation of tonotopic neural responses in human auditory cortex.

Experience-dependent plasticity of receptive fields in the auditory cortex has been demonstrated by electrophysiological experiments in animals. In the present study we used PET neuroimaging to measure regional brain activity in volunteer human subjects during discriminatory classical conditioning of high (8000 Hz) or low (200 Hz) frequency tones by an aversive 100 dB white noise burst. Conditioning-related, frequency-specific modulation of tonotopic neural responses in the auditory cortex was observed. The modulated regions of the auditory cortex positively covaried with activity in the amygdala, basal forebrain and orbitofrontal cortex, and showed context-specific functional interactions with the medial geniculate nucleus. These results accord with animal single-unit data and support neurobiological models of auditory conditioning and value-dependent neural selection.

Adult↗

PubMed1998

A neuromodulatory role for the human amygdala in processing emotional facial expressions.

Localized amygdalar lesions in humans produce deficits in the recognition of fearful facial expressions. We used functional neuroimaging to test two hypotheses: (i) that the amygdala and some of its functionally connected structures mediate specific neural responses to fearful expressions; (ii) that the early visual processing of emotional faces can be influenced by amygdalar activity. Normal subjects were scanned using PET while they performed a gender discrimination task involving static grey-scale images of faces expressing varying degrees of fear or happiness. In support of the first hypothesis, enhanced activity in the left amygdala, left pulvinar, left anterior insula and bilateral anterior cingulate gyri was observed during the processing of fearful faces. Evidence consistent with the second hypothesis was obtained by a demonstration that amygdalar responses predict expression-specific neural activity in extrastriate cortex.

Adult↗

PubMed1998

Rifapentine and isoniazid in the continuation phase of treating pulmonary tuberculosis. Initial report.

A randomized comparison has been made of three times weekly rifampin plus isoniazid (HR3) with rifapentine plus isoniazid given once weekly (HRp1) or on 2 of 3 wk (HRp1.2/3) in the continuation phase of 6-mo regimens (each starting with an initial 2 mo of 4-drug therapy) for the treatment of pulmonary tuberculosis in 672 Chinese patients in Hong Kong. Because of poor bioavailability of the rifapentine used (produced in China), its dose size was increased from 600 mg initially to about 750 mg in the last third of patients to obtain serum concentrations similar to those with rifapentine of Western origin; all doses were given after a meal promoting absorption. After initial exclusions, an intent to treat analysis, done on the remaining 592 patients, showed 45 adverse treatment events in 7 of 190 HR3 patients, in 17 of 199 HRp1 patients, and in 21 of 203 HRp1.2/3 patients; of these, 42 were bacteriological or radiographic relapses after the end of treatment (HR3 versus HRp1, p = 0.04; HR3 versus HRp1.2/3, p = 0.01). Patients with organisms initially sensitive or resistant to isoniazid or streptomycin had similar relapse rates. The high relapse rate in the HRp1 regimen suggests that the rifapentine dose should be increased. Similarity of relapse rates, 8.9% and 10.4%, after the HRp1 and HRp1.2/3 regimens, respectively, indicates that irregularity in taking rifapentine/isoniazid could be tolerated. The few adverse side effects in the continuation phase in the rifapentine regimens were less frequent than in the HR3 regimen.

Adolescent↗

PubMed1998

Design of an epidemiologic study of drinking water arsenic exposure and skin and bladder cancer risk in a U.S. population.

Ingestion of arsenic-contaminated drinking water is associated with an increased risk of several cancers, including skin and bladder malignancies; but it is not yet clear whether such adverse effects are present at levels to which the U.S. population is exposed. In New Hampshire, detectable levels of arsenic have been reported in drinking water supplies throughout the state. Therefore, we have begun a population-based epidemiologic case-control study in which residents of New Hampshire diagnosed with primary squamous cell (n = 900) and basal cell (n = 1200) skin cancers are being selected from a special statewide skin cancer incidence survey; patients diagnosed with primary bladder cancers (n = 450) are being identified through the New Hampshire State Cancer Registry. Exposure histories of these patients will be compared to a control group of individuals randomly selected from population lists (n = 1200). Along with a detailed personal interview, arsenic and other trace elements are being measured in toenail clipping samples using instrumental neutron activation analysis. Household water samples are being tested on selected participants using a hydride generation technique with high-resolution inductively coupled plasma mass spectrometry. In the first 793 households tested arsenic concentrations ranged from undetectable (0.01 microgram/l) to 180 microgram/l. Over 10% of the private wells contained levels above 10 microgram/l and 2.5% were above 50 microgram/l. Based on our projected sample size, we expect at least 80% power to detect a 2-fold risk of basal cell or squamous cell skin cancer or bladder cancer among individuals with the highest 5% toenail concentrations of arsenic.

Adult↗

PubMed1997

Neural responses to salient visual stimuli.

The neural mechanisms involved in the selective processing of salient or behaviourally important stimuli are uncertain. We used an aversive conditioning paradigm in human volunteer subjects to manipulate the salience of visual stimuli (emotionally expressive faces) presented during positron emission tomography (PET) neuroimaging. Increases in salience, and conflicts between the innate and acquired value of the stimuli, produced augmented activation of the pulvinar nucleus of the right thalamus. Furthermore, this pulvinar activity correlated positively with responses in structures hypothesized to mediate value in the brain right amygdala and basal forebrain (including the cholinergic nucleus basalis of Meynert). The results provide evidence that the pulvinar nucleus of the thalamus plays a crucial modulatory role in selective visual processing, and that changes in perceptual salience are mediated by value-dependent plasticity in pulvinar responses.

Adult↗

PubMed1997

Cytogenetic analysis of three breast carcinoma cell lines using reverse chromosome painting.

Chromosome painting was used to determine the copy number and identity of virtually all the chromosomes in three breast cancer cell lines, T-47D, MDA-MB-361, and ZR-75-1. The karyotypes of all three cell lines were very complex, and were consistent with the monosomic pattern of evolution suggested by Dutrillaux, in which nonreciprocal translocations cause an initial reduction in chromosome number, followed by duplication of the entire genome and further chromosome loss. Twenty distinct abnormal chromosomes were identified in T-47D, seven of which were present as two copies. MDA-MB-361 had 27 abnormal chromosomes each as a single copy. Thirteen abnormal chromosomes in ZR-75-1 occurred singly, two were paired, and one was present as three copies. Most of the aberrant chromosomes were nonreciprocal translocations, although deletions, duplications, isochromosomes, and amplifications (HSR of 1q) were also found. Chromosome arms present in abnormal chromosomes in all three lines were 1q, 6p, 7p, 8p, 8q, 10q, 11p, 11q, 12p, 13q, 14q, 15q, 16p, 16q, 17q, and 20q. The only chromosome arms present in four or more copies in all three lines were 8q and proximal 12p, while 1p, 17p, and bands 11q12--13 were the only chromosome regions consistently reduced to two copies. The most striking feature common to all three lines was a translocation breakpoint on the short arm of chromosome 8 at 8p12.

Breast Neoplasms↗