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Biomedical subjects

C A Harris

Publications and source records attributed to C A Harris.

At least 37 records · Page 2Linked to original sources
PubMed1999

Short-term effects of fights for social dominance and the establishment of dominant-subordinate relationships on brain monoamines and cortisol in rainbow trout.

We report changes in brain serotonergic, noradrenergic and dopaminergic activity, along with plasma cortisol concentrations, occurring during the initial 24-h period following the establishment of dominant-subordinate relationships in pairs of rainbow trout. Immediately (within 5 min) after the termination of staged fights for social dominance, a large increase in blood plasma cortisol was observed in both fight losers (future subordinate fish) and winners (future dominant fish). In dominant fish, cortisol decreased rapidly (within 3 h) to the level of unstressed controls, while continuing to increase in subordinate fish. At 3 h following fights, the brain serotonergic system was activated in both dominant fish and subordinate fish, at least in some brain regions (telencephalon). This effect was reversed in dominant individuals within 24 h of social interaction, whereas in subordinate fish a substantial activation of the serotonergic system was manifest in all brain regions by 24 h. Similarly, a strong increase in brain catecholaminergic activation was indicated after 24 h of social interaction in subordinate fish, but not in dominant fish. Relationships between plasma cortisol and brain serotonergic and noradrenergic activity in the various experimental groups suggest that these systems influence cortisol secretion under normal conditions and during moderate or short-term stress.

Aggression↗
PubMed1999

Organochlorine pesticide residues in human milk in the United Kingdom 1997 - 8.

1 The concentrations of a range of organochlorine pesticide residues have been determined in 168 samples of human milk collected between January 1997 and May 1998 in the UK. 2 Of the 18 residues sought, only p,p'-DTT, p,p'-DDE, dieldrin, HCB, beta-HCH and gamma-HCH were detected. 3 The continuing trend of a reduction in the concentrations of these pesticide residues in human milk samples and in the percentage of human milk samples containing residues was seen. 4 Correlations between the concentrations of p,p'-DDE, dieldrin, HCB, beta-HCH and gamma-HCH and age were seen. 5 When compared to studies carried out in Europe over a similar time period, residues in this present study were shown to occur at similar or lower concentrations.

Age Factors↗
PubMed1999

BCL-2 expression and inhibin-A in adrenal neoplasms: a comparative study.

Differential diagnosis between adrenal cortical and adrenal medullary lesions may be difficult in many cases. Different immunohistochemical, histochemical tools as well as ultrastructural diagnostic techniques have been employed to aid in differentiating between these lesions. Recently, both inhibin-A and BCL-2 have been shown to stain selectively adrenal cortical tissue and its derived neoplasms but not adrenal medulla or pheochromocytomas. In this study we compared the staining reactions of inhibin-A and BCL-2 in cases of adrenal cortical adenomas and carcinomas as well as pheochromocytomas. We found that both inhibin-A and BCL-2 stained cortical derived tissues, but not medullary derived tissues. Staining intensity for inhibin-A was significantly weaker than for BCL-2. We found that fixation techniques may influence the staining reactivity, as some cases did not immunoreact with any of the antibodies. We conclude that both inhibin-A, and, preferentially, BCL-2 are useful additions to a staining protocol to help in the differential diagnosis of cortical and medullary neoplasms.

Adenoma↗
PubMed1999

A disease severity scale for systemic sclerosis: development and testing.

OBJECTIVE: To develop and test a severity scale for individual organ involvements in systemic sclerosis (SSc, scleroderma). METHODS: An international study group completed the following tasks: (1) developed a glossary of terms including all pertinent variables for 9 potentially affected organ systems; (2) collected prospective data to determine the feasibility and practicality of each proposed variable; (3) revised the initial list of variables; (4) determined the association of each variable with mortality (a proxy for morbidity) using 579 patients in an existing comprehensive longitudinal scleroderma databank; (5) developed a severity grading scale for each organ system by discussion and consensus; and (6) externally validated the scale using an independent group of 680 patients from the same databank. RESULTS: Nine organ-specific severity scales were developed from 0 (no documented involvement) to 4 (endstage disease). The data required for scale completion are relatively easy and practical for all physicians to obtain. CONCLUSION: This preliminary severity scale will be useful for assessing disease severity status in individual patients both at one point in time and longitudinally. The severity scale will assist in the design and conduct of clinical trials and the comparison of study populations with one another. The scale will serve as a framework for developing a scleroderma disease activity index.

Humans↗
PubMed1998

The development of novel and selective p56lck tyrosine kinase inhibitors.

Early T-cell receptor mediated signal transduction involves the activation of several tyrosine protein kinases. One of these tyrosine kinases, p56lck, is expressed primarily in T-cells and Natural Killer (NK) cells and has been shown to be critical for their proliferative and effector functions. Indandiones have been identified as a potent and selective chemical class that inhibits p56lck.

CSK Tyrosine-Protein Kinase↗
PubMed1998

Detergent-salt resistance of LAP2alpha in interphase nuclei and phosphorylation-dependent association with chromosomes early in nuclear assembly implies functions in nuclear structure dynamics.

Lamina-associated polypeptide (LAP) 2 of the inner nuclear membrane (now LAP2beta) and LAP2alpha are related proteins produced by alternative splicing, and contain a common 187 amino acid N-terminal domain. We show here that, unlike LAP2beta, LAP2alpha behaved like a nuclear non-membrane protein in subcellular fractionation studies and was localized throughout the nuclear interior in interphase cells. It co-fractionated with LAP2beta in nuclear lamina/matrix-enriched fractions upon extraction of nuclei with detergent, salt and nucleases. During metaphase LAP2alpha dissociated from chromosomes and became concentrated around the spindle poles. Furthermore, LAP2alpha was mitotically phosphorylated, and phosphorylation correlated with increased LAP2alpha solubility upon extraction of cells in physiological buffers. LAP2alpha relocated to distinct sites around chromosomes at early stages of nuclear reassembly and intermediarily co-localized with peripheral lamin B and intranuclear lamin A structures at telophase. During in vitro nuclear assembly LAP2alpha was dephosphorylated and assembled into insoluble chromatin-associated structures, and recombinant LAP2alpha was found to interact with chromosomes in vitro. Some LAP2alpha may also associate with membranes prior to chromatin attachment. Altogether the data suggest a role of LAP2alpha in post-mitotic nuclear assembly and in the dynamic structural organization of the nucleus.

Animals↗
PubMed1998

Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production.

Interleukin (IL)-1 is a proinflammatory cytokine with pleiotropic effects in inflammation. IL-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (MAP) kinases, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, as well as transcription factor nuclear factor kappaB (NF-kappaB). IL-1 signaling results in cellular responses through induction of inflammatory gene products such as IL-6. One of the earliest events in IL-1 signaling is the rapid interaction of IL-1 receptor-associated kinases, IRAK and IRAK-2, with the receptor complex. The relative roles of IRAK and IRAK-2 in IL-1 signaling pathways and subsequent cellular responses have not been previously determined. To evaluate the importance of IRAK in IL-1 signaling, IRAK-deficient mouse fibroblast cells were prepared and studied. Here we report that IL-1-mediated activation of JNK, p38, and NF-kappaB were all reduced in embryonic fibroblasts deficient in IRAK expression. In addition, IL-6 production in response to IL-1 was also dramatically reduced in IRAK-deficient embryonic fibroblasts and in skin fibroblasts prepared from IRAK-deficient mice. Our results demonstrate that IRAK plays an essential proximal role in coordinating multiple IL-1 signaling pathways for optimal induction of cellular responses.

Animals↗
PubMed1998

Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.

1. Nicotinylalanine, an inhibitor of kynurenine metabolism, has been shown to elevate brain levels of endogenous kynurenic acid, an excitatory amino acid receptor antagonist. This study examined the potential of nicotinylalanine to influence excitotoxic damage to striatal NADPH diaphorase (NADPH-d) and gamma-aminobutyric acid (GABA)ergic neurones that are selectively lost in Huntington's disease. 2. A unilateral injection of the N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid, into the rat striatum produced an 88% depletion of NADPH-d neurones. Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content. 3. Nicotinylalanine (2.3, 3.2, 4.6, 6.4 nmol 5 microl(-1), i.c.v.) administered with L-kynurenine (450 mg kg(-1)), a precursor of kynurenic acid, and probenecid (200 mg kg(-1)), an inhibitor of organic acid transport, 3 h before the injection of quinolinic acid (15 nmol) produced a dose-related attenuation of the quinolinic acid-induced loss of NADPH-d neurones. Nicotinylalanine (5.6 nmol 5 microl(-1)) in combination with L-kynurenine and probenecid also attenuated quinolinic acid-induced reductions in striatal GABA content. 4. Nicotinylalanine (4.6 nmol, i.c.v.), L-kynurenine alone or L-kynurenine administered with probenecid did not attenuate quinolinic acid-induced depletion of striatal NADPH-d neurones. However, combined administration of kynurenine and probenecid did prevent quinolinic acid-induced reductions in ipsilateral striatal GABA content. 5. Injection of nicotinylalanine, at doses (4.6 nmol and 5.6 nmol i.c.v.) which attenuated quinolinic acid-induced striatal neurotoxicity, when combined with L-kynurenine and probenecid produced increases in both whole brain and striatal kynurenic acid levels. Administration of L-kynurenine and probenecid without nicotinylalanine also elevated kynurenic acid, but to a lesser extent. 6. The results of this study demonstrate that nicotinylalanine has the potential to attenuate quinolinic acid-induced striatal neurotoxicity. It is suggested that nicotinylalanine exerts its effect by increasing levels of endogenous kynurenic acid in the brain. The results of this study suggest that agents which influence levels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage to neurones in the CNS.

Alanine↗
PubMed1998

bcl-2 expression in normal adrenal glands and in adrenal neoplasms.

Archival paraffin-embedded tissue from 5 normal adrenal glands (including 1 from a fetus of 28 weeks' gestation), 6 cases of adrenal cortical hyperplasia, 9 cortical adenomas, 14 cortical carcinomas, and 11 pheochromocytomas were immunostained with monoclonal antibody against bcl-2. Ultrastructural localization of bcl-2 protein was also performed on selected cases. Positive immunostaining for bcl-2 was seen in all of the layers of the normal adrenal cortex, with different staining characteristics. bcl-2 expression was never observed in the normal adrenal medulla. Electron microscopic studies revealed bcl-2 to be localized predominantly to mitochondria, with a small number of labels along the nuclear envelope. Analysis of adrenal neoplasms showed expression of bcl-2 in cortical tumors, but only one positive case in pheochromocytomas. Restriction of bcl-2 expression to adrenal cortex-derived tissue versus adrenal medulla-derived tissue might prove to be helpful for the differential diagnosis between cortical and medullary tumors.

Adolescent↗
PubMed1997

The accuracy of recording of occupational history in patients with bladder cancer.

OBJECTIVE: To determine how accurately information on the occupations of patients with transitional cell carcinoma of the bladder (TCC) was recorded. PATIENTS AND METHODS: Using a semi-structured interview and a standard proforma, 108 patients with TCC of the urinary tract were studied and the results compared with records in their case notes. RESULTS: Case notes were substantially correct in only 39% of patients. Occupations that might have been a significant factor in the aetiology of TCC were omitted in 71% of potentially exposed male patients and no occupational history was recorded in 12% of all patients. CONCLUSIONS: Important clinical information was missing from the case notes that might have been of practical use in determining whether patients might be eligible for financial redress and which might be of use in future clinical research. It is recommended that details of occupational history should be taken using a structured proforma; this could be a suitable topic for regular audit.

Carcinoma, Transitional Cell↗
PubMed1997

Induction of multiple effects on adenylyl cyclase regulation by chronic activation of the human A3 adenosine receptor.

The A3 adenosine receptor (A3AR) contributes to several cardiovascular effects of adenosine, including antihypertensive and cardioprotective effects. Although several studies have detailed the mechanisms underlying agonist-mediated desensitization of the rat A3AR, the regulation of the human A3AR, which displays only a 70% amino acid identity with the rat homologue, has not been addressed. Using a Chinese hamster ovary cell line stably expressing a recombinant human A3AR, we demonstrated that prolonged treatment with the AR agonist 5'-N-ethylcarboxamidoadenosine induces uncoupling of the A3AR from G proteins and functional desensitization. In addition to A3AR desensitization, a 1.5-2.5-fold increase was noted in the adenylyl cyclase (AC) activity achieved in the presence of GTP with or without forskolin. This sensitization of AC activity was not a consequence of the down-regulation of Gi proteins induced by NECA treatment and was not associated with sustained or transient increases in the expression of Gs. Time course experiments revealed that the onset of sensitization was half-maximal between 2 and 3 hr but was not due to the synthesis of new proteins because cycloheximide treatment failed to inhibit sensitization. The inability of the sensitization process to alter the AC activity obtained in the presence of manganese chloride suggests that prolonged A3AR activation increases the coupling efficiency between Gs and AC catalytic units. This phenomenon has implications for long term cellular adaptation to agonist because in agonist-treated cells, the extent to which a suboptimal concentration of forskolin could increase phosphorylation of the cAMP-responsive element binding protein was elevated compared with vehicle-treated controls.

Adenylyl Cyclases↗
PubMed1997

The estrogenic activity of phthalate esters in vitro.

A large number of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. a selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small number of the commercially available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order butyl benzyl phthalate (BBP) > dibutyl phthalate (DBP) > diisobutyl phthalate (DIBP) > diethyl phthalate (DEP) > diisiononyl phthalate (DINP). Potencies ranged from approximately 1 x 10(6) to 5 x 10(7) times less than 17beta-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A number of metabolites were tested, including mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mon-n-octyl phthalate; all were wound to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. analysis by gel chromatography-mass spectometry showed that the preparation exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate standard was responsible for the generation of a dose-response curve--which was not observed with an alternative sample that had not been supplemented with o,p'-bisphenol A--in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixtures of BBP, DBP, and 17beta-estradiol were assessed in the yeast screen. No synergism was observed, although the activities of the mixtures were approximately additive. In summary, a small number of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vivo; this will require tests using different classes of vertebrates and different routes of exposure.

Breast Neoplasms↗
PubMed1996

Cloning and characterisation of the human adenosine A3 receptor gene.

We have cloned the gene for the human adenosine A3 receptor and report characterisation of its intron/exon structure and upstream untranslated region. The open reading frame is interrupted by a single intron of approximately 2.2 kb, within the coding sequence for the second cytoplasmic loop. Sequence analysis of the upstream region reveals no TATA box but the transcriptional start site has been mapped to a common nucleotide in three tissues by 5'-RACE and RT-PCR analysis. Northern blotting, 5'-RACE PCR and analysis of upstream sequences, have provided no evidence for the occurrence of further introns in the upstream untranslated sequence or of transcriptional regulation by alternative splicing in this region.

Amino Acid Sequence↗
PubMed1996

Breast and prostate cancer in the relatives of men with prostate cancer.

OBJECTIVE: To assess the risk of breast, ovarian and prostate cancer in the families of men with prostate cancer. PATIENTS AND METHODS: A case-control study was performed by interviewing patients with prostate cancer and obtaining detailed information on family histories of cancer. Controls were hospital-based patients, of a similar age to the cases, with bladder cancer or benign prostatic hypertrophy. RESULTS: A total of 209 cases and 322 controls were interviewed; of the cases, 22.5% had family members with a history of one or more of breast, ovarian or prostate cancers, compared with 15.2% of controls (P < 0.05). The odds ratio (OR) of having prostate cancer when there was a positive family history was 8.22 and the OR of a female relative of a patient with prostate cancer having breast cancer was 1.51. There was no apparent increased risk of ovarian or any other cancer. CONCLUSIONS: We confirm previous reports of an increased incidence of prostate cancer in the families of men with prostate cancer and report a similarly increased incidence of breast cancer in female relatives. We suggest that detailed family histories be taken routinely and intend to analyse blood samples provided from this study for genetic abnormalities.

Age of Onset↗
PubMed1996

bc1-1 rearrangement and cyclin D1 protein expression in multiple lymphomatous polyposis.

Multiple lymphomatous polyposis (MLP), characterized by multiple polyps involving long segments of the gastrointestinal (GI) tract, is believed to represent GI involvement by mantle cell lymphoma (MCL), primarily based on its histologic and immunophenotypic similarities with MCL. However, rearrangement of the bcl-1 locus, the molecular lesion characteristic of MCL, has not been investigated in this group of patients. The authors evaluated the morphologic, immunophenotypic, and molecular features of 18 cases of MLP and 8 B-cell lymphomas involving the GI tract (including 6 MALT lymphomas). All MLP cases presented with GI disease, and were histologically similar to MCL. DNA extracted from formalin-fixed, paraffin-embedded tissue was analyzed for evidence of bcl-1 rearrangement by PCR, using chromosome 11 specific and consensus JH primers. Amplifiable DNA was obtained in 24 of 26 cases (16 of 18 MLP cases and 8 of 8 controls). bcl-1 rearrangement was detected in 6 of 16 cases (38%), subsequently confirmed by sequencing of the breakpoint region, and in 0 of 8 controls. Immunostaining for cyclin D1 was positive in 14 of 18 MLPs, including the 6 bcl-1 rearranged cases and negative in 6 of 6 evaluable controls. The detection of bcl-1 rearrangement and cyclin D1 expression in cases of MLP supports the view that MLP represents primary MCL, of the GI tract. These techniques may also be helpful in differentiating MLP from other GI lymphomas, particularly low grade lymphomas of MALT, when only small routinely fixed endoscopic biopsies are available.

Adult↗
PubMed1995

Structure and mapping of the human thymopoietin (TMPO) gene and relationship of human TMPO beta to rat lamin-associated polypeptide 2.

Thymopoietins (TMPOs, previously abbreviated TPs) alpha (75 kDa), beta (51 kDa), and gamma (39 kDa) are related nuclear proteins expressed in many or all tissues. TMPO alpha is present diffusely throughout the nucleus, while TMPOs beta and gamma are localized to the nuclear membrane. Here we report the cloning and analysis of a single TMPO gene encoding TMPOs alpha, beta, and gamma, which are produced by alternative mRNA splicing, as previously inferred from cDNA sequences. The eight exons of the TMPO gene are spread over approximately 35 kb. Exon 4, which is spliced into TMPO alpha mRNA, contains sequences that encode a putative basic nuclear localization motif. Exon 8, which is spliced into TMPO beta and gamma mRNAs, encodes a hydrophobic putative membrane-spanning domain that is thought to target TMPOs beta and gamma to the nuclear membrane. TMPO beta appears to be the human homologue of the recently described rat protein LAP2 (lamina-associated polypeptide 2), which is thought to play an important role in the regulation of nuclear architecture by binding lamin B1 and chromosomes in a manner regulated by phosphorylation during mitosis (K. Furukawa and L. Gerace, La Jolla, pers. comm., 22 Nov. 1994). The human TMPO gene maps to chromosome band 12q22.

Amino Acid Sequence↗