Search PubMed⌕ Search

Biomedical subjects

A Mitchell

Publications and source records attributed to A Mitchell.

At least 109 records · Page 6Linked to original sources
PubMed1998

Distinctive patterns of histone H4 acetylation are associated with defined sequence elements within both heterochromatic and euchromatic regions of the human genome.

The pattern of histone H4 acetylation in different genomic regions has been investigated by immunoprecipitating oligonucleosomes from a human lymphoblastoid cell line with antibodies to H4 acetylated at lysines 5, 8, 12 or 16. DNA from antibody-bound or unbound chromatin was assayed by slot blotting. Pol I and pol II transcribed genes located in euchromatin were shown to have levels of H4 acetylation at lysines 5, 8 and 12 equivalent to those in input chromatin, but to be slightly enriched in H4 acetylated at lysine 16. In no case did the acetylation level correlate with actual or potential transcriptional activity. All acetylated histone H4 isoforms were depleted in non-coding, simple repeat DNA in heterochromatin, though the extent of depletion varied with the type of heterochromatin and with the isoform. Two single copy genes that map within or adjacent to blocks of paracentric heterochromatin are depleted in H4 acetylated at lysines 5, 8 and 12, but not 16. Consensus sequences of repetitive elements of the Alu family (SINES, enriched in R bands) were associated with H4 that was more highly acetylated at all four lysines than input chromatin, while H4 associated with Kpn I elements (LINES, enriched in G bands) was significantly underacetylated.

Acetylation↗
PubMed1998

Pattern and significance of cerebral microemboli during coronary artery bypass grafting.

BACKGROUND: Strokes that occur during coronary artery bypass grafting are often caused by embolism. Intraoperative transcranial Doppler monitoring can detect cerebral microemboli. The aims of this study were to identify the pattern of microembolic phenomena during various stages of coronary artery bypass grafting, to verify whether numbers of high-intensity transient signals correlated with early neuropsychologic deficits, and to identify, using magnetic resonance imaging scans, whether radiologic evidence of cerebral infarction correlated with microembolic numbers during the bypass period. METHODS: Forty-one consecutive patients undergoing coronary bypass grafting with transcranial Doppler monitoring were enrolled in this study. All had preoperative and postoperative magnetic resonance imaging brain scans. A subgroup of 32 patients were studied by comparing microembolic load and early neuropsychological outcomes. RESULTS: Transcranial Doppler monitoring confirmed that most microemboli occurred during cardiopulmonary bypass. A significant early neuropsychological deficit after coronary artery bypass grafting did correspond to the total microembolic load during bypass (p = 0.008). However, patients with cerebral infarction on magnetic resonance imaging had significantly more microembolic signal during the preincision phases and not during the bypass period. CONCLUSIONS: Microembolic load during bypass is associated with early neuropsychologic deficits. In contrast, patients who show evidence of strokes during coronary artery bypass grafting have a higher microembolic load during the preincision phase than those without cerebral infarction. Differing mechanisms may be responsible for these different outcomes.

Aged↗
PubMed1998

Expression of prostaglandin G/H synthase type 1, but not type 2, in human ovarian adenocarcinomas.

Prostaglandin endoperoxide synthase (PGHS) is a key rate-limiting enzyme in prostaglandin biosynthesis. PGHS has recently been shown to be expressed in human colorectal cancers and in experimental cutaneous papillomas and carcinomas. However, PGHS expression has not been investigated in ovarian cancers. The objectives of this study were to determine whether PGHS isoenzymes are expressed in human ovarian cancer and, if so, to identify which isoform is involved (PGHS-1 and/or PGHS-2) and to characterize its cellular localization. Sixteen human ovarian adenocarcinomas were studied by immunohistochemistry using specific antibodies recognizing PGHS-1 or PGHS-2. Results showed that all adenocarcinomas demonstrated the presence of tumor cells expressing PGHS-1 but not PGHS-2. Patterns of staining of tumor cells varied among different types of adenocarcinomas, with cells presenting either a mostly diffuse cytoplasmic immunoreactivity or, alternatively, a staining mainly concentrated around the nucleus. No correlation between the intensity of the immunostaining and the degree of malignancy of tumors could be established (r 5 20.03; p>0.05). Immunoblot analysis with PGHS-1-selective antibodies of cell extracts from adenocarcinomas revealed the presence of a characteristic 72,000 Mr immunoreactive band. Therefore, these results show for the first time that PGHS-1 is expressed in human ovarian adenocarcinomas. (J Histochem Cytochem 46:77-84, 1998)

Adenocarcinoma, Mucinous↗
PubMed1998

New concepts regarding the pathogenesis of periodontal disease in HIV infection.

Periodontal manifestations of human immunodeficiency virus (HIV) infection were first described in 1987. Initially, the lesions receiving attention were HIV-associated gingivitis (now known as linear gingival erythema [LGE]) and HIV-associated periodontitis (now known as necrotizing ulcerative periodontitis [NUP]). The true prevalence of LGE was difficult to determine due to variable diagnostic criteria. Recently, LGE has been associated with intraoral Candida infection. The prevalence of NUP is low (< or = 5%), and this lesion is associated with pronounced immunosuppression. Current focus on the periodontal manifestations of HIV infection centers on rapid progression of chronic adult periodontitis in HIV+ patients. Attempts to identify the pathogenesis of the increased progression of periodontitis have not proven successful. For example, analysis of subgingival plaque for the presence of bacterial pathogens has failed to detect differences between HIV+ and HIV- patients. Recently our laboratory has identified alterations in the host response in the gingival crevice of HIV+ patients. Comparing HIV+ and HIV- injecting drug users (IDU), levels of the proinflammatory cytokine interleukin-1 beta (IL-1 beta) in gingival crevicular fluid (GCF) were slightly elevated at sites with a probing depth of 1 to 3 mm. At deeper sites (> or = 4 mm), total IL-1 beta in GCF was significantly greater in HIV+ individuals. Using the lysosomal acid glycohydrolase beta-glucuronidase (beta G) as a measure of the influx of polymorphonuclear leukocytes (PMN) into the gingival crevice, our data indicated a significant correlation of total beta G in GCF and probing depth in the HIV-IDU (r = 76; P = .02). This result was similar to what we have observed in other studies. In contrast, for HIV+ subjects, total beta G was not associated with probing depth (r = .20; NS). These data suggest that HIV+ patients have altered regulation of PMN recruitment into the gingival crevice. We have begun to investigate the conditions under which subgingival Candida may contribute total periodontal lesions in HIV+ individuals. Candida from subgingival sites has been cultured in HIV+ individuals. Subgingival Candida was distinct from Candida isolated from tongue and buccal mucosal surfaces (as indicated by genomic fingerprinting). We hypothesize the absence of adequate priming of PMN by HIV+ patients. This may be due to a reduced Th1 lymphocyte response. The inability of HIV+ individuals to adequately prime PMN may allow Candida to colonize the subgingival environment. In that milieu, it may act directly or in concert with subgingival bacterial pathogens, or as a cofactor (by inducing production of proinflammatory cytokines) to increase the occurrence of periodontal attachment loss.

Candidiasis, Oral↗
PubMed1998

A candidate high density lipoprotein (HDL) receptor, HB2, with possible multiple functions shows sequence homology with adhesion molecules.

High density lipoprotein (HDL), an antiatherogenic lipoprotein comprises several subclasses differing in composition and metabolic function. This physiological complexity appears to be matched with the growing number of candidate HDL receptors, since several HDL binding proteins have recently been identified in various tissues. Because these putative receptors may signal different pathways it is important to identify their structure and potential role in HDL metabolism. We review recent progress in the cloning and characterization of HB2, one of a pair of HDL binding proteins (HB1 and HB2) first purified from rat liver. The structure of HB2 is consistent with a receptor role for this membrane protein and when expressed in cells, increases HDL binding 2 fold. HB2, minimally present in THP-1 cells, is substantially upregulated in macrophages and appears sensitive to cholesterol loading of these cells. The protein shows high homology with adhesion molecules ALCAM and BEN and the possibility that HDL by binding to HB2, reduces adhesion induced arterial wall injury, is discussed in the context of the known protective role of HDL against atherosclerosis. The possible functions of HB2 are also compared with other recently cloned HDL receptors.

Animals↗
PubMed1997

Influence of acute rejection episodes, HLA matching, and donor/recipient phenotype on the development of 'early' transplant-associated coronary artery disease.

BACKGROUND: Transplant-associated coronary artery disease (TxCAD) is the manifestation of chronic rejection in the cardiac allograft. Both immunological and nonimmunological factors contribute to its development. Stratification by the time of development of TxCAD has not been considered previously for an extensive transplant series and may provide a means for apportioning relative risk factors appropriately. Specifically, TxCAD that develops early may have a pathogenesis different from TxCAD that develops later; ie, immunological factors play a more significant role in early development of TxCAD compared with later forms of the disease or in recipients where it has not been found. METHODS AND RESULTS: Between 1980 and 1994, 550 heart transplant recipients with postmortem data or yearly angiograms, donor:recipient serological HLA typing, and biopsy data were reviewed. Recipients were divided into four groups: Very Early (<1 year), Early (1-2 years), Late (3-14 years), and None (clear angio >3 years). There was a significant association between the number of histologically proven acute rejection episodes within 3 months and at 1 year and the development of early TxCAD. The number of acute rejection episodes within 3 months and 1 year is also significantly related to freedom of development of TxCAD. There was no significant association between the mean number of mismatches for Class I or Class II antigens, nor could any Class I/II phenotype for recipient or donor be identified that exerted a protective or deleterious effect. A lack of any association or trend with HLA data is demonstrated. CONCLUSIONS: These differences in pathogenesis between early and late TxCAD help define the importance of acute rejection in the etiology of chronic cardiac rejection. Stratification by time of development of TxCAD may provide further insight into defining the relative importance of other risk factors associated with the development of TxCAD. The lack of association with HLA data is discussed.

Acute Disease↗
PubMed1997

Cloning and characterization of HB2, a candidate high density lipoprotein receptor. Sequence homology with members of the immunoglobulin superfamily of membrane proteins.

The protection against coronary artery disease attributed to high density lipoprotein (HDL) may be associated with several functions, including its central role in reverse cholesterol transport, possible antioxidant and antithrombotic properties and others not yet identified which may depend on specific interactions between HDL and cell receptors. Several HDL-binding proteins have been identified including two candidate liver HDL receptors, HB1 and HB2 recently purified in this laboratory. We now report the cloning, sequencing, and some properties of HB2, the most abundant of the pair. It shows significant homology with the adhesion molecules ALCAM and BEN of the immunoglobulin superfamily and the cDNA, when transfected into HepG2 or COS cells, caused specific HDL3 binding to increase by 80-100%. Further, ligand blotting of glycoproteins isolated from phorbol 12-myristate 13-acetate-treated THP-1 cells or from transfected HepG2 and Chinese hamster ovary cells also provided evidence of increased binding of HDL3 to HB2. Differentiation of THP-1 cells into macrophages resulted in a striking increase in HB2 mRNA which was attenuated if cells were cholesterol-loaded by incubation with acetylated low density lipoprotein. If the interaction between HDL and HB2 reduces the adhesion-induced inflammatory cellular events that characterize arterial wall injury, thereby achieving the protection associated with higher plasma levels of HDL, these findings may provide a clue to one mitigating effect of HDL in heart disease.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1997

Determinants of transplant-related coronary calcium detected by ultrafast computed tomography scanning.

Coronary calcium detected by ultrafast computed tomography (CT) has been shown to be a marker of coronary artery disease in heart transplant recipients. The objective of this study was to examine the possible determinants of coronary calcium after heart transplantation. Over a 15-month period, 102 consecutive cardiac transplant recipients (mean age 53 years, 88 men) underwent ultrafast CT scanning of the heart, in addition to coronary angiography, to determine coronary calcium score on their annual follow-up (a median of 4.6 years [range 63 days to 9.1 years] after transplant). The following data were also recorded: the recipient's sex and date of birth, date of transplantation, date of ultrafast computed tomography and coronary angiography; recipient pretransplant diagnosis, history of diabetes mellitus and systemic hypertension, fasting lipid profile, immunosuppression, number of rejection episodes, and donor organ ischemic time. Forty six patients (45.1%) had total calcium scores >0 and 41 (40.2%) had at least 1 major coronary with angiographic narrowing >24%. On univariate analysis, coronary calcium was significantly associated with dyslipoproteinemia, total cholesterol was >6.0 mmol/L (240 mg/dl), triglycerides were >3.0 mmol/L (265 mg/dl), and lipoprotein(a) >30 mg/ dl; > or =25% angiographic disease was significantly associated with coronary calcium and dyslipoproteinemia. Logistic regression revealed that dyslipoproteinemia, systemic hypertension, and donor ischemic time were significant predictors of coronary calcium in transplanted hearts. We conclude that the prevalence of coronary calcium in heart transplant recipients is high and is related to recipient dyslipoproteinemia, systemic hypertension, and donor organ ischemic time.

Calcinosis↗