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Biomedical subjects

D H Wright

Publications and source records attributed to D H Wright.

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

Bacillus anthracis: medical issues of biologic warfare.

Recent world events refocused attention on the possibility of nations engaging in biologic warfare, including an attack with Bacillus anthracis. The single available anthrax vaccine in the United States for human use, formerly known as MDPH-PA, has decreased ability to protect laboratory animals against virulent B. anthracis strains, especially compared with new vaccines being developed. Studies with these vaccines, however, have several shortcomings. The pathogenesis, diagnosis, treatment, and prophylaxis of anthrax are discussed, as well as the implications that an attack with B. anthracis would place on the health care system.

Anthrax↗
PubMed1999

Implications of vancomycin degradation products on therapeutic drug monitoring in patients with end-stage renal disease.

In renally impaired patients, vancomycin concentrations typically are maintained at body temperature for extended periods of time due to the drug's prolonged half-life. Both time and increased temperature potentiate production of vancomycin crystalline degradation products (CDP-1). Commercially available vancomycin assays, such as fluorescence polarization immunoassay (FPI) and radioimmunoassay, cross-react with CDP-1 isomers. Overestimation of vancomycin concentrations by 40-53% due to cross-reactivity of CDP-1 with active factor B vancomycin occurs with FPI. As FPI is the most common method of analyzing serum vancomycin, clinicians must be aware of its potential shortcomings and be prepared to alter vancomycin dosages in renally impaired patients. The possibility of adverse affects due to elevated concentrations of CDP-1 or therapeutic failures due to subtherapeutic levels of factor B vancomycin cannot be excluded.

Anti-Bacterial Agents↗
PubMed1998

Determination of quinolone antibiotics in growth media by reversed-phase high-performance liquid chromatography.

A simple, accurate, precise, and versatile high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of three quinolone antibodies in Mueller-Hinton broth. The fluoroquinolone agents studied were ciprofloxacin, ofloxacin, and sparfloxacin; other quinolone agents have been identified using this method but not validated in this matrix (levofloxacin, clinafloxacin, temafloxacin, and trovafloxacin). In addition, several other biological growth mediums have been investigated (human serum, human urine, Todd-Hewitt growth media, Ensure enteral feeding solution, and Haemophilus growth media). This method uses UV detection (280 nm), a simple, one-step protein precipitation extraction, and separation using a C18 column with an isocratic, ion-pairing mobile phase. An appropriate internal standard was obtained by using another quinolone antibiotic of differing retention time. The calibration curves were linear (r2> or =0.999) over a concentration range of 0.0625-20.0 microg/ml with a lower limit of quantification of 0.1 microg/ml. The intra-day and inter-day coefficients of variation were less than 15%.

Calibration↗
PubMed1998

Angiogenesis in pathological and surgical scars.

We identified immunohistochemically vessels within cutaneous scars to test the hypothesis that they are qualitatively and quantitatively different in pathological and normally healing scars. The vascular density within and adjacent to 58 cutaneous scars was measured on histological sections stained for factor VIII-related antigen. Four scar types were studied; surgical scars (n = 25), hypertrophic scars (n = 10), keloid (n = 12), and periocular scars (n = 11). Statistical analyses were performed to test the hypothesis that vessel numbers were different in the varying types of scar. Results were also compared with mast cell counts previously derived from the same tissues. A significant reduction was found in the vascular density in keloids compared with surgical and hypertrophic scars (P < .05). No correlation was found between the vascular density and the number of mast cells in the lesions. We have shown quantitatively that keloids have a reduced vascular component compared with hypertrophic scars and normally healing surgical scars at periocular and systemic sites. The formation of keloid scars may be related to their reduced level of vascularization mediated through tissue hypoxia.

Adult↗
PubMed1998

Characterization of the recombinant human prostanoid DP receptor and identification of L-644,698, a novel selective DP agonist.

1. A human embryonic kidney cell line [HEK 293(EBNA)] stably expressing the human recombinant prostaglandin D2 (PGD2) receptor (hDP) has been characterized with respect to radioligand binding and signal transduction properties by use of prostanoids and prostanoid analogues. Radioligand binding studies included saturation analyses, the effects of nucleotide analogues, the initial rate of ligand-receptor association and equilibrium competition assays. In addition, adenosine 3':5'-cyclic monophosphate (cyclic AMP) generation in response to ligand challenge was also measured, as this is the predominant hDP signalling pathway. 2. L-644,698 ((4-(3-(3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl) propyl) benzoic acid) (racemate)) was identified as a novel ligand having high affinity for hDP with an inhibitor constant (Ki) of 0.9 nM. This Ki value was comparable to the Ki values obtained in this study for ligands that have previously shown high affinity for DP: PGD2 (0.6 nM), ZK 110841 (0.3 nM), BW245C (0.4 nM), and BW A868C (2.3 nM). 3. L-644,698 was found to be a full agonist with an EC50 value of 0.5 nM in generating cyclic AMP following activation of hDP. L-644,698 is, therefore, comparable to those agonists with known efficacy at the DP receptor (EC50): PGD2 (0.5 nM), ZK 110841 (0.2 nM) and BW245C (0.3 nM). 4. L-644,698 displayed a high degree of selectivity for hDP when compared to the family of cloned human prostanoid receptors: EP1 (> 25,400 fold), EP2 (approximately 300 fold), EP3-III (approximately 4100 fold), EP4 (approximately 10000 fold), FP (> 25,400 fold), IP (> 25,400 fold) and TP (> 25,400 fold). L-644,698 is, therefore, one of the most selective DP agonists as yet described. 5. PGJ2 and delta12-PGJ2, two endogenous metabolites of PGD2, were also tested in this system and shown to be effective agonists with Ki and EC50 values in the nanomolar range for both compounds. In particular, PGJ2 was equipotent to known DP specific agonists with a Ki value of 0.9 nM and an EC50 value of 1.2 nM.

Adenine Nucleotides↗
PubMed1998

Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis.

The epidemiology of Hodgkin's disease suggests that it is a heterogeneous condition comprising more than one disease entity. The Epstein-Barr virus (EBV) is present in the Reed-Sternberg cells of a proportion of cases and is likely to play a role in the pathogenesis of these cases. In this study we show that EBV association rates vary with age at diagnosis. We suggest that Hodgkin's disease can be divided into three disease entities on the basis of EBV association and age, thereby providing biological support for the multiple aetiology hypothesis proposed by MacMahon (Cancer Res 1966; 26: 1189-1290).

Adolescent↗
PubMed1998

Mast cells in pathological and surgical scars.

AIM: To investigate the role of mast cells in surgical and pathological scar reactions by their identification and quantification using immunohistochemistry. METHODS: Surgical scars and pathological scar reactions were stained immunohistochemically for tryptase to identify mast cells. These were quantified in the scar tissue and surrounding dermis. Statistical analyses were performed to test the hypothesis that mast cell numbers were different in the varying types of scar reaction. RESULTS: A significant difference was found between the mean number of mast cells in periocular scars compared with keloids, hypertrophic scars, and surgical scars from other sites (p < 0.05). No significant difference was found in mast cell numbers between the other scar types either within the lesions or surrounding dermis. There were significantly more mast cells in the dermis than in the scar tissue itself, except for the small group of periocular scars. The ratio of mast cells in the lesion compared with the dermis was not significantly different between the scar types, except for the periocular scars. CONCLUSIONS: Mast cell numbers are similar in and around keloid, hypertrophic, and surgical scars. The increased number of mast cells at periocular scar sites was contrary to expectation since keloids are rare at this site. Absolute mast cell numbers may not be an accurate measure of tissue concentrations of active mast cell products. Further comparisons between immunological characteristics of keloid and periocular scars may elucidate specific immunological abnormalities of keloid scars, and this has implications for the development of immunotherapy.

Adult↗
PubMed1997

Determination of HLA-A*02 antigen status in Hodgkin's disease and analysis of an HLA-A*02-restricted epitope of the Epstein-Barr virus LMP-2 protein.

There is good evidence for an association between Epstein-Barr virus (EBV) and Hodgkin's disease (HD). In approximately one-third of cases, the EBV genome is detectable in Reed-Sternberg (RS) cells and there is expression of the viral nuclear antigen EBNA-1 and the latent membrane protein LMP-1. Expression of LMP-2 has been demonstrated at the mRNA level, and it is presumed that the protein is expressed alongside LMP-1. The LMP-2 protein is known to contain an epitope presented to cytotoxic T-cells which is restricted through the HLA class I antigen A*0201 in healthy seropositive individuals. Since most HLA-A*02-positive Caucasians are HLA-A*0201-positive, it was hypothesized that HLA-A*02-positive individuals would be under-represented among Caucasians with EBV-associated HD. HLA-A*02 status was determined, using flow cytometry and/or the polymerase chain reaction, for 276 individuals including 176 cases of HD. There was no significant difference between the frequency of HLA-A*02 positivity in HD cases and controls, and between EBV-associated and non-associated cases of HD. The A*02 alleles of 14 cases of EBV-associated HD were further subtyped using nested PCR; all except one case were found to be A*0201-positive. We therefore investigated whether there was any evidence for mutation of the epitope representing amino acids 426-434 of LMP-2a which is restricted through HLA-A*0201. In 10/11 cases the nucleotide sequence encoding this epitope was identical to the published sequence; in the remaining case there was a mutation which would not be expected to alter the conformation of the epitope. Overall, our data suggest that other mechanisms of immune escape must be operative in EBV-associated HD.

Adolescent↗
PubMed1997

What is Burkitt's lymphoma?

Burkitt's lymphoma (BL) has been defined on the basis of its characteristic cytomorphology. Although histologically identical, endemic BL and sporadic BL are distinct clinico-anatomical entities. Their morphological identity probably relates to similar chromosomal translocations in both tumours, resulting in c-myc de-regulation and consequent unrestrained proliferation without differentiation. Similar gene rearrangements are found in a proportion of AIDS-related lymphomas that are predominantly extranodal and have the cytomorphology of BL. The term "Burkitt-like lymphoma" (BLL) has been applied to a group of high-grade B-cell lymphomas that appear morphologically intermediate between BL and centroblastic/immunoblastic lymphomas, as detailed in an accompanying paper in this issue. These tumours do not usually show c-myc gene rearrangements. The association of Burkitt's name with such a disparate group of tumours is confusing and new terminology for sporadic BL, AIDS-related BL and BLL is desirable. It is important that clinico-anatomical features, as well as cytomorphology, should be taken into account in the diagnosis of endemic BL. The origin of a case from tropical Africa does not, in itself, imply that it is endemic BL, even more since the AIDS epidemic in that continent.

Burkitt Lymphoma↗
PubMed1997

Epstein-Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells.

Primary Epstein-Barr virus (EBV) infection may manifest itself as a benign lymphoproliferative disorder, infections mononucleosis (IM). EBV infection has been characterized in lymphoreticular tissues from nine patients with IM using the abundantly expressed EBV-encoded nuclear RNAs (EBERs) as a marker of latent infection. Expression of the virus-encoded nuclear antigen (EBNA) 2 and of the latent membrane protein (LMP) 1 was seen in variable proportions of cells in all cases. Double labelling revealed heterogeneous expression patterns of these proteins. Thus, in addition to cells revealing phenotypes consistent with latencies I (EBNA2-/LMP1-) and III (EBNA2+/LMP1+), cells displaying a latency II pattern (EBNA2-/LMP1+) were observed. Cells expressing EBNA2 but not LMP1 were also detected; whilst this may represent a transitory phenomenon, the exact significance of this observation is at present uncertain. EBER-specific in situ hybridization in conjunction with immunohistochemistry revealed expression of the EBERs mainly in B-lymphocytes, many of which showed features of plasma cell differentiation. By contrast, convincing evidence of latent EBV infection was not found in T-cells, epithelial or endothelial cells. Double-labelling immunohistochemistry revealed expression of the replication-associated BZLF1 protein in small lymphoid cells, often showing plasmacytoid differentiation. There was no unambiguous expression of this protein in other cell types. These results suggest that B-cells are the primary target of EBV infection and that plasma cells may be a source of infectious virus found in the saliva of IM patients.

Antigens, Viral↗
PubMed1997

Molecular detection of a B cell clone in a case of PTCL in the absence of T cell clonality.

In this paper we document a case of peripheral T cell lymphoma (PTCL) that exhibited variable T cell histology at presentation and follow-up. Southern blot analysis for T cell receptor (TCR) and immunoglobulin (Ig) receptor gene rearrangements failed to reveal clonal T or B cell populations. TCR gamma (TCRG) and beta (TCRB) chain gene polymerase chain reaction (PCR) amplification of DNA isolated from biopsies was also consistent with polyclonal T cell populations, however Ig PCR revealed clonal Ig rearrangements in follow-up biopsies but not in the presentation biopsy. There was no histological evidence for a neoplastic B cell population in these biopsies although occasional EB virus positive blasts were present. The significance of a cryptic B cell clone is unknown but suggests a relationship with the proliferating polyclonal T cells in this case of PTCL. These data reflect the complexity of PTCL with implications for treatment and patient management.

Aged↗
PubMed1997

Distribution and configuration of c-myc RNA during transcriptional attenuation in differentiating cells in-situ.

Previous northern studies of c-myc RNA downregulation during early cellular differentiation have shown reduced levels of mature transcript within 6-24 h, attributed to attenuation of transcription at pause sites downstream of the P2 promoter. The transcription initiation rate has been shown to be decreased in some and increased in other such studies. We assessed the contribution of RNA trafficking to c-myc reduction during differentiation by examining the localisation and configuration of exon-specific transcripts, using oligonucleotide probes and fluorescent in-situ hybridisation, in HL60 cells induced to differentiate with 12-O-tetradecanoylphorbol-13-acetate. A 2,4-dinitrophenyl-labelled probe to c-myc exon 3 sequences gave a strong cytoplasmic and nucleolar hybridisation signal in undifferentiated cells, which decreased markedly after 24 h of differentiation. Nucleolar staining for c-myc RNA colocalised with that from a probe for ribosomal 28 S RNA. The signal from an exon 1 probe specific for sequences upstream of the c-myc P2 promoter was much weaker, but increased in the nuclei of differentiating cells, which possessed unusual ring-like or lamellar deposits, outside the nucleolus. These deposits appeared faintly together with nuclear staining with the exon 1 sense probe but not the exon 3 sense probe in differentiating cells. These findings demonstrate that within the first 24 h of differentiation, full-length c-myc RNA, which is compartmentalised as expected for a mature transcript, is considerably downregulated but nuclear primary RNA continues to be transcribed from exon 1. This is in a configuration similar to that reported for unspliced transcripts and is not elongated into exon 3. Antisense transcription with these RNA morphological features also occurs in exon 1 during differentiation. These results indicate significant changes in the intracellular dynamics of c-myc RNA during differentiation and support transcriptional attenuation and post-transcriptional processes, such as splicing, rather than reduced transcription initiation as the primary mechanism of c-myc downregulation in the early phases of differentiation.

Cell Differentiation↗
PubMed1997

The accessory cell populations in ulcerative colitis: a comparison between the colon and appendix in colitis and acute appendicitis.

We present an immunohistochemical study of accessory cells in acute appendicitis and ulcerative colitis (UC). By comparing these two diseases, it is possible to distinguish between changes associated with inflammatory bowel disease and those resulting from nonspecific intestinal inflammation. Nine total colectomy specimens from patients with UC, in which the appendix was also involved, were compared with nine cases of acute appendicitis. Accessory cells were stained for CD68 (PGMI), ACPI (acid cysteine proteinase inhibitor), S100 protein, MAC387 (calgranulin), CD1a, factor XIIIa, and WR18 (HLA class II). In ulcerative colitis, but not acute appendicitis, there was extension of a network of S100 positive dendritic cells into the crptal mucosa, and these S100-positive dendritic cells were closely aligned with the epithelium. The epithelium in UC, but not in acute appendicitis, showed intense upregulation of HLA class II, and this was particularly marked at the crypt bases. Dendritic, MAC387-positive cells were seen only in UC. In both diseases there were abundant ACPI-positive accessory cells in the cryptal areas, a population normally restricted to the dome areas. Factor XIIIa- and PGM1-positive cells, although abundant in both conditions, had distributions similar to those that we had previously shown in normal controls. No CD1a-positive cells were identified in either UC or acute appendicitis. We hypothesize that S100 identifies a subpopulation of activated macrophages. The concentration of this subpopulation, in close contact with the epithelium, which also shows altered expression of HLA class II antigens, suggests that a component of the immune response is targeting this area in UC. In addition, we also suggest that the identification of MAC387-positive dendritic cells in UC reflects increased macrophage turnover in inflammatory bowel disease.

Antigen-Presenting Cells↗
PubMed1997

Lymphadenopathy due to amyloid deposition in non-Hodgkin's lymphoma.

BACKGROUND: Amyloidosis is a rare complication of non-Hodgkin's lymphoma. Most of the reported patients have had systemic amyloidosis and have died as a result of complications of this disease. MATERIALS AND METHODS: The clinical cases of two patients with lymphoplasmacytic non-Hodgkin's lymphoma who presented with lymphadenopathy due to localised amyloid deposition are reviewed. Immunohistochemical studies were performed on the amyloid deposits and adjacent lymphoma. RESULTS: The amyloid deposits in both patients were derived from monoclonal light chains of the same isotype as those expressed by the lymphoma cells and were localised to areas adjacent to the lymphoma despite the presence of circulating light chains. Both patients had an indolent clinical course and treatment appeared to have little influence on the amyloid deposition. CONCLUSIONS: Non-Hodgkin's lymphoma may be associated with localised amyloidosis secondary to local production and deposition of amyloid from monoclonal light chains synthesised by the lymphoma cells. This is a rare cause of lymphadenopathy which does not respond to treatment of the underlying lymphoma.

Amyloid↗
PubMed1997

The need for specialist review of pathology in paediatric cancer.

A retrospective histopathological review of 2104 cases of solid tumour was carried out to assess the variability in diagnosis of childhood cancer. Cases were subject to three independent, concurrent opinions from a national panel of specialist pathologists. The conformity between them was analysed using the percentage of agreement and the kappa statistic (kappa), a measure of the level of agreement beyond that which could occur by chance alone, and weighted kappa (w kappa), which demonstrates the degree of variation between opinions. The major groupings of the Birch-Marsden classification were used within which tumours were assigned for kappa analysis according to the clinical significance of the differential diagnoses. The mean agreement for all tumours together was 90%; kappa = 0.82, w kappa = 0.82. Retinoblastoma achieved the highest kappa value (1.0) and lymphoma the lowest (0.66). Of the cases, 16.5% had their original diagnoses amended and the panel confirmed the original diagnosis of paediatric pathologists in 89% of cases compared with 78% for general pathologists. The varying levels of agreement between experts confirm the difficulty of diagnosis in some tumour types, suggesting justification for specialist review in most diagnoses. Specialist training in paediatric pathology is also recommended.

Child↗
PubMed1997

The value of immunohistochemistry on paraffin wax embedded tissue sections in the differentiation of small lymphocytic and mantle cell lymphomas.

AIMS: To determine whether immunohistochemistry applied to paraffin wax embedded biopsy tissue can be used to distinguish between B-small lymphocytic lymphoma (B-SLL) and mantle cell lymphoma (MCL). METHODS: Formalin fixed, paraffin wax embedded tissue blocks of 12 cases of B-SLL and 12 cases of MCL were retrieved from the files of the Department of Pathology, Southampton University Hospitals Trust. Following antigen retrieval, where appropriate, sections were stained for CD3, CD5, CD20, CD23, CD43, Cyclin D, PGP9.5, and MIB1 using a streptavidin-biotin complex technique. RESULTS: CD20 stained the neoplastic cells of B-SLL and MCL, and CD3 labelled the reactive T cells in these tumours. In B-SLL, the T cells were generally dispersed among the tumour cells, whereas in MCL they often formed bands around tumour cell nodules. CD5 could be detected on T cells, following antigen retrieval. The level of expression on B cells of B-SLL and MCL was generally too low to allow detection in paraffin wax embedded tissues. CD23 stained B-SLL but not MCL. However, it could be detected in only five of the 12 cases of B-SLL. CD43 could be detected in most cases of B-SLL and MCL. It is not, therefore, of value in distinguishing between these tumours. It will, however, help in the differentiation of B-SLL and MCL from other low grade B cell lymphomas, such as follicle centre cell and marginal zone lymphomas. Cyclin D was expressed in all of the MCL but in none of the B-SLL. PGP9.5 showed reactivity in most cases of MCL and much weaker reactivity in B-SLL. The proliferation indexes of MCL were generally higher than those of B-SLL, as measured by MIB1 labelling. Both tumours, however, showed a wide range of values and considerable overlap. CONCLUSION: Staining for Cyclin D is the most reliable immunohistochemical mean of differentiating between B-SLL an MCL. High levels of PGP9.5, expressed in MCL, may be related to the degradation of Cyclin D by the ubiquitin pathway.

Aged↗