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K Cooper

Publications and source records attributed to K Cooper.

At least 127 records · Page 7Linked to original sources
PubMed1996

Autopsy prevalence of Wernicke's encephalopathy in alcohol-related disease.

OBJECTIVE: To determine the autopsy prevalence of Wernicke's encephalopathy (WE) in patients dying from alcohol-related diseases. DESIGN: Prospective postmortem macroscopic and microscopic examination. SETTING: Adult autopsies at King Edward VIII Hospital. METHODS: Thirty-one consecutive autopsies were performed on patients who had died from alcohol-related diseases; these formed the study group. The control group comprised 10 patients with a negative history of alcohol and alcohol-related diseases. After examination of the brain, samples for histology were taken from the mamillary bodies and the wall of the third ventricle. Two subjects were excluded on account of additional unrelated brain pathology. RESULTS: Of the 29 patients studied, 17 (59%) were confirmed histologically to have WE. The histological lesions were classified as either acute (5), acute on chronic (9) or chronic (3) according to defined pathological criteria. Macroscopic abnormalities were not obvious in any of the patients in the study group. Chart analysis revealed that a disturbance of the mental state was the commonest neurological finding (9/17). Ocular palsy was not present in any of the subjects. Although 2 patients had been given thiamine prior to death, a clinical diagnosis of WE was not made in any of the cases studied. CONCLUSION: This study proves that WE is a frequent finding in blacks with alcohol-related diseases. The high prevalence of WE found in adult autopsies (6.6%) without documented clinical evidence may have contributed to the mortality in these cases.

Adult↗
PubMed1995

Novel antagonists of platelet-activating factor. 1. Synthesis and structure-activity relationships of benzodiazepine and benzazepine derivatives of 2-methyl-1-phenylimidazo[4,5-c]pyridine.

Following the discovery of moderately potent antagonist activity platelet-activating factor (PAF) in 2-methyl-1-phenylimidazo[4,5-c]pyridine (2) (IC50 = 840 nM), 19 derivatives (3-21) were prepared which incorporated various lipophilic groups attached to the phenyl 4-position. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit the PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. [1,5]Benzodiazepines, e.g., 14 (2,3-dihydro-1-methyl-4-[4-(2-methylimidazo[4,5-c] pyrid-1-yl)phenyl]-1H-[1,5]benzodiazepin-2-one) (IC50 = 4.9 nM, Ed50 = 0.03 mg/kg po), were found to possess equivalent or superior potency to the 1,4-dihydropyridine PAF antagonist UK-74,505 (1,4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl-2- [4-(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5-[N-(2-pyridyl) carbamoyl]pyridine) in vitro and in vivo. Furthermore, a potent benzazepine, 21 (7,8-dichloro-1-methyl-4-[4-(methylimidazo[4,5-c]pyrid-1-yl) phenyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one) (IC50 = 0.5 nM, ED50 = 0.03 mg/kg po), was discovered. These investigations prompted the synthesis and evaluation of additional diazepine derivatives, which are described in the following paper. The relationship between the key PAF antagonist pharmacophores of 2-methyl-1-phenylimidazo[4,5-c]pyridine, a triazolothienodiazepine (WEB2170), and a pyrrolothiazolidine (RP-52,770) is discussed.

Animals↗
PubMed1995

Novel antagonists of platelet-activating factor. 2. Synthesis and structure-activity relationships of potent and long-acting heterofused [1,5]benzodiazepine and [1,4]diazepine derivatives of 2-methyl-1-phenylimidazo[4,5-c]pyridine.

The optimization of in vitro activity and oral potency and duration of action in vivo is described for three novel structural types of platelet-activating factor (PAF) antagonist: [1,5]benzodiazepines 5-12 onto which a variety of other heterocyclic rings were fused, pyrido[2,3-b][1,4]-diazepinones 13-26, and pyrazolo[3,4-b][1,4]diazepinones 27-46. Compounds 5-12 were prepared by elaboration of the [1,5]benzodiazepine-2-thiones 47 and 48, and 13-46 were prepared by cyclocondensation reactions of a variety of 2,3-diaminopyridine and 4,5-diaminopyrazole derivatives with ethyl 4'-(2-methylimidazo[4,5-c] pyrid-1-yl)benzoylacetate (53). The presence of imine-enamine tautomerism was observed in certain diazepine derivatives and is discussed. Structure-activity relationships were evaluated where PAF antagonist activity was measured in vitro by determining the concentration of compound (IC50) required to inhibit PAF-induced aggregation of rabbit washed platelets and in vivo by determining the oral dose (ED50) which protected mice from a lethal injection of PAF. In addition, the duration of action in conscious dogs as measured by determining the oral dose of selected compounds required to inhibit completely PAF-induced whole blood aggregation ex vivo. The most potent compound was 1,6,7,8-tetrahydro-1,8-dimethyl-5-[4-(2-methylimidazo [4,5-c]pyrid-1-yl)phenyl]-7-oxo-3-(3-pyridyl) pyrazolo[3,4-b][1,4]diazepine (43, UK-91,473) (IC50 = 2.4 nM, ED50 = 0.01 mg/kg po), which was found to be significantly more potent in vivo (murine lethality) than the dihydropyridine PAF antagonist 4-(2-chlorophenyl)-1,4-dihydro-3-(ethoxycarbonyl)-6-methyl- 4-[(2-methylimidazo[4,5-c]pyrid-1-yl)phenyl]-5- [N-(2-pyridyl)carbamoyl]pyridine (4, UK-74,505) (ED50 = 0.26 mg/kg po). Compound 43 also possessed a longer duration of action than compound 4 in the conscious dog at one-fourth of the dose. The crystal structure of compound 43, established by X-ray diffraction, is reported.

Animals↗
PubMed1995

Molecular events underlying schistosomiasis-related bladder cancer.

Twenty-one invasive squamous-cell carcinomas (SCC) of the bladder from Schistosoma-hematobium-infected patients were examined immunohistochemically for the expression of p53, Rb, EGFR and c-erbB-2 proteins; and screened by single-strand conformation polymorphism and sequencing for mutations in the ras (H, N, K) codon hotspots (12, 13, 61) and p53 (exons 4-9) genes. Positive staining for p53, EGFR and c-erbB-2 was reported in 38, 67 and 28% of tumors respectively. Only one of the tumors, the only one that was poorly differentiated, displayed an absence of nuclear Rb staining. Ras alterations were detected in the H-ras gene in 3 tumors, 2 of which harbored a codon-13 (Gly-->Arg) and one a codon-12 (Gly-->Ser) point mutation. p53 mutations were recorded in 12 tumors (57%), 6 of which stained positively for p53. Four tumors had exon-7 mutations (codons 235, 241 and 249; one tumor had 2 exon-7 mutations). Eight tumors were mutated in exon 8 (codons 264, 271, 273, 285, 286, 288 and 294), 5 of which harbored multiple mutations. One tumor had an insertion/deletion event in exon 9. The frequency of detection of over-expression of EGFR and c-erbB-2 in bilharzial-bladder lesions is comparable to that reported in TCC, contrasting with the infrequent loss of Rb expression found in invasive lesions associated with schistosomiasis infection. However, the detection of multiple p53 mutations in these lesions is suggestive of the involvement of a carcinogenic agent with maintenance of preferential activation of the H-ras gene.

Animals↗
PubMed1995

Human papillomavirus DNA in oesophageal carcinomas in South Africa.

Using morphological criteria, the presence of human papillomavirus (HPV) in oesophageal carcinomas has been inferred in patients from Finland and South Africa. However, studies to demonstrate the viral antigen in tissue sections of these tumours have proved disappointing. This study investigates 48 archival oesophageal carcinoma biopsies from South Africa for the presence of HPV DNA using non-isotopic in situ hybridization (NISH) with HPV DNA probes to HPV 6, 11, 16, 18, 31, and 33. HPV DNA sequences were detected in 25/48 (52 per cent) oesophageal cancers. HPV 16 was present in 84 per cent of the HPV-positive cancers. A NISH type 2 signal pattern (punctate/dot) was present in all HPV-positive tumours. This signal pattern was previously shown to represent integrated HPV DNA within host chromosome. Integrated HPV DNA in oesophageal cancers has also been demonstrated in patients from China and Japan. In addition, the prevalence of HPV DNA in oesophageal cancers from high-risk countries like South Africa (52 per cent) and China (49 per cent) would appear to be consistent.

Base Sequence↗
PubMed1995

Interphase cytogenetics: analysis of numerical chromosome aberrations in isolated cells.

Probes which recognize pericentromeric repetitive sequences can be used to determine numerical chromosome aberrations in interphase nuclei. Under appropriate stringency conditions, these probes decorate only the chromosome from which they were derived. It has been assumed that abnormalities of signal number in interphase nuclei reflect aneuploidy rather than proliferation, but this has not been clearly demonstrated. In this paper, three alphoid probes (D3Z1, D11Z1, and DXZ1) were localized to the appropriate chromosomes and the factors governing the production of reproducible signal distributions from three aneuploid cervical carcinoma-derived epithelial cell lines were investigated. Abnormalities of signal number represent numerical chromosome aberrations rather than changes associated with proliferation. Using four simple rules of interpretation, reproducible results can be obtained with minimal technical variation and selection bias. These results demonstrate that pericentromeric repetitive probes can be used reproducibly to determine numerical chromosome aberrations independent of cell proliferation in interphase nuclei, a necessary prerequisite for the application of this approach to the analysis of human tumours.

Aneuploidy↗
PubMed1995

Detection of herpes simplex virus DNA in spontaneous abortions from HIV-positive women using non-isotopic in situ hybridization.

The purpose of this study was to determine the prevalence of Herpes simplex virus (HSV) endometritis in spontaneous abortions in HIV-positive women using non-isotopic in situ hybridization (NISH). Post-abortal endometrial curettings from 18 HIV-positive women were investigated for the presence of HSV-1 and HSV-2 DNA with NISH. In addition, 18 unselected post-abortal endometrial curettings in HIV-negative women were used as controls, together with samples of normal proliferative and secretory endometrium. Thirteen of the 18 specimens (72 per cent) from the HIV-positive study group demonstrated the presence of HSV DNA, while 2 of the 18 HIV-negative group (11 per cent) showed a positive signal. Although the prevalence of HSV endometritis in the HIV-positive group was significantly higher than in the HIV-negative group (P < 0.05), a causal role for the virus in inducing the abortion remains to be determined. In addition, the significance of HSV endometritis with regard to the clinical management of HIV-positive patients is as yet uncertain.

Abortion, Spontaneous↗
PubMed1995

The hematotoxic effects of 6-hydroxy-trans,trans-2,4-hexadienal, a reactive metabolite of trans,trans-muconaldehyde, in CD-1 mice.

6-Hydroxy-trans,trans-2,4-hexadienal (CHO-M-OH) is a metabolite of trans,trans-muconaldehyde (muconaldehyde or MUC), a microsomal hematotoxic ring-opened metabolite of benzene. In the present study, the toxicity of CHO-M-OH was examined. In order to assess potential toxic effects of CHO-M-OH on the maturation of erythroid cells in the bone marrow, 10-week-old male CD-1 mice were administered CHO-M-OH intraperitoneally and 59Fe incorporation into erythrocytes was measured. The uptake of 59Fe by erythroid cells was significantly inhibited at doses of 20, 25, and 30 mg/kg. There was no inhibition of 59Fe incorporation at a dose of 15 mg/kg. In other hematotoxicity studies, bone marrow cellularity, peripheral blood cells, and sulfhydryl contents in bone marrow cells were examined in mice administered CHO-M-OH intraperitoneally. An increase in the white blood cell count was observed in mice treated with 5 mg/kg/day for 16 consecutive days, while bone marrow cellularity and red blood cell parameters were not changed. Administration of 10 mg/kg/day for 16 consecutive days caused a significant decrease in sulfhydryls of bone marrow cells but no changes in bone marrow cellularity and peripheral blood parameters compared with controls. At a dose of 25 mg/kg/day for 4 days, there was a significant decrease in nucleated bone marrow cells. The white blood cell count, mainly lymphocytes, also significantly decreased. Our results indicate that CHO-M-OH is a hematotoxin in mice and conceivably could play a role in benzene toxicity.

Aldehydes↗
PubMed1995

Immunohistochemical detection of oncogene proteins and neuroendocrine differentiation in different stages of prostate cancer.

The progression of prostatic adenocarcinoma from localized disease to metastatic carcinoma appears to be a multi-step sequence. The expression of common oncogenes/oncosuppressor genes and the mediating effect of neuroendocrine tumor cells may play a role in this progression. The expression of the more frequently investigated oncogenes/oncosuppressor genes (p53, c-myc, c-erbB-2, bcl-2) and the presence of neuroendocrine cells were assessed in prostatic cancer tissue from patients with localized and metastatic cancer. These oncogenes/oncosuppressor genes were evaluated according to tumor stage and grade and their relationship to one another. Grade was not related to any of the oncogene markers or to the presence of neuroendocrine cells. Advancing stage was associated with a significant increase in p53 expression, while other markers remained constant in all stages. Neuroendocrine cells, p53, c-myc, c-erbB-2 and bcl-2 were rarely co-expressed at any stage of prostate cancer.

Carcinoma↗
PubMed1995

Schistosomiasis and prostate cancer.

In endemic geographical areas schistosomiasis has been implicated as an etiological agent in the pathogenesis of bladder, colorectal and renal carcinoma. In particular bladder cancer commonly occurs in such geographic locations almost 2 decades earlier than in non-endemic areas. A relationship between prostate cancer and bilharzial infestation is not established. This is a report of 3 cases of co-existent schistosomiasis and prostatic adenocarcinoma occurring in unusually young patients.

Adenocarcinoma↗
PubMed1995

Botryomycosis of the liver.

A case of visceral botryomycosis of the liver in a 50-year-old man is reported. The clinical diagnosis was hepatocellular carcinoma. Pathological examination of the surgically resected specimen demonstrated microabscesses containing gram- positive microorganisms with surrounding fibrosis replacing liver parenchyma. An immune deficiency state was not demonstrated. Recognition of this condition is important because of its clinical confusion with malignancy and its histological similarity to actinomycosis, nocardia, and eumycotic infections.

Carcinoma, Hepatocellular↗
PubMed1995

Rheumatic Aschoff nodules revisited: an immunohistological reappraisal of the cellular component.

Rheumatic fever is still the leading cause of acquired heart disease in children and young adults in developing countries. Recent reports have documented a rising incidence of rheumatic fever in both the USA and Europe. The disease is characterized by specific lesions in the heart muscle and valves called Aschoff nodules. The Aschoff nodule has been neglected in the last few decades as most of the studies were conducted in the 1960s on autopsy tissues. This study examines Aschoff nodules using heart valve material obtained at valve surgery with updated commercially available immunohistochemical antibodies to determine the phenotypic characteristics of the cells involved in the formation of these lesions. Fifteen cases of rheumatic valvulitis, as indicated by the presence of Aschoff nodules, were examined. The Anitschkow and Aschoff cells stained prominently with macrophage markers. Three stages of nodules with Aschoff and Anitschkow cells were identified: stage 1, central fibrinoid necrosis without lymphocytes, stage 2 with occasional T lymphocytes (< 10) and stage 3 with lymphoid aggregates containing both T- and B-lymphocytes (with occasional admixed macrophages). We propose that the stage 1 lesion is the earliest granulomatous stage with the lymphoid aggregates being a later stage in the development of Aschoff nodules. The Aschoff and Anitschkow cells demonstrated mitotic activity and stained with antibodies to the proliferation cell nuclear antigen (PCNA) suggesting that the multinucleated giant cells may be formed, at least partially, by nuclear division rather than fusion.

Biomarkers↗