Biomedical subjects
Publications and source records attributed to D B Jones.
Corneal subepithelial infiltration resembling adenoviral keratitis developed in two patients with serologic evidence of systemic Epstein-Barr viral (EBV) infection and nondetectable antibody levels for adenovirus (ADV). These cases suggest that EBV is capable of mimicking more commonly recognized corneal infectious disease entities.
A previous study of the patterns of visual evoked responses (VERs) in rats was interpreted as providing support for the synergistic neurotoxins hypothesis of the pathogenesis of hepatic encephalopathy (HE) due to fulminant hepatic failure (FHF). In contrast, other studies of the patterns of VERs in rabbits with different encephalopathies were interpreted as providing support for the concept that increased GABA-ergic tone may contribute to the neural inhibition of HE due to FHF. To attempt to resolve the discordant findings in these studies, additional studies of VERs have been undertaken in rats. To induce increased tissue levels of ammonia, mercaptans and fatty acids which are found in HE due to FHF, carefully predetermined doses of urease, dimethyldisulphide and octanoic acid were administered. The (pre-seizure) encephalopathy induced by these three agents was associated with abnormalities of the VER waveform that were fundamentally different from the abnormalities of the VER waveform associated with HE due to thioacetamide-induced FHF. However, the VER waveform in this model of HE due to FHF resembled closely that associated with pentobarbital-induced encephalopathy. These findings are in satisfactory agreement with those in the previous analogous studies in rabbits. They do not provide support for the synergistic neurotoxins hypothesis of the pathogenesis of HE, but are entirely consistent with increased GABA-ergic tone contributing to the neural inhibition of HE due to FHF.
The proliferation rate of non-Hodgkin's lymphomas (NHL) was estimated by using 3 different methods. In cell suspension we determined the proportion of cells in cycle with the monoclonal antibody (Mab) Ki-67 and also in S-phase after the incorporation of bromo-deoxyuridine (BrdU) utilizing Mab anti-BrdU. In low grade lymphomas 3.5 +/- 1.6% of the cells were in cycle and 1.2 +/- 0.9% in S-phase, the corresponding values for high grade lymphomas were 22.5 +/- 18.7% and 8.9 +/- 7.8% respectively. Frozen sections of NHL were reacted with an antibody to the transferrin receptor (TR) and Ki67 as markers for proliferative activity. A high number of TR positive cells was found in low grade lymphomas of all histological types, whereas Ki67 positivity correlated closely with grading. With a few exceptions, low grade lymphomas contained less than 25% Ki67 positive cells within the tumour cell population. This observation is relevant to treatment strategies for low grade NHL.
Intestinal permeability in controls and in patients with active rheumatoid arthritis was assessed by measuring the radioactivity in 24-h urine collections after oral administration of 51Cr-EDTA. Intestinal permeability in the patients was found to be significantly increased in comparison to controls. Of the patients, 6/7 (86%) not taking any prescribed nonsteroidal anti-inflammatory drug (NSAID) at the time of study had normal results, whereas 23/29 patients (79%) taking prescribed NSAIDs displayed increased intestinal permeability. It has not been determined beyond doubt whether this finding is due to disease process or therapy with oral NSAIDs.
Sepsis is occasionally accompanied by jaundice which is marked by an intrahepatic cholestasis and scant hepatocyte necrosis. The pathogenesis is unknown. The bile fistula rat was used in this study to investigate the possibility that intrahepatic cholestasis is one of the many systemic effects of the major endogenous pyrogen, interleukin-1. The effect of acute administration of endotoxin, interleukin-2 and recombinant rat interferon gamma on biliary secretion and biliary transport mechanisms was also studied. Basal bile flow, peak bile flow and peak sodium taurocholate output were measured after 1 h in all cases, except with recombinant rat interferon gamma where the time interval was 3 h. Endotoxin significantly reduced basal and sodium taurocholate-stimulated bile flow, as well as sodium taurocholate secretion. No such effect was noted after acute administration of any of these lymphokines or chronic administration of interleukin-1. The cholestasis induced by endotoxin administration is not mediated by interleukin-1, interleukin-2 or recombinant interferon gamma.
FVMany different dosage schedules of antisecretory drugs for the treatment of duodenal ulcer are recommended. The relationship between degree of acid suppression and therapeutic efficacy has not been precisely defined for these drugs. We have examined the association between suppression of intragastric acidity and duodenal ulcer healing rates for a number of therapeutic regimens. For the H2 receptor antagonists alone, the most significant correlation with healing rates was with suppression of intragastric acidity at night (r = 0.926; p = 0.0001). When other classes of drug: high dose antacid, omeprazole and a synthetic prostaglandin (enprostil) were included in the analysis, the closest correlation was with suppression of total 24 hour intragastric acidity (r = 0.911; p less than F0.0001). Stepwise linear regression analysis was used to investigate the relative contributions to healing of suppression of acidity during the day and night. Suppression of nocturnal acidity was found to be the single most important factor in explaining healing rates. No further benefit was obtained with daytime suppression for H2 receptor antagonists; suppression of acidity at night accounted for 86.1% of the observed variation in healing rates among different regimens of H2 receptor antagonists. When all classes of drugs were analysed, inclusion of daytime suppression produced a significant improvement in correlation over nocturnal suppression alone. Drug regimens providing potent suppression of nocturnal acidity produce the highest healing rates in controlled clinical trials. The healing rate for any dose regimen of an antisecretory drug can be predicted from a knowledge of its effect on intragastric acidity. For the H2 receptor antagonists, suppression of nocturnal acidity is the most relevant in this context. Moderate suppression of acidity achieves ulcer healing rates at four to eight weeks which are comparable with those seen with potent suppression at two to four weeks. Increasing degrees of suppression merely accelerate healing.
The value of DNA hybridisation (using immunoglobulin and T cell receptor gene probes) was assessed during the diagnosis of problematical lymphoid tissue biopsy specimens. In 14 of 18 specimens (78%), which contained a malignant lymphoproliferation of uncertain aetiology, this technique permitted the demonstration of a monoclonal proliferation of B cells (nine cases) or T cells (five cases). In five further lymph node biopsy specimens, in which the differential diagnosis lay between a reactive or malignant process, a clonal proliferation was shown in three cases. DNA analysis is, therefore, of practical value in resolving many of the diagnostic problems that arise in the assessment of lymphoid tissue biopsy specimens.
A mouse monoclonal antibody (MAC 387) with specificity for monocytes and tissue histiocytes was produced by immunization of a BALB/c mouse with peripheral blood monocyte components derived by affinity chromatography of detergent-solubilized monocyte material on Sepharose 4B coupled to rabbit anti-monocyte antibodies. MAC 387 strongly stained the cytoplasm of cells of the monocyte/macrophage series on paraffin sections after controlled trypsinization of sections. The antibody showed broad reactivity for a variety of tissue histiocytes, including infiltrating and reactive histiocytes, alveolar macrophages, Kupffer cells, follicle-center macrophages, splenic red pulp macrophages, tumor-infiltrating macrophages, sinus histiocytes, epithelioid giant cells (variably), and cases of histiocytosis X and dermatopathic lymphadenopathy. Molecular weight data obtained by Western blotting, immunoprecipitation, and immunoaffinity-purification revealed that the antigen was present in different forms in the monocyte and granulocyte. In the granulocyte, free alpha (Mr 12 KD) and beta (Mr 14 KD) chains expressing the MAC 387 epitope were found together with associations of one alpha and one beta chain linked by disulfide bonds to yield a heterodimer of Mr 26 KD. In the monocyte, free alpha and beta chains are not found, but instead the heterodimer and associations of two (Mr 56 KD) and four (Mr 112 KD) heterodimers are disulfide-linked together. This new monoclonal reagent should have particular value for identification of tissue histiocytes in routine paraffin sections and particularly for demonstration of histiocytes in malignant lymphomas.
Eighteen hirsute women (8 with polycystic ovarian syndrome, 10 with idiopathic hirsutism) were treated for up to 12 months with cyproterone acetate, 150 mg daily, and ethinyl oestradiol, 50 micrograms on days 5-25 of the menstrual cycle. Hair growth rate and density were measured from standardized serial photographs of a shaved skin area. A significant reduction was seen in mean hair growth rate, total plasma testosterone, free testosterone index, plasma dehydroepiandrosterone, and plasma androstenedione. LH and FSH also fell and sex hormone binding globulin level increased. No significant changes occurred in hair density or in serum PRL levels. A significant correlation was observed between hair growth rate and total plasma testosterone for the pooled results (r = 0.35, P less than 0.005). No significant correlations were seen between hair density and the endocrine parameters studied.
The possible involvement of the lipoxygenase pathway of arachidonic acid metabolism in the events which take place during ACTH-induced stimulation of corticosterone secretion has been studied using an isolated rat adrenal cell system. Incubation with arachidonic acid resulted in an inhibition of ACTH-stimulated corticosterone production. The lipoxygenase pathway inhibitors nordihydroguaretic acid (NDGA), eicosatetraynoic acid (ETYA) and compound BW755C also produced inhibition of ACTH-stimulated corticosterone synthesis. The concentrations of the inhibitors at which 50% inhibition occurred were 15, 34 and 37 mumol/l respectively. The inhibitions produced by NDGA and ETYA were independent of cyclic AMP output. NDGA also inhibited corticosterone production induced by dibutyryl cyclic AMP but had no effect on corticosterone synthesis induced by pregnenolone. Preincubation of adrenal cells with the lipoxygenase products 5, 12 and 15 hydroxyeicosatetraenoic acid (HETE) and with leukotrienes A4, B4, C4, D4 and E4 resulted in significant inhibitions of corticosterone production in response to ACTH with leukotriene A4 (LTA4) and with 15HETE and 5HETE. Conversely, incubation with glutathione (GSH), which is known to reduce intracellular LTA4 levels, produced stimulation (at 5 mmol GSH/l) and inhibition (at 50 mmol GSH/l) of corticosterone output. These studies suggest that the lipoxygenase pathway may be involved in ACTH-stimulated corticosterone synthesis.
We have studied certain aspects of the natural history of acute herpes zoster ophthalmicus in placebo-treated patients followed prospectively over one year as part of a therapeutic drug trial. Observations on the incidence of ocular complications relating to the efficacy of oral acyclovir in this disease have been previously published. This report provides supplemental observations on the natural history of frequently observed ocular complications of zoster ophthalmicus: corneal hypesthesia, episcleritis, dendritiform keratopathy, stromal keratitis, anterior uveitis, and post herpetic neuralgia. These ocular complications of zoster typically present within the first two weeks of the diagnosis. This report characterizes the onset of corneal hypesthesia, episcleritis, dendritiform keratopathy, stromal keratitis, and anterior uveitis as well as interrelationships amongst these sequellae of herpes zoster ophthalmicus. Post-herpetic neuralgia occurs in 52% of patients and persists beyond a year in 22% of those affected.
Primary hepatocellular carcinoma (HCC) is an important cause of death in patients with chronic liver disease and in carriers of hepatitis B virus. Because of its relative frequency in certain geographic areas, such as Asia and sub-Saharan Africa, mass screening programs have been instituted to implement secondary prevention. It is believed that early diagnosis provides the best chance of successful surgical resection and hopefully prolonged survival. Although a number of serological and imaging tests are available, the most cost-effective modality is serum alphafetoprotein (AFP) and real-time ultrasound (USS) used together. The current recommendation is recognition of high-risk groups (cirrhosis, chronic active hepatitis, and chronic hepatitis B carriers) and provision of AFP and USS testing at 3 to 6 months intervals, with recourse to fine-needle aspiration biopsy and celiac angiography for individuals who test positive with either test.
Intestinal permeability in adults with inflammatory gastrointestinal diseases was investigated by measuring the 24-h urinary excretion of orally administered 51Cr-EDTA. Eighty controls along with 100 patients with Crohn's disease, 46 patients with ulcerative colitis, 20 patients with gluten-sensitive enteropathy, and 18 patients with other diseases were studied. In controls, the median 24-h excretion was 1.34%/24 h of the oral dose. Patients with Crohn's disease (median 2.96%/24 h), ulcerative colitis (median 2.12%/24 h), and untreated gluten-sensitive enteropathy (median 3.56%/24 h) had significantly elevated urinary excretion of the probe compared to controls (p less than 0.0001). Increased 24-h urinary excretion of 51Cr-EDTA had a high association with intestinal inflammation (p less than 0.0001). Test specificity and sensitivity were 96% and 57%, respectively. A positive test has a 96% probability of correctly diagnosing the presence of intestinal inflammation, whereas a negative test has a 50% probability of predicting the absence of disease.
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Ten (17%) of 58 patients with chronic viral hepatitis treated with a four- to 12-month course of recombinant human interferon alfa developed psychiatric side effects. The psychiatric side effects fell into three categories: an organic personality syndrome characterized by irritability and short temper; an organic affective syndrome marked by extreme emotional lability, depression, and tearfulness; and a delirium marked by clouding of consciousness, agitation, paranoia, and suicidal potential. These psychiatric side effects appeared after one to three months of therapy, usually improved within three to four days of decreasing the dose of interferon alfa, and invariably resolved once therapy was stopped. The organic personality and affective syndromes tended to occur in patients who received the highest dose of interferon alfa, who had relatively mild hepatitis, and who lost weight during interferon treatment. Delirium tended to occur in patients with severe hepatitis who had previous evidence of organic brain injury or dysfunction or previous drug and alcohol abuse. Failure to recognize these side effects quickly and to treat them with supportive therapy and modification of the dose of interferon alfa could result in limitation of therapy and serious personal and interpersonal consequences.
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The role of the transferrin receptor and of cell proliferation during human renal embryogenesis has been studied by using immunocytochemical techniques. Tissue sections of human fetal kidneys have been stained using monoclonal antibodies to the cell surface transferrin receptor (HB21) and the nuclear proliferation antigen (Ki67). Both antigens appear during nephron induction, are strongly expressed during the early stages of renal tubulogenesis, but are lost with progressive maturation. Simultaneous changes in the intermediate filament phenotype at this developmental stage have also been demonstrated by the use of monoclonal antibodies to vimentin and low molecular weight cytokeratin. This study provides immunocytochemical evidence that in the human kidney, as in in vitro development of the mouse kidney, one of the early events in tubule induction involves transferrin-dependent proliferation.