Oral tolerance in experimental autoimmune encephalomyelitis: specificity of peptide-induced oral tolerance.
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Administration, Oral↗
Biomedical subjects
K Cox
Publications and source records attributed to K Cox.
Oral tolerance in myelin basic protein TCR transgenic mice.
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Administration, Oral↗
Organisational audit. A plaudit for audit.
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England↗
Elevated germ cell markers in carcinoma of uncertain primary site do not predict response to platinum based chemotherapy.
We carried out a retrospective review of the medical records of patients with metastatic carcinoma of unknown primary and either raised alpha fetoprotein (AFP) or beta human chorionic gonadotrophin (beta HCG) over a period of 6 years at three teaching hospital oncology units to assess response to platinum based chemotherapy. 15 patients were identified who fitted these criteria. Of these, 3 received no treatment because of poor functional status, 2 patients received only radiotherapy for symptomatic disease and died within 3 months of diagnosis and 1 patient died 2 weeks after diagnosis having received his first cycle of cisplatin-based chemotherapy. 9 patients received at least 2 cycles of chemotherapy. A complete tumour response was seen in only one patient who presented with midline lymphadenopathy and remains disease-free 46 months after treatment. This presentation was consistent with disease already known to herald platinum sensitivity. In the other 8 patients, there was only one partial response that lasted 2 months. The median survival for this group of 9 patients was 4.5 months (range 3 to > 46 months). Our data do not support the postulate that elevated germ cell markers in patients with carcinoma of unknown primary predict a response to cisplatin based chemotherapy.
Adult↗
Psychosocial aspects of participation in early anticancer drug trials. Report of a pilot study.
Despite improvements in the treatment of many cancers, the need for effective new therapies is as great as ever. However, evaluating new drug treatments for cancer in clinical practice raises complex problems. Early trials of new drugs offer little in the way of therapeutic benefit, since their main aim is to identify toxic effects of the drug and subsequent doses for testing. The ethical and practical problems that these trials raise have received some attention in the literature. The main focus of previous studies has been the process of informed consent for trial participation, which has tended to reflect the perspective of the clinicians involved. Little attention has been given to patients' views in this context, and still less work has explored the total experience of clinical trial participation. In order to address these gaps in the literature, a research study was developed to explore the psychosocial aspects of participation in early anticancer drug trials from the perspective of the patient. This article reports the findings of a pilot study. The pilot study obtained the views of seven patients as they progressed through an anticancer drug trial. The informed consent process, the reasons behind decision-making concerning trial participation, and the impact of participation on the lives of the patients were explored, along with changing needs for information, care, and support as the trial progressed. Findings identify psychosocial aspects of clinical trial participation related to information, decision-making, and support from the perspective of those actually taking part.
Aged↗
Ethical and practical problems of early anti-cancer drug trials: a review of the literature.
Early clinical trials for new anti-cancer drug treatments typically use patients with cancer as research subjects. This paper identifies some of the ethical and practical concerns that arise from the recruitment of a vulnerable group of patients and their exposure to a drug of unknown risk or benefit. This review discusses the ethical principles related to recruitment and informed consent in cancer trials, and indicates that there is a lack of consensus concerning the requirements, process and practice of informed consent. It is suggested that, as yet, little is known about patients' decision making framework in this situation, and the need for further work that concentrates on the patient's point of view is highlighted. The paper concludes by discussing some of the difficulties associated with obtaining patients' opinions, and suggests that the use of a qualitative approach may overcome some of these problems.
Antineoplastic Agents↗
Teaching and learning clinical perception.
A central task in clinical teaching is organization of the students' experience in clinical perception--the ability to observe, to recognize, to discriminate and to interpret clinical evidence. We cannot teach sensory perceptual experience. Students must experience the clinical phenomena for themselves. But we can ensure that what the student experiences is most likely to be turned into clinical learning. This paper dissects the learning task in order to derive plans for teaching clinical perception. A major purpose is to encourage closer study of physical examination, which has largely been upstaged by investigations. Students learn inductively from their experiences of examining patients, cumulating a 'clinical memory' of images of patients with diseases. Reflection on that experience with the clinical teacher translates the sensory evidence into words. Teachers link the clinical observations of 'disease in patients' with previously learned images of 'diseases in organs', to ensure that clinical features and underlying basic science knowledge are clearly integrated. Perception is an active process, not a passive reception of observational data. Learning and teaching clinical perception uses both the student's direct 'sense' experiences and the teacher's guidance in 'making sense' of them.
Australia↗
The fibrinolytic system is not impaired in older men with hypertension.
The fibrinolytic system is thought to be impaired in older hypertensive adults, thus contributing to the elevated risk of atherothrombosis, stroke, and acute myocardial infarction in this population. However, studies that have examined the fibrinolytic system in hypertensive individuals have failed to control for the confounding effects of other metabolic risk factors, making it difficult for one to determine the independent effect of hypertension on the fibrinolytic system. The purpose of the present study was to test the hypothesis that the fibrinolytic system is not impaired in older sedentary hypertensive men when the confounding effects of cardiovascular disease, diabetes, and dyslipidemia are controlled. Plasma concentrations of tissue-type plasminogen activator antigen and activity as well as plasminogen activator inhibitor-1 antigen and activity were measured under resting conditions in 12 hypertensive (69.4 +/- 1.4 years) and 11 normotensive 65.2 +/- 1.3 years) older men. The hypertensive and normotensive subjects had similar anthropometric and metabolic characteristics. There were no significant differences between the hypertensive and normotensive men in tissue-type plasminogen antigen (7.3 +/- 0.5 versus 6.1 +/- 0.6 ng/mL) and activity (1.8 +/- 0.3 versus 1.7 +/- 0.2 IU/mL) or plasminogen activator inhibitor-1 antigen (14.1 +/- 2.3 versus 10.8 +/- 2.2 ng/mL) and activity (17.4 +/- 1.2 versus 17.5 +/- 1.8 arbitrary units [AU]/mL) levels. In addition, the molar concentration ratio of active tissue type plasminogen activator to active plasminogen activator inhibitor-1 did not differ between the hypertensive (1:9.7 +/- 2.3) mmol/L) and normotensive (1:10.5 +/- 2.2 mmol/L) subjects, indicative of no impairment in fibrinolytic potential in either group. These results support the hypothesis that hypertension does not directly result in impaired fibrinolytic function in older adults. Furthermore, our findings suggest that abnormalities in fibrinolytic function in older hypertensive men are likely due to the primary effects of other metabolic disorders that usually accompany hypertension, such as hyperinsulinemia and dyslipidemia.
Aged↗
The effects of aging on the bone inductive activity of recombinant human bone morphogenetic protein-2.
We examined the effects of gain on the ectopic bone-forming ability of recombinant human BMP-2 (rhBMP-2) in rats and investigated the mechanism by which aging might affect this type of bone. Bone formation induced after 12 days of sc implantation of 5 micrograms rhBMP-2 was reduced as animals aged from 1-16 months. The osteocalcin messenger RNA levels of implants also declined in aging animals. When the implant period was doubled, 16-month-old rats formed amounts of bone equivalent to those in 3-month-old rats. Increasing the dose of rhBMP-2 increased bone formation in older rats. To get a response comparable to that seen in 1-month-old rats given 5 micrograms rhBMP-2 for 12 days, 3-month-old rats required 30 micrograms rhBMP-2, whereas 16-month-old rats required 60 micrograms. Treatment with either GH or 1,25-dihydroxyvitamin D3 during the 12-day implantation period returned the bone formation in 16-month-olds rats to that in 3-month-old rats. These studies show that aging blunts rhBMP-2 inducted bone formation in rats. We speculate that the decreased response may be due in part to a decrease in the number of mesenchymal stem cells present in order rats or to a change in the responsiveness of these target cells to rhBMP-2.
Aging↗
Recombinant human bone morphogenetic protein-2 induces a hematopoietic microenvironment in the rat that supports the growth of stem cells.
In the mammalian bone marrow, stromal components support the growth and differentiation of blood cells. To study this complex system, we used a rat model in which ectopic hematopoietic tissue was induced to form after subcutaneous implantation of recombinant human bone morphogenetic protein (rhBMP-2). We showed that this organoid contained clonogenic precursors of both erythroid and myeloid lineages and progenitors competent to regenerate splenic lymphopoiesis. Furthermore, stem cells derived from ectopic foci conferred both short-term (30 day) and long-term (>6-month) protection in vivo against radiation-induced marrow aplasia. Lead shielding of the ectopic marrow in situ also permitted endogenous recovery of hematopoiesis after sublethal irradiation. Extending previous observations that most fibroblastoid cells of the marrow stain with the anti-ST3 antibody (but minimally with anti-ST4), whereas those growing from nonhematopoietic tissues react with anti-ST4, we found that analogous cells of the ectopic foci stained predominantly with anti-ST3. The ability to induce formation of a hematopoietic microenvironment from mesenchymal precursors may make possible the development of new strategies for the treatment of primary disorders of stem cells and irreversible stromal injury.
Animals↗
The effects of intravenous lidocaine in the prevention of postoperative sore throat.
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Adult↗
Centrifugal projections upon the retina: an anterograde tracing study in the pigeon (Columba livia).
Previous work has shown that the avian retina receives two types of centrifugal fibers from the brain. These types can be distinguished based on the size and the morphology of their terminal endings and have been termed convergent and divergent. The centrifugal fibers arise from the isthmooptic nucleus (ION) and the surrounding ectopic cell region (ECR). We used injections of anterograde tracers either to the ION/ECR or to the ECR only to determine the morphology, depth of termination, and regional distribution of the centrifugal fibers arising from each. We found that the ECR gives rise only to the divergent type of the centrifugal fiber, whereas the ION gives rise mainly to the convergent type but may also send some fibers of the divergent type. Most of the fibers project contralaterally, although a few from the ECR project ipsilaterally. The terminals of either type are not uniformly distributed throughout the retina; instead, they are found mainly in the inferior, midtemporal, to nasal portion of the retina and appear to avoid the fovea and most of the red field. By comparison, the ION receives a major projection from portions of the tectum that receive input from the fovea and the red field in a type of neural loop. The neural loop does not project to the same point (homotopic), but projects from the red field to the inferior retina (heterotopic), as was recently proposed by Holden (1990; Vis. Neurosci. 4:493-497). The distribution of centrifugal axons corresponds to displaced ganglion cells that selectively innervate the nuclei of the accessory optic system (AOS), including the nucleus of the basal optic root (dorsal, ventral, and lateral) and the nucleus lentiformis mesencephali, pars magnocellularis. We suggest that the centrifugal axons act by increasing the gain on the AOS, thereby enhancing retinal stabilization of gaze with improved accuracy of pecking of small objects.
Animals↗
Bicyclomycin and dihydrobicyclomycin inhibition kinetics of Escherichia coli rho-dependent transcription termination factor ATPase activity.
The primary site of action for the novel antibiotic, bicyclomycin, in Escherichia coli has been identified to be the rho transcription termination factor. The inhibition of rho poly(C)-stimulated hydrolysis of ATP by bicyclomycin has been found to proceed by a non-competitive, reversible pathway with respect to ATP (Ki = 20 microM). Inhibition by dihydrobicyclomycin was similar (Ki = 75 microM). No change in the inhibitory properties of the antibiotic was observed under the assay conditions with the two rho mutants, Cys202Gly and Cys202Ser, indicating that Cys-202 does not affect drug binding to rho. Prolonged incubation (32 degrees C, 12 h) of wild-type rho with bicyclomycin (20 mM) led to protein degradation and a slow, permanent loss of rho ATPase activity after dialysis. Evidence was obtained that trace amounts of proteases present with bicyclomycin were responsible for the observed protein degradation. Treatment of wild-type and mutant rho proteins with purified bicyclomycin (25 mM) led to approximately 80% loss of ATPase activity after dialysis with no apparent loss of protein. However, a reduction of the electrophoretic mobility of the bicyclomycin-treated rho versus wild-type rho was seen. Addition of either ATP or poly(C) to wild-type rho led to partial protection against bicyclomycin inactivation, while inclusion of both ligands provided near complete protection against inactivation. The observed loss of ATPase activity upon prolonged incubation of rho with excess purified bicyclomycin is attributed to the covalent modification of the protein by the antibiotic at multiple sites.
Adenosine Triphosphatases↗
A reassessment of ABO incompatibility in pediatric liver transplantation.
The present study examined 144 pediatric liver transplants to determine the impact of ABO matching on liver allograft outcome. Pediatric transplants were divided into 3 groups: ABO identical (ABO-Id; n = 108), ABO-compatible nonidentical (ABO-Comp; n = 22), and ABO incompatible (ABO-Inc; n = 14). A higher proportion of United Network for Organ Sharing status 4 recipients in the ABO-Comp group (50% vs. 22% and 36% for ABO-Id and ABO-Inc, P < 0.05) and less time spent on the waiting list for ABO-Inc recipients (46 +/- 12 vs. 87 +/- 11 and 61 +/- 20 days for ABO-Id and ABO-Comp, P < 0.01) were noted. OKT3 induction therapy was greater in ABO-Inc grafts (57% vs. 19% and 14% for ABO-Id and ABO-Comp, P < 0.05), as was incidence of acute cellular rejection (79% vs. 59% and 41% for ABO-Id and ABO-Comp, P = 0.08). One- and 3-year patient survival rates were 87% and 83% in the ABO-Id group, 95% and 88% in the ABO-Comp group, and 79% and 79% in the ABO-Inc group (P = NS). One- and 3-year graft survival rates were 83% and 78% in the ABO-Id group, 87% and 80% in the ABO-Comp group, and 71% and 71% in the ABO-Inc group (P = NS). ABO-Inc transplantations can be performed successfully in pediatric recipients and warrant a reassessment of the utilization of ABO-Inc livers.
ABO Blood-Group System↗
Intratelencephalic projections of the visual wulst in pigeons (Columba livia).
The visual wulst is the telencephalic target of the thalamofugal visual pathway of birds, and thus the avian equivalent of the striate cortex of mammals. The anterograde tracer Phaseolus vulgaris leucoagglutinin was used to follow the intratelencephalic connections of the major constituents of the visual wulst in pigeons. In particular, efferent pathways from the granular layer (Intercalated nucleus of the hyperstriatum accessorium, IHA), supragranular layer (hyperstriatum accessorium, HA), and infragranular layers (hyperstriatum intercalatus superior and/or hyperstriatum dorsale, HIS/HD) were investigated. These efferent projections were confirmed by injections of the retrograde tracer cholera toxin subunit B into their terminal fields. When a deposit of the anterograde tracer was centered in IHA, which receives the visual thalamic input, efferent fibers were seen mainly dorsomedially to IHA. When a deposit of the anterograde tracer was centered in HA, efferent fibers were seen to extend mainly in three directions: 1) medially to the tractus septomesencephalicus, which sends projections to extratelencephalic visual nuclei: 2) ventrolaterally to the lateral portion of the neostriatum frontale, where there were also labeled cells after the retrograde tracer was injected in HA; and 3) ventromedially to the paleostriatal complex, which is the avian equivalent of the mammalian caudale, 5) neostriatum intermedium, 6) archistriatum intermedium, and 7) hyperstriatum laterale. Finally, HIS/HD have projections predominantly to HA and the dorsocaudal telencephalon (area corticoidea dorsolateralis and area parahippocampalis), as well as relatively minor projections to the areas which also receive projections from HA. No anterogradely labeled fibers were seen in the tractus septomesencephalicus following the tracer injections in HIS/HD. These results indicate that the visual information from the granular layer is distributed via the supragranular layer HA to multiple areas within the telencephalon, such as the neostriatum frontale and paleostriatal complex. In addition, HA is the source of an extratelencephalic projection via the tractus septomesencephalicus. Thus, the avian supragranular layer HA contains neurons which are the source of both intratelencephalic and extratelencephalic projections, whereas neurons of the mammalian cortex are segregated into two distinct layers, supragranular and infragranular layers, based on the targets of their projections. The findings are further discussed and compared to the mammalian striate cortex.
Animals↗
Isolated alkaline phosphatemia following pediatric liver transplantation in the FK506 ERA.
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Adolescent↗
Differential patterns of circulating intercellular adhesion molecule-1 (cICAM-1) and vascular cell adhesion molecule-1 (cVCAM-1) during liver allograft rejection.
During allograft rejection, adhesion molecules play an integral role in infiltration, activation, and binding of effector cells to target tissue. Some adhesion molecules, including ICAM-1 and VCAM-1, exist in soluble, circulating forms that retain ligand-binding activity. In the present study the levels of circulating ICAM-1 (cICAM-1) and VCAM-1 (cVCAM-1) were compared in the serum and bile of pediatric liver recipients. The cICAM-1 was significantly elevated in the serum during allograft rejection and infection relative to periods when no rejection was apparent. Biliary cICAM-1, however, was specifically elevated during rejection and not during infection or when no rejection was apparent. The cVCAM-1 levels were elevated in the serum during rejection compared with levels when no rejection was evident. In contrast, cVCAM-1 was not detected in the bile. Serum levels of both cICAM-1 and cVCAM-1 decreased rapidly following successful treatment for rejection, whereas elevated levels persisted, or increased, in ongoing rejection. The differential patterns of the circulating forms of ICAM-1 and cVCAM-1 were consistent with the membrane expression of these molecules during graft rejection. ICAM-1 expression was extensive on bile duct epithelium, endothelium, hepatocytes, and infiltrating leukocytes during rejection, while VCAM-1 was restricted to endothelium. These findings indicate that the release of circulating adhesion molecules is a prominent feature of liver allograft rejection. Measurement of these markers may be useful in distinguishing rejection from infection and in determining the efficacy of treatment for rejection.
Adolescent↗
Viral and immunologic aspects of Epstein-Barr virus infection in pediatric liver transplant recipients.
Pediatric allograft recipients in particular are at increased risk for Epstein-Barr virus (EBV)-associated disorders. Early identification and diagnosis of EBV-associated disorders is critical, since disease progression can often be halted by reduction of immunosuppression. In this study we examined viral and immunologic parameters of EBV infection in the circulation of pediatric liver recipients to identify factors associated with disease. Peripheral blood DNA from pediatric liver recipients was analyzed by PCR for the EBV genes coding for the nuclear antigen 1 (EBNA-1) and the viral capsid antigen gp220. Sequences for these viral genes could be readily detected in the circulation of 36.5% of patients. Moreover, identification of the EBV genome was associated with symptomatic infection, suggesting that circulating EBV may be a useful marker of disease. Since EBV-infected B cells release the low-affinity IgE receptor (sCD23), we measured sCD23 in the circulation of pediatric liver recipients and found it to be elevated in patients with detectable virus or symptoms of infection. However, sCD23 was also elevated in cases where no EBV was detectable, suggesting that factors other than viral infection could stimulate release of sCD23. To further characterize the immune response to EBV infection, the peripheral levels of IL-4, IL-5, IL-10, and IFN-gamma were determined in pediatric liver recipients. Each of these cytokines was elevated in patients with symptoms or circulating virus compared with stable, age-matched liver recipients. IL-4, in particular, was significantly increased, indicating an important role for this cytokine in EBV infection. Together, these findings suggest that (1) monitoring circulating levels of EBV may be useful in patients at high risk and (2) cytokines that promote B cell growth and differentiation contribute to EBV-associated disorders.
Adolescent↗