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Biomedical subjects

A Miller

Publications and source records attributed to A Miller.

At least 289 records · Page 16Linked to original sources
PubMed1993

Epitopes of myelin basic protein that trigger TGF-beta release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression.

We have been studying the suppression of experimental autoimmune encephalomyelitis in the Lewis rat after oral administration of myelin basic protein (MBP). Suppression is mediated by CD8+ T cells that adoptively transfer protection and suppress immune responses in vitro. This suppression is mediated by secretion of TGF-beta following triggering by the fed antigen. In the present study, we tested the ability of overlapping 20 amino acid peptides from MBP to trigger suppression mediated by spleen cells from Lewis rats orally tolerized to MBP. Using a transwell system, we found that spleen cells from MBP orally tolerized animals stimulated by residues 21-40, 51-70 and 101-120 of MBP suppress proliferative responses of an ovalbumin specific cell line. This suppression correlated with secretion of TGF-beta by cells stimulated with the peptide. In addition, T cells from animals fed the tolerogenic peptide 21-40 alone secreted TGF-beta whereas no TGF-beta release or in vitro suppression was observed in animals fed the MBP encephalitogenic determinant 71-90. The 71-90 peptide triggered proliferation of MBP primed cells from animals immunized with MBP/CFA whereas the suppressor epitopes identified above did not. Furthermore, oral administration of peptide 21-40 suppressed disease induced by peptide 71-90. DTH responses to 71-90 were not affected by oral administration of peptide 21-40 whereas DTH responses to whole MBP were suppressed. These results demonstrate that distinct suppressor determinants exist on MBP which are separate from encephalitogenic determinants, and that epitope-driven bystander suppression plays an important role in down-regulation of tissue specific autoimmune processes following oral tolerization. These findings have important implications for the design of tissue specific targeted immunotherapy by oral tolerization in humans.

Administration, Oral↗
PubMed1993

Acid stabilization of insulin.

The effect of pH on the conformational stability of insulin was studied. Surprisingly, the Gibbs free energy of unfolding increased approximately 30% by acidification. pH titration of insulin's conformational stability is described by a transition involving a single proton with an apparent pK(a) of 7.0. The acid stabilization of insulin's conformation was attributed to the protonation of histidine at position 5 on the B-chain (HB5) as determined by 1H-NMR of the histidines, selective amino acid alteration, and enthalpies of ionization. Further acidification (at least to pH 2) does not decrease the free energy of unfolding. A conformational change in the tertiary structure, as indicated by the near-UV circular dichroism spectrum, accompanies this change in stability. We propose that this acid stabilization of insulin is physiologically important in maintaining insulin stability in the acid environment of the secretory/storage granules of the beta-cell of the pancreatic islets of Langerhans.

Chemical Phenomena↗
PubMed1993

Detection of anti-pituitary autoantibodies by immunoblotting.

A new approach to the detection of anti-pituitary autoantibodies by immunoblotting is presented. This method distinguishes pituitary membrane fraction from cytosolic fraction autoantigens and characterizes them by their molecular weight. A 45 kDa pituitary specific membrane protein was identified as an autoantigen in one of 19 patients with idiopathic growth hormone deficiency and the empty sella syndrome. A 43 kDa membrane protein in pituitary and brain was identified as an autoantigen in one other patient with idiopathic growth hormone deficiency and in one of 14 patients with secondary growth hormone deficiency. These autoantibodies were not seen in any of 27 control subjects. Anti-pituitary autoantibodies can be demonstrated by immunoblotting at titres of up to 1/1000. We conclude that immunoblotting is a useful method for the detection of anti-pituitary autoantibodies.

Adolescent↗
PubMed1993

The in vivo glycation of diabetic tendon collagen studied by neutron diffraction.

Glycation (non-enzymatic glycosylation) sites in the axial unit cell of diabetic tendon collagen were investigated by neutron diffraction. Samples of diabetic and control tendon were reacted with sodium borodeuteride and sodium cyanoborodeuteride. This facilitated deuteration at aldimine, aldol or ketoimine groups in the molecule. These are natural collagen cross-links and sites where non-enzymatic glycation had occurred. The introduction of a deuteron at specific locations allowed the diabetic glycation collagen to be treated as multiple isomorphous derivatives for neutron fibre diffraction. Neutron diffraction was conducted at the Institut Laue Langevin, Grenoble. Standard crystallographic refinement techniques (modified for axial projections) were used to determine the structure of the control (non-diabetic) and diabetic samples. The results are shown as difference maps, these indicate that glycation takes place at different rates within the collagen axial unit cell. The position of glycation correlates well with the position of hydroxylysine residues. The reactions of periodate with enzymatically attached sugars, proteoglycan, natural cross-links and glycation products lead to complications in map interpretation.

Animals↗
PubMed1993

Improved quality of diabetic foot care, 1984 vs 1990. Reduced length of stay and costs, insufficient reimbursement.

Ischemic foot ulceration in the diabetic patient is a source of great physical and emotional strain for the patient and represents a significant financial burden for the health care system responsible for the cost of such care. Limb salvage remains the primary therapeutic goal; yet, fiscal constraints imposed by diagnosis related group-based reimbursement systems require maximal cost efficiency in the care process. Between 1984 and 1990, the changes in our team management approach to this problem, emphasizing aggressive surgical revascularization of threatened limbs, have improved the quality of care and dramatically reduced the major and minor amputation rate. In the process, we have reduced the length of hospital stay and the overall cost of care. Despite this improvement in outcome and efficiency, Medicare reimbursement remains insufficient, with an average loss of $7480 per admission.

Aged↗
PubMed1993

Diffuse thickening superimposed on circumscribed pleural thickening related to asbestos exposure.

Circumscribed and diffuse pleural thickening (PT), the most common radiographic manifestations of asbestos-related disease, have different pathogeneses, differential diagnostic criteria, and effects on pulmonary function. The important distinction between the two disorders is demonstrated by six patients in whom typical circumscribed PT was followed by diffuse PT in the same hemithorax. The diffuse PT came on 18-47 (mean 32.3) years after first exposure to asbestos. In four patients, clinically evident pleural effusions preceded the diffuse PT; the latter left all with moderate to severe restrictive ventilatory impairment. Patients with stable pleural plaques are at risk for diffuse PT and consequent greater ventilatory impairment, even though they are many years from first exposure to asbestos.

Aged↗
PubMed1993

Maternal HEL immunization has no lasting effects on the immune response of offspring to immunization with hen egg-white lysozyme.

The effect of prior maternal immunization on the murine offspring response to subsequent immunization with hen egg-white lysozyme was examined. Adult female A/J mice were immunized with 100 micrograms HEL-CFA intraperitoneally 10-27 weeks before conception. The offspring of these experimental female mice were then immunized with HEL-CFA at differing ages. Suppression of the anti-HEL IgG B cell response was observed when the offspring were immunized prior to 3 weeks of age when high levels of maternal antibody were still present. Older offspring, more than 8 weeks of age, were immunized with HEL-CFA to determine if exposure to maternal immunoglobulin early in ontogeny had primed or altered the offspring response to HEL. At this age, suppressive effects of transferred maternal antibody were no longer evident. Priming was not detected in the offspring as judged by the total magnitude of the anti-HEL antibody response or the kinetics of the response when experimental and age-matched control offspring were examined. Furthermore, qualitative differences in the response as evidenced by IgG vs IgM content and fine specificity of the response (primary vs secondary antibody) were not observed. No evidence was found to suggest that exposure to polyclonal maternal anti-HEL antibody had primed the offspring for a more efficient or qualitatively different response to immunization with the protein antigen HEL. After maternal antibody levels decreased, the offspring response was similar to that of controls, suggesting that the response had not been permanently altered by the prior exposure early in ontogeny to polyclonal maternal antibody.

Animals↗
PubMed1993

Pulmonary function in asbestosis and asbestos-related pleural disease.

This review begins with the classic physiologic syndrome of interstitial lung disease (ILD) described in established asbestosis in the 1950s: reduced VC and pulmonary compliance, maintenance of airflow (measured indirectly), decreased diffusing capacity (a laborious undertaking in those years), and hyperventilation, increased dead space (VD/VT), and desaturation on exercise. Small airways dysfunction (SAD) was recognized in the 1960s and 1970s as the physiologic counterpart of the early peripheral bronchiolar inflammatory and fibrotic narrowing reported in experimental animals and in asbestos workers. SAD is nonspecific and is often overshadowed by more severe obstruction caused by smoking or by the countervailing effects of increased lung recoil caused by interstitial fibrosis. Airtrapping secondary to SAD may explain some of the reduction in VC in asbestos exposed workers whose FEV1/FVC is normal. There may be a greater frequency of obstructive airways disease in asbestos workers who smoke than in other smokers, suggesting an interaction between these two noxious inhalants. An interaction is seen in the greater frequency and severity of radiographic asbestosis in smokers at equivalent durations of exposure and in the greater reduction in FVC in smokers at equivalent ILO profusion scores. The functional importance of PT is well documented by lower values for FVC at equivalent profusions of parenchymal disease. This is true of circumscribed PT but much more so of diffuse PT, which can occasionally result in ventilatory failure and death. Incremental exercise testing often reveals evidence of excessive ventilation and abnormal gas exchange (VD/VT) attributable to ILD, when standard tests of pulmonary function and chest radiography are normal. These abnormalities help explain dyspnea in such patients.

Asbestos↗
PubMed1993

Respiratory findings among millwright and machinery erectors: identification of health hazards from asbestos in place at work.

Asbestos-associated diseases are prevalent in the construction trades primarily because of the previously widespread use of asbestos-containing insulation materials. Workers in metal-related trades, employed at construction sites and power facilities, but who do not routinely handle such materials as part of their work, may also be at risk for significant asbestos exposure. In order to evaluate such risk, a clinical field survey was conducted of 110 millwright and machinery erectors from the New York metropolitan area. A high prevalence of chest roentgenologic abnormalities was found. Forty-nine (44.5%) of the examined workers had pleural abnormalities consistent with asbestos-induced effects. Eighteen workers showed evidence of unilateral pleural thickening. Duration from onset of employment was significantly longer for those with pleural abnormalities (mean 32.3 years) as compared to those with normal chest radiographs (mean 18.5 years). Thirteen workers (11.8%) had radiographic signs of interstitial lung disease. The workers with pleural abnormalities had lower mean values of restrictive and obstructive lung function parameters than those with normal pleura. Multivariate and logistic regression analyses demonstrated association between duration of employment in the millwright trade and pleural abnormalities which was independent of smoking status. These findings suggest that millwright and machinery erectors employed in work environments where there is potential for primarily indirect exposure to airborne asbestos-containing dust are at risk for adverse effects from such exposure.

Adult↗
PubMed1993

Prognostic factors and long-term survival in endometrial adenocarcinoma with cervical involvement.

The clinical, surgical, and histopathologic data from 202 patients with endometrial adenocarcinoma with cervical involvement are presented. One hundred fifty-one (75%) had histopathologically confirmed cervical involvement at the time of their definitive surgery, while in 51 (25%) no cervical involvement was conclusively identified. The 5-year actuarial survival for patients with true surgical stage II endometrial carcinoma (N = 24) was 76%. Extrauterine disease was documented in 32% (27/84) of patients in which the primary treatment modality was surgical. The 5-year actuarial survival was 65% for all patients with clinical surgical stage II disease. There appeared to be a survival advantage for patients treated by radical surgery as compared with more conventional treatments, especially in patients with numerous high-risk factors. The subgroup of patients (N = 53) having tumor grossly involving the cervix had a 5-year survival of 48%. In this subgroup of patients, radical hysterectomy offered improved 5-year survival over more traditional forms of treatment, particularly compared with simple hysterectomy or combined treatment with radiation and surgery. Multivariate analysis positively correlated myometrial invasion, grade, uterine serosal involvement, lower uterine segment involvement, adnexal metastasis, pelvic metastasis, aortic node metastasis, and peritoneal cytology, with disease-free survival. Clinical and surgical findings correlated poorly; therefore, primary surgical evaluation is recommended when possible.

Adenocarcinoma↗
PubMed1993

A Monte Carlo pharmacophore generation procedure: application to the human PAF receptor.

A novel pharmacophore definition procedure is described, which uses a Monte Carlo method to superimpose molecules. Pharmacophore space is searched by a technique similar to high temperature annealing. Subsequent refinement of candidate pharmacophores by energy minimization produces low-energy conformations that may be involved in receptor binding. The method has been applied to compounds that bind to the human platelet-activating factor (PAF) receptor. Alternative binding site models for the PAF receptor are presented and discussed.

Binding Sites↗
PubMed1993

Review of the pH of hemostatic agents used in tissue displacement.

Newer hemostatic agents such as the tetrahydrozolines and oxymetazolines have a more acceptable pH and should be kinder to tooth structure and soft tissue than the conventional solutions. Although additional study is needed, it would seem prudent to be cautious in using low pH hemostatic agents and avoid the exposure to sensitive intraoral tissues-particularly delicate tissues--or tooth preparation close to the dental pulp.

Alum Compounds↗
PubMed1993

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. VI. Suppression of adoptively transferred disease and differential effects of oral vs. intravenous tolerization.

Antigen-driven tolerance is an effective method of suppressing cell-mediated immune responses. We have previously shown that oral administration of myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis (EAE) when it is actively induced by MBP emulsified in complete Freund's adjuvant. In order to further study antigen-driven tolerance in this model, we investigated the effect of oral tolerization on adoptively transferred EAE and compared oral tolerance to intravenously (i.v.) administered MBP in both actively induced EAE and adoptively transferred EAE. Although orally tolerized animals were not protected from adoptively transferred EAE, spleen cells from orally tolerized animals suppressed adoptively transferred EAE when co-transferred with encephalitogenic cells or when injected into recipient animals at a different site at the time encephalitogenic cells were transferred. This suppression was mediated by CD8+ T cells, correlated with suppression of DTH responses to MBP, and was associated with decreased inflammation in the spinal cord. Unlike oral tolerization, spleen cells from i.v. tolerized animals did not suppress adoptively transferred EAE when co-transferred with encephalitogenic cells although i.v. tolerized animals were protected from adoptively transferred EAE. MBP peptides were then utilized to further characterize differences between i.v. and oral tolerization in the actively induced disease model. Both orally and intravenously administered MBP suppressed actively induced EAE. However, EAE was only suppressed by prior i.v. tolerization with the encephalitogenic MBP peptide 71-90, but not with the non-encephalitogenic peptide 21-40, whereas prior tolerization with 21-40 did suppress actively induced EAE when administered orally. These results suggest a different mechanism of tolerance is initiated by oral vs. intravenous administered antigen. Specifically, oral tolerization suppresses primarily by the generation of active suppression whereas the dominant mechanism of suppression associated with i.v. tolerization appears most consistent with the elicitation of clonal anergy.

Administration, Oral↗
PubMed1993

Differential effects of prolactin upon activation and differentiation of human B lymphocytes.

The effects of human prolactin on enriched peripheral B lymphocytes obtained from healthy males were examined. Immunoregulation by prolactin was studied in B cells activated with either anti-IgM alone, or anti-IgM antibodies and recombinant interleukin-2 (r-IL-2), as well as control resting B cells. Expression of IL-2 receptors (IL-2R), and IgM and IgG in the culture supernatants were used as a measure of B cell activation and differentiation. Prolactin significantly synergized with IL-2 in the enhancement of surface expression of IL-2R on anti-IgM treated B cells. Although no differentiating effect was observed on resting B cells, prolactin (0.2-100 ng/ml) exhibited a dose-dependent enhancement upon both IgM and IgG secretion from B cells treated with anti-IgM and IL-2. In the absence of exogenously added IL-2 similar differentiating effect were observed in B cells treated with anti-IgM at prolactin concentrations of 0.2-10 ng/ml, but not 100 ng/ml. Thus, the present results demonstrate the modulatory effect of prolactin on activation and differentiation of anti-IgM triggered human B cells, and emphasize the importance of co-stimulatory signal mediated by IL-2 in B cell responses to high prolactin levels. These findings extend the immunoregulatory effects of prolactin, previously confirmed for T cells, to the B cell arm of the immune response, and suggest an important role of prolactin in mediating adaptation and communication between the nerve and immune systems.

Adult↗
PubMed1993

The synaptic organization of the neocortex in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by a progressive deterioration of cognitive functions. Recent studies have shown that, in addition to the classically described lesions (plaques and tangles) found in AD, this neurodegenerative disorder is characterized by neuronal and synaptic loss and by synapto-axonal pathology. Stepwise regression analysis has shown that the major correlate of cognitive deficiency is the synapse loss in the prefrontal cortex, contributing about 70% of the strength of the correlation with global psychometric tests. We review evidence that supports the theory that most of the synaptic loss in the neocortex is derived from loss of cortico-cortical associational input into the modules. This hypothesis also predicts that neuritic plaque formation in the neocortical modules could represent an aberrant sprouting reaction of associational fibers responding to abnormal growth stimuli or to local damage. On these bases, it is also proposed that the cellular substrate of AD pathology is synapto-axonal, while in certain other forms of dementia such as Creutzfeldt-Jacob disease (CJD) and HIV encephalitis (HIVE) it is primarily dendritic.

Afferent Pathways↗
PubMed1993

The use of intravenous ketorolac for the treatment of renal colic in the emergency department.

The objective of this study was to report the authors' experience using intravenous ketorolac (Syntex Laboratories, Palo Alto, CA) as an analgesic in the treatment of renal colic in a convenience sample at three suburban community hospital emergency departments. Twenty-five patients with renal colic were participants. Pregnant women, patients with a history of renal or hepatic impairment, bleeding diathesis, active peptic ulcer disease, or hypersensitivity to aspirin or nonsteroidal antiinflammatory drugs (NSAID) were excluded. Ketorolac 30 mg administered intravenously during a 1-minute period, and the following parameters were monitored at times 0, 5, 10, 20, 30, and 60 minutes: pain on a scale of 0 to 10, pulse rate, blood pressure, and adverse side effects. A total of 25 patients were included in our series. Initially, they had a median pain score of 9 with an interquartile range of 1. Thereafter, the median pain scores and (interquartile ranges) were 8 (three) at 5 minutes, 5 (four) at 10 minutes, 2 (four) at 20 minutes, 1 (three) at 30 minutes, and 0 (one) at 60 minutes. There were no adverse side effects observed in any patients. Therefore, it can be concluded that intravenous ketorolac is an effective analgesic agent for the control of pain in patients with renal colic.

Adult↗
PubMed1993

Measuring lung volumes in advanced asbestosis: comparability of plethysmographic and radiographic versus helium rebreathing and single breath methods.

Total lung capacity was measured in 16 workers with pulmonary asbestosis using four standard methods: body plethysmography, radiographic lung area, helium dilution by multiple breath and by single breath (alveolar volume). All men had irregular opacities of ILO profusion category 2/1 or greater and four had pleural plaques in addition. The radiographic and plethysmographic methods produced virtually identical mean values for TLC of 7.52 l and 7.64 l and for RV of 4.06 l and 4.32 l and all values were larger than those by helium dilution. The closed circuit helium dilution method systematically underestimated TLC with a mean of 5.89 l as did single breath helium dilution with a mean of 6.39 l. These men had a larger mean RV/TLC, measuring 56.9% by body plethysmography and 54.6% by X-ray area than by the rebreathing dilutional method which was 43.8%. Air trapping within a normal TLC which characterizes asbestosis is revealed by radiographic and plethysmographic methods but concealed by gas dilution methods. Use of the latter is at least partly responsible for the impression that asbestosis is a 'restrictive disease'.

Aged↗