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Biomedical subjects

J Rogers

Publications and source records attributed to J Rogers.

At least 19 recordsLinked to original sources
PubMed1992

Complement activation by beta-amyloid in Alzheimer disease.

Alzheimer disease (AD) is characterized by excessive deposition of the beta-amyloid peptide (beta-AP) in the central nervous system. Although several lines of evidence suggest that beta-AP is neurotoxic, a mechanism for beta-AP toxicity in AD brain remains unclear. In this paper we provide both direct in vitro evidence that beta-AP can bind and activate the classical complement cytolytic pathway in the absence of antibody and indirect in situ evidence that such actions occur in the AD brain in association with areas of AD pathology.

Alzheimer Disease↗
PubMed1992

Interfacial catalysis by phospholipase A2: the rate-limiting step for enzymatic turnover.

The kinetics of the phospholipase A2-catalyzed hydrolysis of bilayer vesicles and mixed micelles of several oxyglycero and thioglycero analogues of phospholipids have been studied. The results with vesicles show that, depending on the source of the enzyme, the rates of hydrolysis of the oxy-containing long-chain phosphatidylmethanols are 2.5- to 28-fold higher compared to the rates of hydrolysis of the analogous thio substrates. The oxygen to sulfur substitution does not significantly alter the affinities of the enzymes for the reaction products or calcium. Since it is unlikely that sulfur substitution changes the rate constants for the formation and dissociation of the enzyme-product complex by the same factor, the element effects seen in the rates of hydrolysis of the oxy- and thioester phospholipids in vesicles are primarily due to a change in the rate constant for the chemical step of the catalytic turnover cycle. For bovine pancreatic phospholipase A2, various mutants with lower catalytic activity were used to show that the value of the element effect does not increase in the mutants. These results establish that, for the pancreatic phospholipase A2, the element effect is fully expressed, and the chemical step is fully rate-limiting for both oxyglycero and thioglycero phospholipids in vesicles. It was found that the element effect decreases from 7 to 1 when long-chain phosphatidylmethanols are present in micelles of a neutral diluent. This result suggests that the chemical step is not rate-limiting during the hydrolysis of these mixed micelle substrates.

Animals↗
PubMed1992

Basis for the anomalous effect of competitive inhibitors on the kinetics of hydrolysis of short-chain phosphatidylcholines by phospholipase A2.

The effect of four specific competitive inhibitors on the kinetics of hydrolysis of short-chain diacyl-sn-glycero-3-phosphocholines below their critical micelle concentrations was examined. The kinetics of hydrolysis of short-chain substrates dispersed as solitary monomers were generally consistent with the classical Michaelis-Menten formalism; i.e., hydrolysis began without any latency period, the steady-state rate was observed at higher substrate concentrations, the steady-state initial rate showed a linear dependence on the enzyme concentration, and the hyperbolic dependence of the initial rate on the substrate concentration could be described in terms of KM and Vmax parameters. The competitive nature of the inhibitors used in this study has been established by a variety of techniques, and the equilibrium dissociation constants for the inhibitors bound to the enzyme were measured by the protection method [Jain et al. (1991) Biochemistry 30, 7306-7317]. The kinetics of hydrolysis in the presence of competitive inhibitors could be described by a single dissociation constant. However, the value of the dissociation constant obtained under the kinetic conditions was comparable to that obtained by the protection method for the inhibitor-enzyme complex bound to a neutral diluent, rather than to the value of the dissociation constant obtained with solitary monomeric inhibitors and the enzyme in the aqueous phase. Spectroscopic methods showed that the effectively lower dissociation constant of an inhibitor bound to PLA2 at the interface is due to the stabilization of the enzyme-inhibitor complex by interaction with other amphiphiles present in the reaction mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1992

Augmentation of in vivo cytotoxic T lymphocyte activity and reduction of tumor growth by large multivalent immunogen.

Class I alloantigen incorporated into cell-size supported membranes provides an effective stimulus for in vitro stimulation of CTL responses. When alloantigen-bearing cell-size (5 microns) microspheres, termed large multivalent immunogen (LMI), were administered in vivo, no primary cytotoxic response to the Ag could be detected. However, coadministration of LMI and allogeneic tumor stimulator cells resulted in substantial augmentation of the resulting CTL response, compared with that obtained from mice that received just stimulator cells. Responses were augmented only when the same alloantigen was present on the LMI and on the stimulator cells, and the effector cells remained specific for the cognate alloantigen-bearing targets. The physical form of the alloantigen was critical for augmentation; alloantigen in liposomes had no effect on response levels. Tumor cell Ag in the form of purified plasma membrane vesicles can also be incorporated onto the surface of cell-size microspheres. As with allogeneic responses, tumor Ag on LMI specifically augmented the in vivo CTL activity generated in response to irradiated tumor cells in syngeneic mice. Administration of Ag-bearing LMI to mice inoculated i.p. with live P815, EL4, or RDM4 tumor cells resulted in a significant reduction in growth of the tumors in their syngeneic hosts. Similarly, LMI treatment significantly reduced growth of P815 as a solid s.c. tumor. LMI-mediated growth reduction occurred only when plasma membrane Ag from the cognate tumor was used to prepare the LMI, and Ag in the form of free plasma membrane vesicles was not effective. Although Ag has been used to manipulate in vivo humoral and Th responses, this has proven to be much more difficult for CTL responses. The ability of Ag-bearing LMI to affect significantly the in vivo levels of cytolytic response and to reduce syngeneic tumor growth has potential for application to tumor immunotherapy and, possibly, treatment of other diseases in which CTL can provide a protective effect.

Adjuvants, Immunologic↗
PubMed1992

Paleohistology of Paget's disease in two medieval skeletons.

Paget's disease has been ascribed several times to specimens of archeological bone but, in the absence of microscopic examination, the evidence remains insubstantial. Suspected metabolic bone disease is described here in the archeological remains of a skeleton from a 16th century burial ground at Wells Cathedral, England and from a single medieval sacrum recovered from a large deposit of disarticulated bones from a churchyard at Barton-on-Humber, England. Radiographs showed apparent structural abnormality in one femoral shaft and calcaneus and in the isolated sacrum. Histomorphometry on undecalcified bone cores confirmed the regions of abnormality and showed not only increased trabecular width but also areas of "mosaic" woven bone together with extensive resorption cavities; these features contrasted with the normal structure and organized lamellar bone from sites elsewhere. Despite post-interment changes in surrounding tissues, the morphological stability of some of the osteocytes was remarkable. Preservation of the histology was sufficient to permit the assignment of a metabolic bone disorder and the nature of the sclerosis was consistent with Paget's disease.

England↗
PubMed1992

Marathon running: physiological and chemical changes accompanying late-race functional deterioration.

Twenty-one experienced runners were studied before, during and immediately after a marathon race to ascertain whether either depletion of energy substrate or rise in body temperature, or both, contribute to late-race slowing of running pace. Seven runners drank a glucose/electrolyte (GE) solution ad libitum (Na+ 21 mmol l-1, K+ 2.5 mmol l-1, Cl- 17 mmol l-1, PO4(2-) 6 mmol l-1, glucose 28 mmol l-1) throughout the race; 6 drank water and 8 drank the GE solution diluted 1:1 with water. Although average running speeds for the three groups were not significantly different during the first two-thirds (29 km) of the race, rectal temperature was significantly higher (P < 0.05) and reduction of plasma volume was greater (P < 0.05) in runners who replaced sweat losses with water. During the last one-third of the race, the average running pace of the water-replacement group slowed by 37.2%; the pace slowed by 27.9% in the 8 runners who replaced their sweat loss with GE diluted 1:1 with water (1/2 GE) and 18.2% in runners who replaced fluid loss with full-strength solution (GE). Eleven runners (5 in the water group, 4 in the 1/2 GE group and 2 in the GE group) lapsed into a walk/run/walk pace during the last 6 miles of the race. Ten of these had a rectal temperature of 39 degrees C or greater after 29 km of running, and plasma volume in these runners was reduced by more than 10%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Testing for and the role of anal and rectal sensation.

The rectum is insensitive to stimuli capable of causing pain and other sensations when applied to a somatic cutaneous surface. It is, however, sensitive to distension by an experimental balloon introduced through the anus, though it is not known whether it is the stretching or reflex contraction of the gut wall, or the distortion of the mesentery and adjacent structures which induces the sensation. No specific sensory receptors are seen on careful histological examination of the rectum in humans. However, myelinated and non-myelinated nerve fibres are seen adjacent to the rectal mucosa, but no intraepithelial fibres arise from these. The sensation of rectal distension travels with the parasympathetic system to S2, S3 and S4. The two main methods for quantifying rectal sensation are rectal balloon distension and mucosal electrosensitivity. The balloon is progressively distended until particular sensations are perceived by the patient. The volumes at which these sensations are perceived are recorded. Three sensory thresholds are usually defined: constant sensation of fullness, urge to defecate, and maximum tolerated volume. The modalities of anal sensation can be precisely defined. Touch, pain and temperature sensation exist in normal subjects. There is profuse innervation of the anal canal with a variety of specialized sensory nerve endings: Meissner's corpuscles which record touch sensation, Krause end-bulbs which respond to thermal stimuli, Golgi-Mazzoni bodies and pacinian corpuscles which respond to changes in tension and pressure, and genital corpuscles which respond to friction. In addition, there are large diameter free nerve endings within the epithelium. The nerve pathway for anal canal sensation is via the inferior haemorrhoidal branches of the pudendal nerve to the sacral roots of S2, S3 and S4. Anal sensation may be quantitatively measured in response to electrical stimulation. The technique involves the use of a specialized constant current generator and bipolar electrode probe inserted in the anal canal. The equipment is generally available and the technique has been shown to be an accurate and repeatable quantitative test of anal sensation.

Anal Canal↗
PubMed1992

DNA sequence polymorphism within hominoid species exceeds the number of phylogenetically informative characters for a HOX2 locus.

Within- and between-species variability was examined in a noncoding 238-bp segment of the HOX2 cluster. DNA of 4-26 individuals of four species (Pongo pygmaeus, Pan troglodytes, Gorilla gorilla, and Homo sapiens) was PCR amplified and electrophoresed in a denaturing gradient gel to screen for variability. Coupled amplification and sequencing was used to determine the complete sequence for each of the different alleles identified, one each in humans and orangutans, two in chimpanzees, and four in gorillas. Maximum-parsimony methods were used to construct a gene tree for these sequences. Alleles in all four species cluster into groups consisting of only one species (i.e., alleles within a species are monophyletic). The number of base-pair differences observed among alleles within P. troglodytes and within G. gorilla is larger than the number of base-pair substitutions that phylogenetically link Pan with Homo. Given these and other published data, it is premature to accept any particular phylogenetic tree that relates these three genera through two separate speciation events.

Animals↗
PubMed1992

Oral or intravenous erythromycin has no effect on human distal colonic motility.

Erythromycin is a prokinetic agent for the lower oesophageal sphincter, the stomach, the gallbladder and the small bowel, acting directly on motilin receptors. Its effect on pressure activity of the human colon has not been investigated. Eight healthy volunteers were studied on 2 occasions and given intravenous or oral erythromycin, or placebo in a single-blind, randomized crossover study. Sigmoid pressure activity was measured using a 4-lumen water perfused system placed sigmoidoscopically at 50, 45, 30 and 15 cm from the anal verge. The pressures were analysed for activity index (mmHg.min) for the 35 cm colonic study segment using dedicated software. No significant difference was found in the activity index following oral erythromycin (500 mg) or placebo, or following intravenous erythromycin 1.8 mg/kg or placebo. A further 8 subjects were studied in a single-blind crossover study to determine the effect of oral erythromycin (500 mg) b.d. on colonic transit, measured with radio-opaque markers and a single abdominal X-ray. Mean or segmental colonic transit times were not statistically significantly different (Student's paired t-test) in the subjects on placebo or erythromycin. This lack of effect of erythromycin on the distal large intestine may indicate the absence of receptors for motilin in that part of the gut.

Administration, Oral↗
PubMed1992

Phase II clinical trial of recombinant alpha-2 interferon for biopsy-proven metastatic or recurrent renal carcinoma.

Twenty patients with histologically confirmed metastatic or recurrent renal carcinoma were treated in a phase II study with alpha-interferon (2-5 x 10(6) U/m2 subcutaneously, 3 times a week). Nineteen patients had multiple sites of disease and 18 had previously undergone nephrectomy; 9 had an ECOG performance status of 0.1, and 11 had a performance status of 2-3. There was one partial response, yielding an overall response rate of 5%. Treatment was well tolerated, although 7 patients developed influenza-like symptoms, and in 2 cases this was sufficiently severe for the patients to request cessation of treatment. As a single agent at this dose schedule, alpha-interferon has minimal activity in the treatment of renal carcinoma and cannot be recommended as standard therapy. The difference in outcome between this and some published series may reflect the stringent requirement for histological proof of the presence of metastases.

Adult↗
PubMed1992

Immunogold and fluorescein immunolabelling of Legionella pneumophila within an aquatic biofilm visualized by using episcopic differential interference contrast microscopy.

Biofilms containing diverse microflora were developed in tap water on glass and polybutylene surfaces. Legionella pneumophila within the biofilms was labelled with monoclonal antibodies and visualized with immunogold or fluorescein isothiocyanate conjugates. Development of a differential interference contrast technique in an episcopic mode enabled simultaneous visualization of the total biofilm flora and gold-labelled legionellae. The legionellae occurred in microcolonies within the biofilm in the absence of amoebae, suggesting that the bacterial consortium was supplying sufficient nutrients to enable legionellae to grow extracellularly within the biofilm.

Antibodies, Monoclonal↗
PubMed1992

Radiographic assessment of the knee joint in osteoarthritis.

The development of radiographic systems for the grading of osteoarthritis requires knowledge of the reproducibility of their individual component features. This paper reports the reproducibility, both within and between observers, for five commonly used radiographic features of osteoarthritis in the tibiofemoral and patellofemoral compartments of the knee joint. The results suggest that assessments of joint space narrowing, osteophyte, and bony contour in the tibiofemoral compartments are more reproducible than those of sclerosis and cyst. Patellofemoral assessments, with the exception of osteophyte, are considerably less reproducible between observers than tibiofemoral assessments.

Aged↗
PubMed1992

Anti-inflammatory agents as a therapeutic approach to Alzheimer's disease.

Postmortem analyses of Alzheimer's disease (AD) brain tissue reveal reactive microglia expressing high levels of major histocompatibility complex (MHC) glycoproteins, immunoglobulin receptors, and complement receptors; small but significant numbers of T-lymphocytes infiltrating tissue; enhanced cytokine and cytokine receptor expression; and profuse immunoreactivity for complement proteins of the classic pathway colocalized with senile plaques, dystrophic neurites, and some neurofibrillary tangles. Protectin, clusterin, and vitronectin, three proteins designed to defend host cells against "bystander lysis" caused by the membrane attack complex of complement, are all expressed at high levels in AD tissue but not in normal tissue. Taken together, these findings indicate that immune-mediated autodestructive processes may occur in AD. In view of the urgency to find treatments for AD and disappointing results with the many classes of pharmacologic agents that have so far been given clinical trials, exploration of the effectiveness of anti-inflammatory agents may now be warranted.

Alzheimer Disease↗
PubMed1992

Large-scale finite element analysis of the beating heart.

The regional mechanics of the beating heart are directly related to factors such as ventricular pumping performance, coronary blood flow, myocardial energetics and oxygen consumption, vulnerability to ischemia and injury, hypertrophy and remodeling, and arrhythmogenesis. Important characteristics include: the complex three-dimensional geometry and fibrous architecture; the nonlinear, nonhomogeneous, anisotropic material properties of the myocardium; the hierarchical collagen connective tissue matrix; the time- and history-dependent active tension development of the cardiac muscle cells; and the three-dimensional anisotropic patterns of cardiac impulse propagation. To model these features realistically requires large-scale computational analysis with sophisticated numerical methods. As described in the chapter by Dr. Hunter and colleagues, an accurate three-dimensional finite element model has been developed to describe the geometry, fiber architecture, and extracellular matrix structure of the heart. The model is based on extensive anatomical measurements in the left and right ventricles (LV and RV) of the canine heart. In this chapter, we illustrate some new approaches to the special problems of large-scale finite element modeling in biomechanics using examples from the analysis of stress and electrical activation in the heart. Prospects for further progress--particularly in coupled problems such as cardiac electromechanics--are examined in light of new developments in high-performance computing.

Animals↗
PubMed1991

Active-site-directed specific competitive inhibitors of phospholipase A2: novel transition-state analogues.

More than 100 amphiphilic phosphoesters, possible tetrahedral transition-state analogues capable of coordinating to the calcium ion at the active site of phospholipase A2, were designed, synthesized, and tested as inhibitors for the hydrolysis of 1,2-dimyristoyl-sn-glycero-3-phosphomethanol vesicles in the scooting mode. This assay system permits the study of structurally diverse inhibitors with phospholipase A2S from different sources, and it is not perturbed by factors that change the quality of the interface. As a prototype, 1-hexadecyl-3-trifluoroethylglycero-2-phosphomethanol (MJ33) was investigated in detail. Only the (S)-(+) analogue of MJ33 is inhibitory, and it is as effective as the sn-2 phosphonate or the sn-2 amide analogues of sn-3 phospholipids. The inhibitory potencies of the various phosphoesters depended strongly on the stereochemical and structural features, and the mole fractions of inhibitors required for 50% inhibition, X1(50), ranged from more than 1 to less than 0.001 mole fraction. The affinity of certain inhibitors for enzymes from different sources differed by more than 200-fold. The inhibitors protected the catalytic site residue His-48 from alkylation in the presence of calcium but not barium as expected if the formation of the EI complex is supported only by calcium. The equilibrium dissociation constant for the inhibitor bound to the enzyme at the interface was correlated with the XI(50) values, which were different if the inhibition was monitored in the pseudo-zero-order or the first-order region of the progress curve. These results show that the inhibitors described here interfered only with the catalytic turnover by phospholipase A2's bound to the interface, their binding to the enzyme occurred through calcium, and the inhibitors did not have any effect on the dissociation of the enzyme bound to the interface.

Animals↗
PubMed1991

Interfacial catalysis by phospholipase A2: determination of the interfacial kinetic rate constants.

Hydrolysis of vesicles of 1,2-dimyristoyl-sn-glycero-3-phosphomethanol (DMPM) by pig pancreatic phospholipase A2 (PLA2) occurs in a highly processive "scooting" mode, and the rate is comparable to or exceeds the rates observed with detergent-dispersed mixed micelles under optimal conditions. A complete kinetic description of the steady-state time course of the hydrolysis is developed. The analysis covers the whole Michaelis-Menten space: it emphasizes the key features of interfacial catalysis by a detailed theoretical analysis, describes the experimental protocols to determine the values of the kinetic and equilibrium constants for interfacial catalysis, and provides an interpretation of the effect of calcium, substrate, products, apparent activators, and competitive inhibitors on the reaction progress curve by a single set of rate and equilibrium parameters. In this paper, the integrated reaction progress curve was rigorously interpreted in terms of a minimal model involving the Michaelis-Menten reaction sequence in the interface: E* + S in equilibrium E*S----E*P in equilibrium E* + P, and most of the individual rate and equilibrium constants for the catalytic cycle were determined. This rigorous description of interfacial catalysis was made experimentally possible by examining the action of PLA2 in the scooting mode under conditions of at most one enzyme per vesicle, where it hydrolyzed all of the substrate in the outer monolayer of vesicles without leaving the surface. Other experimentally verified constraints for this analysis include the following: all enzyme was bound to vesicles; the integrity of vesicles was maintained during the course of hydrolysis; and the substrate, enzyme, and products did not exchange between vesicles nor did they exchange across the bilayer. The mechanistic significance of the rate constants is discussed in the accompanying papers.

Animals↗