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At least 685 records · Page 38Linked to original sources
PubMed2002

Pathogenesis of autoimmune hepatitis.

Autoimmune hepatitis is initiated by CD4 T cells that recognize self-antigen. The effector cells differentiate into functional phenotypes according to cytokines in the microenvironment and the nature of the triggering antigen. Hepatocytes can express class II molecules and present antigenic peptides through a bystander mechanism. NKT cells reside in the normal liver but may be involved in liver cell damage possibly through the expression of Fas ligand. Autoantibodies may also participate in the process by complexing with antigen on the hepatocyte membrane surface and by interacting with mononuclear cells with Fc receptors. Molecular mimicry generates cross-reactivities that predispose the immune system to cross-react with self-antigens. Multiple exposures to pathogens with antigenic similarities may prime a cross-reactive subset of T cells in the genetically predisposed host. Autoimmunity against one self-antigen may then spread through molecular mimicry to other homologous self-antigens and may lead to overt autoimmune disease. Anatomically distant tissues may also become involved as autoreactive T cells that had been activated in one organ expand and infiltrate other organs that express similar epitopes.

Antibody Formation↗
PubMed1997

Mutation Val235Ala weakens binding of the 33-kDa manganese stabilizing protein of photosystem II to one of two sites.

The 33-kDa protein of the photosynthetic O2-evolving complex, also known as manganese stabilizing protein, contributes to the structural stability of the photosystem II tetranuclear Mn cluster and stimulates the water-oxidizing activity of this cluster. Quantification of extrinsic polypeptides in photosystem II has yielded data that support stoichiometries of either one or two copies of each protein per photosystem II reaction center. We recently described the cold-sensitive assembly of a mutant 33-kDa protein with a single amino acid replacement (Val235Ala) [Betts, S. D., Ross, J. R., Pichersky, E., & Yocum, C. F. (1996) Biochemistry 35, 6302-6307]. We have extended the characterization of this mutation. When photosystem II membranes depleted of the 33 kDa extrinsic protein are exposed to mixtures of wild type and Val235Ala manganese stabilizing protein, binding of the wild type protein is strongly preferred. If, however, protein containing the Val235Ala mutation is first bound to photosystem II only half of this protein (about 1 mol/mol of photosystem II reaction centers) is susceptible to displacement by the wild type protein, even after multiple exposures to the latter. These results support the conclusion that 2 mol of manganese stabilizing protein are bound per reaction center. Our data show as well that the mutant 33-kDa protein competes with the wild type protein for at least one of two binding sites on photosystem II and that the mutant protein binds tightly to only one of two sites. These results demonstrate that the two binding sites on photosystem II for the 33-kDa protein have different properties with respect to recognition and binding of this protein.

Arabidopsis↗
PubMed2005

Effect of a coadsorbent on the performance of dye-sensitized TiO2 solar cells: shielding versus band-edge movement.

The mechanism by which the adsorbent chenodeoxycholate, cografted with a sensitizer onto TiO2 nanocrystals, alters the open-circuit photovoltage and short-circuit current of dye-sensitized solar cells was investigated. The influence of tetrabutylammonium chenodeoxycholate on dye loading was studied under a variety of conditions in which the TiO2 films were exposed to the sensitizing dye and coadsorbent. Photocurrent--voltage measurements combined with desorption studies revealed that adding chenodeoxycholate reduces the dye loading by as much as 60% while having a relatively small effect on the short-circuit photocurrent. Calculations along with measurements showed that even at low loading, enough dye is present to absorb a significant fraction of the incident light in the visible spectrum. In concurrence with the observations of others, we find evidence for weakly and strongly adsorbed forms of the dye resulting from either different binding conformations or aggregates. The most strongly adsorbed dyes are less susceptible to displacement by chenodeoxycholate than those that are weakly adsorbed. While having no observable effect on dye coverage, multiple exposures of a TiO2 film to a dye solution substantially increased the fraction of strongly adsorbed dye as judged by the resistance of the adsorbed dye to displacement by chenodeoxycholate. Measurements of the open-circuit voltage as a function of the photocharge density, determined by infrared transmittance, showed that chenodeoxycholate not only shifts the conduction band edge to negative potentials, but also significantly increases the rate of recombination. The net effect of adding chenodeoxycholate is, however, to improve the photovoltage.

Journal Article↗
PubMed2001

Quantitative distinctions of active site molecular recognition by P-glycoprotein and cytochrome P450 3A4.

The bulk of characterized xenobiotic defense and disposition is conferred by the abundant enzymes cytochrome P450 3A4 and P-glycoprotein. Although expressed in many tissues, these enzymes are most abundant in the liver and intestine and seem to share most substrates and inhibitors, with the apparent synergy between these two promiscuous enzymes asserted because of their extensive overlap of substrates and shared tissue location. Since the broad-spectrum tolerance to lipophilic compounds of various sizes naturally results in a similar pattern of substrate/inhibitor recognition, the cause or mechanism of many drug/drug and drug/herb interactions can be difficult to determine. These two seemingly indiscriminate enzymes, however, do not share some unique inhibitor selectivity. Particularly, we show various potent CYP3A4 inhibitors that do not affect P-gp active transport function. Remarkably, we have also identified several compounds-valinomycin, norverapamil, reserpine, nobiletin, emetine, gallopamil, fluphenazine-that uniquely inhibit P-gp function with affinities comparable to benchmark P-gp inhibitors despite a lack of effect on CYP3A4 function at physiologically relevant concentrations. Indeed, valinomycin inhibits P-gp with an IC(50) similar to cyclosporin A yet apparently does not affect CYP3A4 function, and emetine and nobiletin are also specific for interaction with P-gp. Additionally, norverapamil and reserpine have, respectively, a 60- and 40-fold preference for inhibition of P-gp over CYP3A4. Some striking structural analogies among these compounds are discussed. These distinguishing qualities of substrate recognition between CYP3A4 and P-gp should reveal nuances of active-site architecture unique to each and could serve as tools to probe for the specific discernment of P-gp-mediated drug/drug or drug/herb interactions. Learning more about binding distinctions and quantitative activity relationships of substrate/inhibitor interactions with these two enzymes and the differences between them may indicate how they recognize such a wide variety of molecules as substrates (and/or inhibitors). Moreover, identification of specific inhibitors will allow the determination of which enzyme is responsible for drug interactions and/or the extent of contribution in a multiple exposure situation.

3T3 Cells↗
PubMed2003

Infections and risk of type I diabetes in childhood: a population-based case-control study.

OBJECTIVE: This study focuses on the evaluation of some infectious diseases as risk determinants of type I diabetes mellitus (DM). METHODS: A population-based case-control study was carried out by referring to the type I DM population-based register of the Abruzzo region of Italy as it includes all type I DM cases since January 1 1990, the point at which the register became operative. The pediatric population (age: 0-14), living in the same municipalities of the cases, was selected as the control population. Data were collected through questionnaires submitted by a physician to parents of cases and controls. Conditional logistic regression models were used to evaluate association between determinants and onset of type I DM. RESULTS: The risk of diabetes for children exposed to only one infection (morbilli, parotitis, rubella, pertussis or varicella) is not statistically significant: OR: 0.778; CI: 0.427-1.370. On the contrary, when two infections are contracted statistically significant results occur: OR: 2.375; CI: 1.149-4.914; for more than two infections values are: OR: 6.786; CI: 2.881-17.877. No substantial difference in odds ratios (ORs) after adjustment for confounding variables was found. A significant decrease in OR was noted for pertussis and MMR vaccinations, respectively: OR: 0.015; CI: 0.001-0.251; OR: 0.400; CI: 0.201-0.799. CONCLUSIONS: Since the higher the number of contracted infections, the higher the risk of diabetes, contracted infections can be considered potential accelerating factors of clinical manifestation of type I DM. Therefore multiple exposures might speed up the onset of diabetes in children. This study suggests the utility of applying the risk model method to wider populations, especially if the geographical variability of standardised incidence rates of type I DM in pediatric age is taken into consideration.

Adolescent↗
PubMed1999

Posttraumatic stress disorder in a national sample of female and male Vietnam veterans: risk factors, war-zone stressors, and resilience-recovery variables.

Relationships among pretrauma risk factors (e.g., family instability, childhood antisocial behavior), war-zone stressors (e.g., combat, perceived threat), posttrauma resilience-recovery variables (e.g., hardiness, social support), and posttraumatic stress disorder (PTSD) symptom severity were examined. Data from a national sample of 432 female and 1,200 male veterans were analyzed using structural equation modeling. For both genders, direct links to PTSD from pretrauma, war-zone, and posttrauma variable categories were found; several direct associations between pretrauma and posttrauma variables were documented. Although war-zone stressors appeared preeminent for PTSD in men, posttrauma resilience-recovery variables were more salient for women. Researchers, policymakers, and clinicians are urged to take a broad view on trauma and its sequelae, especially regarding possible multiple exposures over time and the depletion and availability of important resources.

Adult↗
PubMed2000

When false recognition is unopposed by true recognition: gist-based memory distortion in Alzheimer's disease.

The authors examined false recognition of semantic associates in patients with probable Alzheimer's disease (AD), older adults, and young adults using a paradigm that provided rates of false recognition after single and multiple exposures to word lists. Using corrected false recognition scores to control for unrelated false alarms, the authors found that (a) the level of false recognition after a single list exposure was lower in AD patients than in controls; (b) across 5 trials, false recognition increased in AD patients, decreased in young adults, and showed a fluctuating pattern in older adults; and (c) all groups showed an increase in true recognition over the 5 trials. Analyses suggested that AD patients built up semantic gist across trials, whereas both control groups were able to use increased item-specific recollection and more conservative response criteria to suppress gist-based false alarms.

Adult↗
PubMed2003

The influence of preexperimental experience on social discrimination in rats (Rattus norvegicus).

The authors used laboratory rats (Rattus norvegicus) of known relatedness and contrasting familiarity to assess the potential effect of preexperimental social experience on subsequent social recognition. The authors used the habituation-discrimination technique, which assumes that multiple exposures to a social stimulus (e.g., soiled bedding) ensure a subject discriminates between the habituation stimulus and a novel stimulus when both are introduced simultaneously. The authors observed a strong discrimination if the subjects had different amounts of preexperimental experience with the donors of the 2 stimuli but a weak discrimination if the subjects had either equal amounts of preexperimental experience or no experience with the stimuli. Preexperimental social experience does, therefore, appear to influence decision making in subsequent social discriminations. Implications for recognition and memory research are discussed.

Animals↗
PubMed1976

Habituation and tonic immobility in domestic chickens.

The habituation of tonic immobility in chickens was examined in six studies. It was shown that repeated elicitation of immobility, and not just handling, was responsible for reduced response durations after multiple exposures to manual restraint. Habituation was a function of the number of stimulus presentations and, in addition, proved surprisingly durable, with diminished reactions using lasting at least 2.5 mo. Strain differences were found in the number of trials required to reach a criteria of habituation, and habituation proceeded faster when immobility termination was self-paced as opposed to experimenter induced. Also, massed trials produced robust sensitization effects rather than diminished responsiveness.

Animals↗
PubMed1977

Heart rate and cardiac phase influences on visual perception.

Twenty-six subjects were tested with a tachistoscopic recognition task while heart rate and several other autonomic indexes were monitored. In Experiment 1, heart rate was employed as an independent variable, and stimulus presentation was contingent upon the presence of individually determined low, middle, and high heart rates. The results indicated that low heart rate facilitated performance especially for stimuli presented at the fastest exposure. In Experiment 2, stimulus presentation was dependent upon cardiac phase. The findings indicated that stimulus recognition was enhanced during the cardiac P wave, but the effect was apparent only during the fastest exposure. Multiple regression analyses of the individual subject's data during both experiments indicated that highly idiosyncratic patterns of physiological responses predicted perceptual performance. The results were interpreted as being consistent with the formulations of the Laceys and also suggested that cerebral perfusion be considered as a relevant determinant of behavior.

Adult↗
PubMed2001

High resolution protein localization using soft X-ray microscopy.

Soft X-ray microscopes can be used to examine whole, hydrated cells up to 10 microm thick and produce images approaching 30 nm resolution. Since cells are imaged in the X-ray transmissive "water window", where organic material absorbs approximately an order of magnitude more strongly than water, chemical contrast enhancement agents are not required to view the distribution of cellular structures. Although living specimens cannot be examined, cells can be rapidly frozen at a precise moment in time and examined in a cryostage, revealing information that most closely approximates that in live cells. In this study, we used a transmission X-ray microscope at photon energies just below the oxygen edge (lambda = 2.4 nm) to examine rapidly frozen mouse 3T3 cells and obtained excellent cellular morphology at better than 50 nm lateral resolution. These specimens are extremely stable, enabling multiple exposures with virtually no detectable damage to cell structures. We also show that silver-enhanced, immunogold labelling can be used to localize both cytoplasmic and nuclear proteins in whole, hydrated mammary epithelial cells at better than 50 nm resolution. The future use of X-ray tomography, along with improved zone plate lenses, will enable collection of better resolution (approaching 30 nm), three-dimensional information on the distribution of proteins in cells.

3T3 Cells↗
PubMedDate not supplied

Modified fluid gelatin in leukapheresis accumulation and persistence in the body.

Current methods for centrifuged granulocyte procurement involve the use of an agent to produce red cell rouleaux and enhance separation of leukocytes. Hydroxyethyl starch (HES), the agent most frequently used, has the disadvantage of causing progressive volume expansion and persisting in the circulation for long periods. We therefore assessed modified fluid gelatin (MFG) as a possible replacement for HES during granulocyte collection. We found that MFG is cleared more rapidly from the circulation with no traces remaining 7 days after multiple exposure, as determined by hydroxyproline measurement. However, after four consecutive daily infusions, we measured 0.60 liters plasma expansion in four individuals tested, somewhat lower than the 0.85 liters previously reported for HES. Modified fluid gelatin causes no impairment of coagulation with normal prothrombin time (PT), partial thromboplastin time (PTT), and platelet function.

Cell Separation↗
PubMed2004

[Delayed onset of malignant hyperthermia crisis during a living donor liver transplantation caused by sevoflurane].

We report on a 25-year old ASA physical status I patient, who developed within 20 minutes a full-blown malignant hyperthermia (MH) in the context of a living donor liver transplantation after 180 minutes of uneventful anaesthesia. The only trigger substance applied was Sevoflurane. The patient had already received a short, uneventful anaesthesia with Isoflurane a couple of years ago. In the context of the special constellation an initial dose of Dantrolene of 10 mg/kg body weight was administered. The patient was stabilised within 30 minutes, and the enzyme levels remained low compared with other case reports. The post-operative in vitro caffeine halothane contracture testing confirmed that son and mother were susceptible to MH, contracture testing in the father was negative. All known triggers may cause life-threatening MH crisis - even after hours and after inconspicuous multiple exposures to known trigger substances. Therefore all trigger substances must be avoided in all patients susceptible to MH.

Adult↗
PubMed1988

Enzymatically controlled drug delivery.

An approach for providing feedback control for polypeptide drugs in a polymeric controlled-release system uses a trigger molecule and a polymer-bound enzyme that, in the presence of that trigger molecule, will cause an acid or a base to form. When the pH inside the polymer system changes, the solubility of the drug shifts dramatically, which changes the diffusion or dissolution driving force, and hence the release rate changes correspondingly. This concept was tested using a controlled-release system of ethylene/vinyl acetate copolymer containing insulin and immobilized glucose oxidase. The enzymatic reaction of glucose to gluconic acid reduces the pH in the polymer microenvironment. Since insulin solubility increases with decreasing pH (at physiologic pH, this is true for an insulin with an isoelectric point of 7.4 or higher), the release of insulin increases in response to glucose concentration. The feasibility of this concept has been shown using trilysyl insulin with an isoelectric point of 7.4. Multiple exposures to buffered glucose solutions over several weeks caused insulin release to reversibly increase during each exposure. Polymer-implanted diabetic rats infused with glucose solutions showed a significant increase in insulin concentration in 30 min-an effect not observed in three different sets of control rats.

Animals↗
PubMed1997

Mismatch repair defects and O6-methylguanine-DNA methyltransferase expression in acquired resistance to methylating agents in human cells.

Fifteen variants with >/=30-fold resistance to N-methyl-N-nitrosourea were isolated from the Burkitt's lymphoma Raji cell line. Eight had received a single treatment with a highly cytotoxic dose. The remainder, including the previously described RajiF12 cell line, arose following multiple exposures to initially moderate but escalating doses. Surprisingly, methylation resistance arose in three clones by reactivation of a previously silent O6-methylguanine-DNA methyltransferase gene. Five clones, including RajiF12, displayed the microsatellite instability and increased spontaneous mutation rates at the hypoxanthine-guanine phosphoribosyltransferase locus, consistent with deficiencies in mismatch repair. Defects in either the hMutSalpha or hMutLalpha mismatch repair complexes were identified in extracts of these resistant clones by in vitro complementation using extracts from colorectal carcinoma cell lines. Defects in hMutLalpha were confirmed by Western blot analysis. Remarkably, five methylation-resistant clones in which mismatch repair defects were demonstrated by biochemical assays did not exhibit significant microsatellite instability.

Blotting, Western↗
PubMedDate not supplied

Correlation of the bovine cervical mucus penetration test with human sperm characterisitics in 1,406 ejaculates.

The bovine cervical mucus penetration test (BCMPT) was performed to determine its usefulness in screening the ability of sperm to successfully penetrate mucus in vitro. Ejaculates were obtained by masturbation from patients attending an infertility clinic. Routine semen analysis was performed using a microcomputerized multiple-exposure photography system. The BCMPT was performed. Overall, the average penetration of the mucus was 38 +/- 0.46 mm. Of the 1,406 ejaculates analyzed, 244 (17%) displayed a negative result (0-20 mm), 291 (21%) a questionable result (21-30 mm), and 871 (62%) a positive result (>30 mm). A highly significant (p < .001) correlation between mucus penetration distance and sperm MD (r = 0.541), MI (r = 0.484), count (r = 0.475), motility (r = 0.448), velocity (r = 0.400) and morphology (r = 0.369) was observed. Overall, the finding of an abnormal semen parameter resulted in a 34 +/- 5% accurate prediction of a negative or questionable BCMPT (<30 mm), while a normal semen parameter resulted in a 90 +/- 4% accurate prediction of a positive BCMPT (>30 mm). Sperm MD showed the strongest positive predictive value (98%), while morphology showed the greatest negative predictive value (50%). Of the 1,406 samples, 25 +/- 2% of the samples with normal semen parameters displayed a negative BCMPT. Conversely, 6 +/- 2% of samples with abnormal parameters showed a positive BCMPT. The BCMPT successfully identifies a significant subpopulation of patients as having an inadequate penetration of mucus with otherwise normal semen characteristics.

Animals↗
PubMed2000

Reconstruction of laser-scanned 3D torso topography and stereoradiographical spine and rib-cage geometry in scoliosis.

Assessments of scoliosis are routinely done by means of clinical examination and full spinal x-rays. Multiple exposure to ionization radiation, however, can be hazardous to the child and is costly. Here, we explain the use of a noninvasive imaging technique, based on laser optical scanning, for quantifying the three-dimensional (3D) trunk surface topography that can be used to estimate parameters of 3D deformity of the spine. The laser optical scanning system consisted of four BIRIS laser cameras mounted on a ring moving along a vertical axis, producing a topographical mapping of the entire torso. In conjunction with the laser scans, an accurate 3D reconstruction of the spine and rib cage were developed from the digitized x-ray images. Results from 14 scoliotic patients are reported. The digitized surfaces provided the foundation data to start studying concordance of trunk surface asymmetry and spinal shape in idiopathic scoliosis.

Calibration↗
PubMed2000

Brief negotiation program for promoting behavior change: the Kaiser Permanente approach to continuing professional development.

BACKGROUND: Behavior change counseling is one of the most difficult and constant challenges faced by health providers. It has a significant impact on clinical outcomes as well as patient and provider satisfaction. By encouraging patients to participate in a partnership with health care professionals, Brief Negotiation offers techniques to motivate behavior change successfully. We review the key components of Brief Negotiation and describe how one large group model health maintenance organization was able to identify key staff members, develop educational opportunities and implement Brief Negotiation system-wide into standard care practices. OBJECTIVES: To expose a maximum number of health care professionals to a recommended model of behavior change counseling; to increase the satisfaction and confidence of health care professionals in counseling for behavior change; and to increase the likelihood of improved patient health outcomes. METHOD: Two departments created one-day, two-day, six-hour and one-to-two-hour skill-based programs targeted to physicians, nurse practitioners, care managers, clinical health educators, behavioral medicine specialists, physical therapists, pharmacists and medical assistants. Practice protocols, strategic departmental alliances and intranet sites complemented the educational interventions. RESULTS: Over 1000 health care professionals have been exposed to the Brief Negotiation model in over two years. A mailed survey to graduates of the one- and two-day programs indicated that 67% of physicians and 79% of other health professionals felt more confident about working with patients on behavior change after having attended the Brief Negotiation program. CONCLUSIONS: System-wide professional development requires multiple exposures to the Brief Negotiation model, considerable resources for curriculum development, training time and follow-up, and credible clinical trainers. Questions remain about the amount of training needed for long-term clinician behavior change and for improved health outcomes in patients.

Journal Article↗