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Biomedical subjects

J Miller

Publications and source records attributed to J Miller.

At least 469 records · Page 26Linked to original sources
PubMed1995

Early, but not late, antiepileptic treatment reduces relapse of sound-induced seizures in the post-ischemic rat.

Global ischemia was used to induce a sensitivity to sound-triggered generalized seizures in 24 male Long-Evans rats. All showed a generalized seizure when exposed to a 108 dB bell for 1 min. They were assigned randomly to 3 groups of 8, and received 30 additional sound exposures. The early treatment group was injected with valproate (200 mg/kg i.p) 1 h prior to each of the first 10 sound exposures. The late treatment group received the same treatment during the second set of 10 sound exposures after 10 sound exposures without treatment. The third group was untreated. Both early and late treated groups had a significant reduction in seizure incidence during the treatment period, i.e. both groups showed seizure control. However, in the late group seizures returned promptly when valproate treatment was discontinued, while the early group showed a sustained reduction in seizure susceptibility. Since this outcome corresponds to seizure remission, the findings of this study favor early treatment.

Acoustic Stimulation↗
PubMed1995

Efficient internalization of MHC class II-invariant chain complexes is not sufficient for invariant chain proteolysis and class II antigen presentation.

In Ag-presenting cells, MHC class II molecules bind antigenic peptides in endocytic compartments and transport them to the cell surface for presentation to CD4+ T cells. Newly synthesized class II alpha beta heterodimers associate with a third polypeptide, invariant chain (Ii), in the endoplasmic reticulum. This association may prevent class II molecules from binding peptides until they are transported to endocytic compartments where Ii is proteolyzed. Signals in the Ii cytosolic tail are believed to be responsible for the targeting of class II-Ii complexes to endocytic compartments, but it is unclear whether this targeting event occurs at the trans face of the Golgi or at the plasma membrane. In this report, we address whether the endosomal localization signal in the Ii cytosolic tail can be functionally substituted with a tyrosine-based signal for rapid internalization from the cell surface. A chimeric protein was generated in which the Ii cytosolic tail was replaced in its entirety with the cytosolic tail from transferrin receptor. In cells expressing this chimeric form of Ii, newly synthesized class II-Ii complexes travel rapidly to the cell surface and are internalized efficiently, but Ii proteolysis is delayed and class II Ag presentation is inhibited. These results suggest that targeting class II-Ii complexes to early/recycling endosomes from the cell surface does not in itself lead to Ii proteolysis; subsequent delivery to later endosomes may be required. The data suggest that signals for this targeting event may lie in residues 18 to 29 of the Ii cytosolic tail.

Amino Acid Sequence↗
PubMed1995

De novo membranoproliferative glomerulonephritis in hepatitis C virus-infected renal allograft recipients.

Hepatitis C virus (HCV) is the leading cause of non-A, non-B hepatitis among renal allograft recipients. We sought to identify and describe a proteinuric renal disease occurring in our HCV-infected renal transplant patients. Patients with proteinuria exceeding 1 g/day were identified from a cohort of 98 HCV-infected kidney recipients. Qualitative and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and restriction fragment-length polymorphism of the amplified RT-PCR product was performed to detect circulating HCV RNA, viral titer, and strain type, respectively. An immune complex nephritis (ICN) of the membranoproliferative pattern (MPGN) was found on five of eight biopsies. Two patients infected with the Hutch strain-type developed nephrotic-range proteinuria within three months posttransplant while the remaining three MPGN patients had been transplanted greater than 5 years prior to the onset of proteinuria. Testing for rheumatoid factors, cryoglobulins, hypocomplementemia, and circulating immune complexes failed to show a consistent pattern. Sucrose density gradient (SDG) equilibrium centrifugation was used to determine the buoyant-density of HCV virions from control (HCV-infected nonproteinuric recipients; n = 5) and nephrotic patients (n = 5). Whereas HCV virions from the control patients had a low buoyant density on sucrose gradients, a substantial percentage of the circulating HCV RNA from the MPGN patients was present in the high-density fractions in association with IgM and IgG. Treatment of the pooled high-density layers with NP40 followed by recentrifugation resulted in a shift of the HCV RNA to the medium-density layers. In conclusion, MPGN developed in five HCV-infected kidney recipients despite pharmacologic immunosuppression. Both the physicochemical properties of the HCV virions on SDG and their association with IgG and IgM in the high-density layers provide indirect evidence for the presence of circulating complexes of anti-HCV antibody and HCV antigen(s).

Adult↗
PubMed1995

B7-1 expression by a non-antigen presenting cell-derived tumor.

The existence of a naturally occurring immunosurveillance against neoplastic cells is controversial. A difficulty with this concept is that tumor-specific antigen-reactive T cells would not be expected to become activated after encountering tumor cells, since T cells that bind to antigen in the absence of the costimulation provided by antigen-presenting cells may be inactivated. We studied a transgenic model of tumorigenesis where T cells reactive to a particular tumor-specific antigen are lost prior to the development of non-antigen-presenting cell-derived tumors; therefore, the tumors that develop are not subjected to immunosurveillance. We found that a tumor cell line derived from one such tumor expresses the T-cell costimulatory molecule B7-1, the expression of which is normally restricted to antigen-presenting cells. In addition, we found that several immortalized cell lines, which are nontumorigenic and thus have suffered only early genetic events in the tumorigenesis process, express B7. This suggests that a host cell can be induced to express surface B7-1 molecules after suffering an oncogenic insult, which might possibly be a primary mechanism of immunosurveillance against tumors.

3T3 Cells↗
PubMed1995

Identification of a unique costimulatory activity for murine T helper 1 T cell clones.

We have examined the ability of several class II-positive tumor cell transfectants to stimulate murine Th1 clones. Most of the transfectants failed to activate the Th1 clones and, in fact, induced Ag-specific anergy. However, we found that one tumor, a UV-induced fibrosarcoma (6130-VAR1), was capable of stimulating both cytokine production and proliferation in Th1 clones. We believe that 6130-VAR1 cells possess a unique costimulatory activity for the following reasons. First, these cells fail to express known costimulatory molecules including B7-1 and B7-2. Second, 6130-VAR1-mediated stimulation of Th1 clones was not blocked by anti-CD28 Fab or by CTLA4Ig, which suggests that members of the B7 family were not up-regulated during the course of stimulation and that activation does not occur via a CD28-dependent pathway. Third, 6130-VAR1 could provide costimulation when presented on a different surface than the class II/peptide ligand for the TCR. This last finding suggested that the activity on these cells was not simply an adhesion molecule that facilitated increased efficiency of T cell:MHC interactions. Finally, like B7-1 transfectants, stimulation by class II-positive 6130-VAR1 cells prevented the induction of anergy in the Th1 clones. Taken together, these results strongly suggest that 6130-VAR1 expresses a unique costimulatory activity (VAM-1) that, like B7-1, can promote T cell activation and prevent anergy induction.

Animals↗
PubMed1995

Acute graft loss secondary to necrotizing vasculitis. Evidence for cytokine-mediated Shwartzman reaction in clinical kidney transplantation.

A small number of kidney transplant recipients abruptly lose function secondary to acute renal artery or vein thrombosis or more rarely a form of necrotizing vasculitis. We report a group of four kidney transplant recipients who lost renal function and share the following features: (1) diabetes (type I, insulin-dependent diabetes mellitus, type II or steroid-induced); (2) abrupt change/loss of renal function; (3) a concomitant clinical event (fever, viral symptoms, menometrorrhagia, viremia, bacteremia); (4) severe necrotizing vasculitis with hemorrhagic necrosis on histopathology; (5) patent renal artery and vein at time of transplant nephrectomy (i.e., no vascular thrombosis); and (6) high levels of peripheral serum gamma-IFN 1-5 days before transplant nephrectomy (467 +/- 175 pg/ml) compared with that of patients experiencing severe rejection (8.4 +/- 3.7 pg/ml) (P < 0.002). These data support the concept of a cytokine (IFN-gamma)-mediated accelerated inflammatory response resulting in graft loss from necrotizing vasculitis--the clinical equivalent of an organ-specific Shwartzman reaction.

Adult↗
PubMed1995

Lack of effectiveness of magnesium in chronic stable asthma. A prospective, randomized, double-blind, placebo-controlled, crossover trial in normal subjects and in patients with chronic stable asthma.

BACKGROUND: Magnesium sulfate has been helpful in the treatment of acute exacerbations of asthma. We hypothesized that magnesium would also be an effective bronchodilator in patients with chronic stable asthma. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled, crossover trial in 15 patients with chronic, stable asthma and 10 nonasthmatics. On study day 1, spirometry and albuterol challenge were used to confirm the presence of asthma according to American Thoracic Society criteria. On study day 2, subjects received intravenous magnesium sulfate (2 g) or placebo (saline). On study day 3, subjects were crossed over to receive the other drug. Spirometry was performed before, during, and after drug or placebo administration. Circulating ionized magnesium concentrations were determined before and after intravenous magnesium or placebo administration. RESULTS: Magnesium infusion caused no statistically significant changes in forced expiratory volume in 1 second (mean +/- SEM, 1.92 +/- 0.13 L before, 1.98 +/- 0.12 L during, and 2.01 +/- 0.14 L after magnesium administration), forced vital capacity (mean +/- SEM, 3.44 +/- 0.25 L before, 3.60 +/- 0.26 L during, and 3.59 +/- 0.25 L after magnesium administration), or maximum forced expiratory flow rate (mean +/- SEM, 5.42 +/- 0.44 L/second before, 5.46 +/- 0.46 L/second during, and 5.57 +/- 0.49 L/second after magnesium administration). Placebo caused no changes in these three physiologic variables. CONCLUSION: Magnesium is not effective as a bronchodilator in chronic, stable asthmatics or in normal non-asthmatic adults.

Adult↗
PubMed1995

Binding of major histocompatibility complex class II to the invariant chain-derived peptide, CLIP, is regulated by allelic polymorphism in class II.

Major histocompatibility complex class II-associated invariant chain (Ii) provides several important functions that regulate class II expression and function. One of these is the ability to inhibit class II peptide loading early in biosynthesis. This allows for efficient class II folding and egress from the endoplasmic reticulum, and protects the class II peptide binding site from loading with peptides before entry into endosomal compartments. The ability of Ii to interact with class II and interfere with peptide loading has been mapped to Ii exon 3, which encodes amino acids 82-107. This same region of Ii has been described as a nested set of class II-associated Ii peptides (CLIPs) that are transiently associated with class II in normal cells and accumulate in human histocompatibility leukocyte antigen-DM-negative cell lines. Currently it is not clear how CLIP and the CLIP region of Ii blocks peptide binding. CLIP may bind directly to the class II peptide binding site, or may bind elsewhere on class II and modulate class II peptide binding allosterically. In this report, we show that CLIP can interact with many different murine and human class II molecules, but that the affinity of this interaction is controlled by polymorphic residues in the class II chains. Likewise, structural changes in CLIP also modulate class II binding in an allele-dependent manner. Finally, the specificity and kinetics of CLIP binding to class II molecule is similar to antigenic peptide binding to class II. These data indicate that CLIP binds to class II in an analogous fashion as conventional antigenic peptides, suggesting that the CLIP segment of Ii may actually occupy the class II peptide binding site.

Alleles↗
PubMed1995

Molecular dynamics simulations of the effects of ring-saturated thymine lesions on DNA structure.

The effect of thymine lesions produced by radiation or oxidative damage on DNA structure was studied by molecular dynamics simulations of native and damaged DNA. Thymine in position 7 of native dodecamer d(CGCGAATTCGCG)2 was replaced by one of the four thymine lesions 5-hydroxy-5,6-dihydrothymine, 6-hydroxy-5,6-dihydrothymine (thymine photohydrate), 5,6-dihydroxy-5,6-dihydro-thymine (thymine glycol), and 5,6-dihydrothymine. Simulations were performed with Assisted Model Building with Energy Refinement force field. Solvent was represented by a rectangular box of water with periodic boundary conditions applied. A constant temperature and constant volume protocol was used. The observed level of distortions of DNA structure depends on the specific nature of the lesion. The 5,6-dihydrothymine does not cause distinguishable perturbations to DNA. Other lesions produce a dramatic increase in the rise parameter between the lesion and the 5' adjacent adenine. These changes are accompanied by weakening of Watson-Crick hydrogen bonds in the A6-T19 base pair on the 5' side of the lesion. The lesioned bases also show negative values of inclination relative to the helical axis. No changes in the pattern of backbone torsional angles are observed with any of the lesions incorporated into DNA. The structural distortions in DNA correlate well with known biological effects of 5,6-dihydrothymine and thymine glycol on such processes as polymerase action or recognition by repair enzymes.

Base Sequence↗
PubMed1995

Measles antibodies in women and infants in the vaccine era.

The present investigation was done to determine whether measles enzyme immune assay (EIA) absorbency values were lower in women born in the vaccine era after 1963 and their infants in an upstate New York metropolitan area, an area of low measles incidence during the past 10 years compared with women born before the measles vaccine era who had natural measles. Aliquots of 202 sera from mother-infant pairs collected for other purposes from November 1990 to June 1991 at Albany Medical Center Hospital were tested by EIA. The demographic data available for analysis were maternal age and infant gestational age. Measles mean absorbency values were analyzed according to maternal age. Of 202 mother-infant pairs, 30% of mothers and 17% of their infants were seronegative (EIA < 0.16). Mothers born before 1963 and their infants had significantly higher mean EIA absorbency values than mothers born after 1963 and their infants (P < 0.002). The percent seropositive for measles antibodies by EIA for mothers born before 1963 and their infants, 87% and 94%, respectively, was significantly higher than the percent seropositive for mothers born after 1963 and their infants, 61% and 69%, respectively (P = 0.0001). Since the mean measles antibodies as measured by EIA absorbency were significantly lower in the mothers born after 1963 and their infants compared with women born before the vaccine era, the strategy for measles control in the future may have to include lowering the age of infant immunization.

Adolescent↗
PubMed1995

Validation of a nitrogen washout system to measure functional residual capacity in premature infants with hyaline membrane disease.

A multiple-breath nitrogen washout system designed to measure lung volume in mechanically ventilated infants was validated by assessing three performance criteria: 1) accuracy of lung volume measurements in the presence of an endotracheal tube leak was assessed by comparing the measurements of functional residual capacity (FRC) in a mechanical lung model with and without airway leak; 2) in vivo accuracy was assessed in rabbits by comparing FRC measurements obtained by this system with measurements obtained by helium dilution; and 3) in vivo precision was assessed by analyzing measurements of FRC obtained in replicate measurements at different times in ventilator-dependent premature infants with hyaline membrane disease. The average difference between the measurements of FRC in a mechanical lung model with airway leak and without leak was 3.0 +/- 9.4% (mean +/- SD, P > 0.2), and no difference was greater than 20%. There was a significant correlation between the measurements of FRC in rabbits by nitrogen washout and by helium dilution (r = 0.93, P < 0.0001), and 65.4% of the paired measurements were within 20% of their average. The 95% limits of agreement within pairs of measurements by the two techniques ranged from -4.0 to + 6.5 mL/kg. FRC measured by helium dilution was slightly higher (1.3 +/- 2.7 mL/kg, P < 0.01) than FRC measured by nitrogen washout, and positive end-expiratory pressure was a significant predictor of this difference (P < 0.0001). The regression between the individual FRC measurements obtained in premature infants and the average of the other replicates was significant (r2 > 0.98, P < 0.0001). The coefficient of variation was 12.3%. These findings provide further validation of this multiple-breath nitrogen washout system for measuring FRC in premature infants during mechanical ventilation.

Animals↗
PubMed1995

Genetic map of rat chromosome 5 including the fatty (fa) locus.

Thirteen loci, including the obesity gene fatty (fa), were incorporated into a linkage map of rat Chromosome (Chr) 5. These loci were mapped in obese (fa/fa) progeny of a cross between BN x 13M-fal+F1 animals. Obese rats were scored for BN and 13M alleles at four loci (Ifna, D1S85h, C8b, and Lck1) by restriction fragment length polymorphisms and at eight additional loci (Glut1, Sv4j2, R251, R735, R980, R252, R371, and R1138) by simple sequence length polymorphisms (SSLP). The resulting map spans 67.3 cM of Chr5, presenting nine previously unmapped loci and one locus (Lck1) previously assigned to Chr 5 by use of somatic cell hybrid lines. Seven of the eight SSLP loci are newly identified; the SSLP linkage group alone spans 56.8 cM. The order of the loci is Sv4j2-R251-R735-R980-R1138-Ifna-fa-+ ++D1S85h-C8b-(Glut1-R252-R371)-Lck1. One locus, D1S85h, was found to lie only 0.4 cM from fa, close enough to serve as a reliable marker for the prediction of phenotype from genotype, and will be useful also for studies on the development of obesity in the fatty rat.

Alleles↗
PubMed1995

Transmission of hepatitis C virus by kidney transplantation: impact of perfusion techniques and course of viremia post transplant.

Hepatitis C virus (HCV) infection is the leading cause of post-transplant non-A, non-B hepatitis. Although many end-stage renal disease patients present for transplantation already infected with HCV, some recipients acquire the infection by transmission from the donor organ. We have detected serological evidence for HCV infection in 6.8% of our organ donors using second-generation anti-HCV assays. Approximately one-third of the patients who received an organ from a HCV carrier donor developed chronic transaminasemia and 8 of 14 (56%) patients converted from HCV RNA negative to positive in the posttransplant period. Demonstration of the course of viremia and transaminasemia is presented for 2 patients in whom transmission of HCV occurred. Using pulsatile machine perfusion, we were able to demonstrate that a standard perfusion of 20 h reduced the viral load in the kidney by 75%, additional flushes and a subsequent perfusion reduced the total viral titer by more than 99%. Thus, although transmission of HCV does occur with solid-organ transplantation, differences in the incidence of transmission between centers may be related to techniques of organ preservation.

Hepacivirus↗
PubMed1995

A Green's function method for heavy ion beam transport.

The use of Green's function has played a fundamental role in transport calculations for high-charge high-energy (HZE) ions. Two recent developments have greatly advanced the practical aspects of implementation of these methods. The first was the formulation of a closed-form solution as a multiple fragmentation perturbation series. The second was the effective summation of the closed-form solution through nonperturbative techniques. The nonperturbative methods have been recently extended to an inhomogeneous, two-layer transport media to simulate the lead scattering foil present in the Lawrence Berkeley Laboratories (LBL) biomedical beam line used for cancer therapy. Such inhomogeneous codes are necessary for astronaut shielding in space. The transport codes utilize the Langley Research Center atomic and nuclear database. Transport code and database evaluation are performed by comparison with experiments performed at the LBL Bevalac facility using 670 A MeV 20Ne and 600 A MeV 56Fe ion beams. The comparison with a time-of-flight and delta E detector measurement for the 20Ne beam and the plastic nuclear track detectors for 56Fe show agreement up to 35%-40% in water and aluminium targets, respectively.

Aluminum↗
PubMed1995

Effects of caffeine deprivation on complex human functioning.

Twenty-five managers who reported an average daily caffeine consumption of 575 mg participated in two complex simulations. A double-blind cross-over design was employed to assess the effects of normal caffeine consumption versus caffeine deprivation upon seven validated measures of managerial effectiveness. Data from a Caffeine Withdrawal Questionnaire indicated discomfort upon deprivation. Systolic blood pressure increased during "normal" caffeine consumption levels but fell quickly and remained lower during deprivation. Several measures of managerial performance indicated decreased effectiveness upon caffeine deprivation. In contrast to prior research from simpler task settings, cognitive effectiveness (during complex task performance) was diminished. However, a measure of strategic performance which requires a relatively high level of cognitive effort showed no impact of caffeine deprivation.

Adult↗
PubMed1995

Overlapping stage models and reaction time additivity: effects of the activation equation.

Many experimental factors have been found to affect mean reaction time (RT) additively in factorial experiments. What sorts of RT models are compatible with this fact? Sternberg (1969) showed that serial, discrete-stage models are consistent with additivity, and as a result additivity has sometimes been regarded as evidence in favor of such models. However, McClelland (1979) showed that an alternative "cascade" model, which violates crucial assumptions of discrete-stage models, also predicts RT additivity in many cases. This article examines various modified versions of the cascade model, and shows that mean RT additivity arises from many overlapping stage models, including some with thresholds, information quantization, and nonlinear activation transformations. This suggests that other aspects of the data besides mean RT additivity should be examined to distinguish between serial and overlapping stage models.

Arousal↗
PubMed1995

Potent effects of low levels of MHC class II-associated invariant chain on CD4+ T cell development.

Invariant chain (Ii)-negative mice exhibit defects in MHC class II assembly and transport that results in reduced levels of surface class II, altered antigen presentation, and inefficient positive selection of CD4+ T cells. Many CD4+ T cells that do mature in Ii-negative mice express a cell surface phenotype consistent with aberrant positive selection or peripheral activation. Reconstitution of these mice with low levels of either the p31 or p41 form of Ii does not restore transport of the bulk of class II or class II surface expression, but surprisingly does restore positive selection as measured by numbers and surface phenotype of CD4+ T cells. Thus, an Ii-dependent process, independent of effects on class II surface density, appears to be required for normal positive selection of CD4+ T cells.

Animals↗