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Biomedical subjects

R Roth

Publications and source records attributed to R Roth.

At least 73 records · Page 4Linked to original sources
PubMed1997

Valaciclovir versus acyclovir in the treatment of first-episode genital herpes infection. Results of an international, multicenter, double-blind, randomized clinical trial. The Valaciclovir International Herpes Simplex Virus Study Group.

BACKGROUND AND OBJECTIVES: Valaciclovir, the L-valine ester prodrug of acyclovir, is much better absorbed than acyclovir and produces acyclovir exposures three to five times those attainable with the parent drug. GOALS: To determine whether the improved bioavailability of valaciclovir and a more convenient, less frequent dose regimen can maintain the clinical efficacy previously demonstrated for acyclovir. STUDY DESIGN: This was an international, multicenter, randomized, double-blind clinical trial comparing 10-day regimens of valaciclovir (1000 mg, twice daily) and acyclovir (200 mg, 5 times daily) in the treatment of 643 otherwise healthy adults (> or = 18 years of age) with first-episode genital herpes. Patients were evaluated clinically and lesions were staged and cultured on days 1, 2, 3, 5, 7, 10, 14, and then twice weekly until healed. Blood for herpes serology tests was obtained on days 1 and 14; hematology and chemistry toxicity screening was done on days 1 and 7. RESULTS: Valaciclovir and acyclovir did not differ significantly in efficacy with respect to duration of viral shedding (hazard ratio, 1.00; 95% confidence interval [CI], 0.84-1.18), time to healing (hazard ratio, 1.08; 95% CI, 0.92-1.27), duration of pain (hazard ratio, 1.0; 95% CI, 0.85-1.18), and time to loss of all symptoms (hazard ratio, 1.02; 95% CI, 0.85-1.22). Patients with primary genital herpes (no preexisting antibody to either herpes simplex virus type at enrollment with seroconversion at day 14) had longer times to healing and longer duration of viral shedding and pain than patients with nonprimary first genital episodes. Adverse experiences were generally infrequent and mild and were comparable in the two treatment groups. CONCLUSIONS: Twice-daily valaciclovir proved as effective and well tolerated in the treatment of first-episode genital herpes as five-times-daily acyclovir. Valaciclovir provides a useful alternative to acyclovir with the advantage of a more convenient dosing regimen and the potential for improved compliance.

Acyclovir↗
PubMed1997

B7-1 and B7-2 monoclonal antibodies modulate the severity of murine Lyme arthritis.

We assessed the role of B7-1 and B7-2 costimulatory molecules on the course of murine Lyme borreliosis because experimental Lyme arthritis is dependent, at least partially, upon the development of the host immune response and these costimulatory molecules have been implicated in CD4+ T-cell differentiation. We demonstrated that Borrelia burgdorferi infection upregulated the surface expression of B7-1 and B7-2 in macrophages and B7-2 expression in B cells. Anti-B7-2 monoclonal antibody (MAb) or both anti-B7-2 and anti-B7-1 MAbs produced a dose-dependent increase in the severity of Lyme arthritis in C3H/HeN mice. In contrast, the administration of an anti-B7-1 MAb reduced the degree of arthritis. These effects occurred independently of significant alteration in B. burgdorferi-specific immune responses, including splenocyte proliferative responses to B. burgdorferi, B. burgdorferi antibody levels and specificity, and mRNA levels of gamma interferon, interleukin-4 (IL-4), IL-10, and IL-12 in the spleen. These results demonstrate that signaling delivered by B7-1 and B7-2 plays a role in determining the severity of acute murine Lyme arthritis.

Animals↗
PubMed1997

Trafficking of adoptively transferred B lymphocytes in B-lymphocyte-deficient mice.

Many studies have investigated the fate of adoptively transferred lymphocytes in recipient mice, although little is known of the sites where these transferred cells reside at particular time points. Using flow cytometry, we analyzed the trafficking pattern of adoptively transferred naive B cells into the lymphoid organs of syngeneic B-cell-deficient (microMT) mice. Within the first 24 h of transfer, the location of B cells was highly dependent on the mode of B-cell transfer. When B cells were injected subcutaneously into microMT mice, they showed a different trafficking pattern from cells administered into the peritoneal cavity or injected intravenously. After subcutaneous transfer into the thigh, the greatest number of B cells was detected in the popliteal lymph node nearest to the injection site, whereas the lowest number was detected in the axillary lymph node opposite to the injection side. Within the first 24 h of either intraperitoneal and intravenous injection, B cells were found in approximately equal numbers in the lymph nodes and the spleen. Two days later, the B-cell distribution in the lymphoid organs appeared to be independent of the mode of B-cell transfer. A transient decrease in the numbers of splenic and lymph node B cells occurred 9 days after B-cell transfer (a decrease from 70 to 87%) prior to the outgrowth of B cells that occurs 21 days after transfer. These studies are useful for understanding the numbers of B cells that may be required in adoptive transfer studies and their potential cellular interactions at particular physiological sites based on the route of cell transfer.

Adoptive Transfer↗
PubMed1997

Psychological aspects in diabetes prevention trials.

Growing understanding of the pathogenetic process of insulin-dependent diabetes mellitus diabetes has favoured attempts to predict the clinical manifestation of the metabolic disorder in people at risk by some easily measurable marker or markers and, subsequently, to prevent its onset. This complicated process includes the screening procedure based on the assumption of an eventually positive finding, the detection of islet cell antibody positivity, metabolic tests for the evaluation of the actual state of energy metabolism, the categorization of the respective individual's risk to develop diabetes, the commencement of some placebo-controlled interventive measure, and finally the chance to fail to prevent the disease. Every step in this process may constitute both a threat and a severe burden to the affected individual and his/her family, eventually arousing conflicts and depression, and hopefully also attempts to deal and cope with them. The coping procedure, however, may be greatly influenced by various pre-existing primary and acquired secondary factors. Because at present prevention trials are justified only in families already exposed to this disease, the latter may depend upon the impact of diabetes in one (or more) member(s) of the family, and upon their acquired competence to cope with the various challenges it brings. On the other hand, personal characteristics, such as individual maturity, emotional stability and the integrity of one's self-image in spite of this threat, and the competence of the family to support the threatened member may be important codeterminants of the individual's response to disease prediction and preventive activities. In order to understand the impact of disease prediction and prevention on the individual better, but also to increase his coping potential by competent advice, future prevention trials should be accompanied by psychological research and competent offers of support for the affected individuals and their families.

Clinical Trials as Topic↗
PubMed1996

B7 costimulation and autoantigen specificity enable B cells to activate autoreactive T cells.

This study examines the role of B cells as auto-APCs in activating autoimmune T cells responses. Mice immunized with their own cytochrome c (cyt c) elicit no detectable B or T cell responses. However, mice first primed with a cryptic self peptide, mouse cyt c 81-104, followed at 3 wk with a boost of whole cyt c, elicit autoreactive T cells specific to self cyt c. T cell autoimmunity is not elicited in similarly immunized B cell-deficient (mu MT) mice. The expression of the B7-2 and/or B7-1 costimulatory molecules, as well as specificity to a self Ag, cyt c, enabled B cells to activate T cells to proliferate and to express IFN-gamma, IL-4, IL-5, and IL-10 cytokine mRNAs. In contrast, neither adoptively transferred B7- B cells nor nonspecific B7+ B cells were able to activate naive T cells. Moreover, anti-B7-2 treatment of mice prevented the in vivo expression of the IL-4, IL-5, and IFN-gamma cytokine mRNA responses. Our results suggest a major role of autoantigen-specific, B7-bearing B cells in breaking T cell tolerance to self Ag.

Adoptive Transfer↗
PubMed1996

Comparison of monocytes and B cells for activation of human T helper cell subsets.

Human rye grass allergen Lol p I-specific T helper cell clones of Thp, Th0, Th1 and Th2 subtype were activated with Lol p I and monocytes or B cells as antigen-presenting cells, and cell proliferation, interleukin (IL)-2, interferon-gamma, and IL-4 secretion were measured. Monocytes induced activation of T cell clones of all four T helper cell subsets and were usually more potent antigen-presenting cells than B cells. B cells and monocytes similarly induced proliferation and IL-4 secretion by Th2 clones, whereas B cells, in contrast to monocytes, only weakly activated Th1 clones. However, exceptions to this rule existed within each T helper cell subset suggesting that individual T cell clones, regardless of the subset to which they belong, may have quantitatively and/or qualitatively different requirements for secondary activation signals which are provided by the antigen-presenting cells. The data demonstrate that, in general, monocytes are more effective than B cells in activating human T cell clones of all subtypes and that B cells were efficient antigen-presenting cells only for Th2 cells. However, individual T cell clones of any given T helper cell subset vary with respect to their activation by monocytes or B cells.

Allergens↗
PubMed1996

Carbon monoxide ... the silent killer with an audible solution.

Carbon monoxide (CO) is responsible for more poisoning fatalities each year than any other toxic agent. The often insidious nature of the symptom progression and its ability to imitate many common illnesses may result in the failure to diagnose a potentially fatal outcome. CO detectors equipped with an audible alarm can alert potential victims of CO poisoning before toxic sequelae develop. A study was conducted in which all calls to 911 concerning a CO detector in alarm or regarding possible CO poisoning were investigated by a paramedic crew; 101 possible CO exposures were investigated. CO detectors with audible alarms were the genesis of 59.4% of the calls. Detectable CO levels were found in 69.3% of the investigations, and 80% of the homes with detectors had verifiable CO concentrations. The mean CO concentration in homes with detectors was 18.6 ppm, compared with 96.6 ppm when no detector was available; 63.4% of the victims with no alarm were symptomatic, compared with 13.3% of victims with alarms. CO detectors with audible alarms were effective in alerting the potential victims of CO poisoning to its presence. Persons with CO detectors were less likely to become symptomatic from a CO exposure than those who did not have CO detectors.

Carbon Monoxide↗
PubMed1996

Activation of cloned human CD4+ Th1 and Th2 cells by blood dendritic cells.

Dendritic cells (DC) have been reported to be the most potent antigen-presenting cells (APC) for the activation of naive T cells and to be 10-100-fold more potent APC than monocytes (M phi) in the mixed lymphocyte reaction. In this study the authors compared human blood DC with M phi and B cells for their ability to activate cloned rye grass allergen Lol p I specific CD4+ Th1 and Th2 cells. In the presence of Lol p I, all three types of APC activated Th1 and Th2 cells to a similar extent, as shown by T-cell proliferation and interferon-gamma, interleukin-2 (IL-2) or IL-4 secretion. However, at low APC:T cell ratios, M phi were the most potent APC for both Th1 and Th2 cells followed in decreasing order by DC and B cells. This hierarchy was observed with APC preparations isolated by negative selection or highly purified by positive selection using fluorescent cell sorting for HLA-DR(high)-DC, CD14(pos)-M phi and CD19(pos)-B cells. The data demonstrate that, in contrast to what has been reported for naive T cells, human blood DC activate cloned memory Th1 and Th2 cells to a similar extent as M phi and B cells presumably because the requirements for activation of memory type T cells are less stringent than those for naive T cells.

Antigen-Presenting Cells↗
PubMed1996

[Endovascular therapy of visceral aneurysms].

Sixteen cases of endovascular treatment of aneurysms and pseudoaneurysms were reported; five patients had true aneurysms, 11 presented pseudoaneurysms of splanchnic arteries. In all cases embolization was performed with coils; in one case we used coils in combination with Ethibloc. In 14 of 16 patients definite occlusion of the aneurysms was achieved without further surgical intervention.

Adult↗
PubMed1995

Activation of complement by human hemoglobin and by mixtures of hemoglobin and bacterial endotoxin.

Purified human hemoglobin is being developed as an alternative to transfusions of homologous erythrocytes. However, toxicity associated with infusion of hemoglobin has limited the development of this resuscitation fluid. Some observed toxicities, including activation of the complement cascade, have been associated with contamination of hemoglobin solutions by bacterial endotoxin. Recent studies have demonstrated complex formation between hemoglobin and endotoxin, and have documented a resultant increase in the ability of endotoxin to activate coagulation, stimulate tissue factor production by human peripheral blood mononuclear cells, and stimulate tissue factor activity and protein synthesis in cultured human endothelial cells. The process of hemoglobin enhancement of endotoxin toxicity suggests a possible mechanism by which the consequences of endotoxin contamination of hemoglobin solutions, including complement activation, could be magnified. Therefore, we studied the potential of hemoglobin to either fix complement directly, or modify the ability of endotoxin to fix complement. Human crosslinked and native hemoglobins, at concentrations between 0.2 mg/ml and 3 mg/ml, were shown to fix complement. Complement fixation by hemoglobin was identical in normal human serum or in factor B-depleted serum, suggesting that fixation occurred via the classical pathway of complement activation. Complement fixation then was examined with a battery of smooth and rough endotoxins tested in the absence and presence of hemoglobin. Addition of hemoglobin to a solution of a rough Salmonella endotoxin partial structure, from which a single fatty acid had been hydrolyzed from the lipid A portion of the macromolecule, resulted in decreased efficiency of complement fixation. However, addition of hemoglobin had little or no effect on the intrinsic complement fixing abilities of eight other smooth endotoxins, rough endotoxins, or endotoxin partial structures. Our results demonstrated the ability of hemoglobin to fix complement at hemoglobin concentrations which would be achieved during infusion for resuscitation, but failed to demonstrate a reproducible effect of hemoglobin on the activation of complement by endotoxin.

Bacterial Toxins↗
PubMed1995

FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae.

Type 1 pili are heteropolymeric mannosebinding fibers produced by all members of the Enterobacteriaceae family. The bulk of the fiber is composed of FimA. Two macromolecular complexes responsible for mediating an interaction with mannose-containing receptors were purified from fimA- Escherichia coli by mannose affinity chromatography and ion-exchange chromatography. One complex contained only the mannose-binding adhesin, FimH, associated with FimG, a minor component of the type 1 pilus. In the other complex the FimG-FimH moiety was loosely associated with a chaperone-minor subunit complex (FimC-FimF), possibly representing an intermediate in tip fibrilla assembly. The FimC chaperone has also been shown to form a preassembly complex with FimH that has been purified and characterized previously. Purified FimC did not bind to the FimG-FimH complex but did recognize FimH dissociated from the FimG-FimH complex. Quick-freeze deep-etch electron microscopy revealed that the FimG-FimH complex had a thin fibrillar architecture. High-resolution electron microscopy of type 1 pili revealed that a 16-nm fibrillar tip structure with an architecture identical to that of the FimG-FimH complex was joined end-to-end to the pilus rod. In a fimH- deletion mutant, the tip fibrillae joined to pilus rods were approximately 3 nm in length. The full-length tip fibrilla was restored by complementation with the fimH gene in trans. The bipartite nature of the type 1 pilus was also demonstrated on pili purified from clinical isolates of members of the Enterobacteriaceae family arguing that it is a conserved feature of the type 1 pilus.

Adhesins, Escherichia coli↗
PubMed1995

Effects of a heterogeneous set of xenobiotics on RNA synthesis of yeast cells.

Previously the toxicity of 45 heterogeneous environmental chemicals on growth and membrane functions in Saccharomyces cerevisiae and Chinese hamster ovary (CHO) cells (Cascorbi et al., 1993) was examined. In this study the inhibitory effects of the same set of chemicals on yeast RNA synthesis rate, measuring [2-14C]uracil uptake during cell proliferation are presented. The sensitivity of this test system was three to six times higher than that of the proliferation rate assay. In addition, the range of the EC20 values were similar to the range from the mammalian CHO cell proliferation test. The relatively good correlation with the yeast cell growth rate (r = 0.78, P = 0.0001) suggests that yeast RNA synthesis is a simple and rapid method of detecting a wide range of toxic compounds without the disadvantage of the insensitivity of the growth rate assay.

Allyl Compounds↗
PubMed1995

Developmental toxicity study of clarified slurry oil (CSO) in the rat.

Pregnant CD rats were exposed dermally to 0.05, 1, 10, 50, and 250 mg/kg/day of Clarified Slurry Oil (CSO) on Days 0-19 of gestation to determine its potential developmental toxicity. Untreated and vehicle controls were included in the study. Day 20 of gestation Caesarean-derived fetuses were examined for gross, external, and visceral or skeletal alterations. Dosages of 1 mg/kg/day and higher significantly decreased maternal body weight, body weight gain, feed consumption, gravid uterine weight, and live litter size and significantly increased resorption rate. These dosages also significantly reduced fetal weights and retarded development of the brain, kidney, thoracic and caudal vertebrae, metacarpals, and hindpaw phalanges in dosage groups with live fetuses (high dosage group dams resorbed all conceptuses). The 50- and 250-mg/kg/day dosage group dams had only placentas and/or dark red viscous fluid in the uterus or vagina and significant body weight loss (associated with resorption). The highest dosage also caused emaciation, slight dehydration, and swollen dark anogenital areas. These results indicate that CSO produces adverse developmental effects at maternally toxic dosages. The maternal and developmental NOAELs (no observed adverse effect levels) were 0.05 mg/kg/day. In a second study, groups of 10 mated female rats were exposed to "pulse" exposures and dosages of 1, 50, or 250 mg/kg/day of CSO applied dermally for 2- or 3-day intervals that spanned the gestation period. All dosages reduced maternal feed consumption and body weight gain during the treatment period. Dosages of 50 and 250 mg/kg/day also produced early resorptions when administered on Days 6 through 8 and 9 through 11 of gestation. However, no increase in fetal alterations occurred, indicating that the effects on embryo-fetal development were due to early death and not to the death of malformed conceptuses.

Abnormalities, Drug-Induced↗