Search PubMed⌕ Search

Biomedical subjects

R E Miller

Publications and source records attributed to R E Miller.

At least 73 records · Page 4Linked to original sources
PubMed1995

Description and evaluation of the Res-Q Arrhythmia Control Device.

The Res-Q Arrhythmia Control Device (Intermedics Inc.) is one of the latest entries into the growing implantable cardioverter defibrillator (ICD) market. Dysrhythmias are classified according to their zone of detection, with a bradycardia zone, up to 3 tachycardia zones, and a fibrillation zone. Detection criterion, therapies, and redetection criterion within each zone are independently programmable, tailoring the setup to each individual's needs. In a hierarchical manner, this allows efficacy, urgency, and patient comfort to be appropriately balanced. Tachycardia therapy options include antitachycardia pacing (ATP), low-energy cardioversion, and high-energy shock, while VVI pacing provides bradycardia therapy. ATP programming is extremely flexible. Biphasic waveform and a maximum output of 700 V have yielded a high rate of successful implantation. Unique features include the multiprogrammable sensing autogain, which tracks evoked T waves during pacing, as well as the use of the pulse generator to perform implant testing. Major strengths include programming flexibility and individualized therapy for multiple dysrhythmias. The major shortcoming relates to a lack of stored electrograms. Although long-term follow-up is not yet available, the Res-Q appears to be a capable challenger to a peer group of advanced generation ICDs.

Arrhythmias, Cardiac↗
PubMed1994

Interleukin 7 promotes long-term in vitro growth of antitumor cytotoxic T lymphocytes with immunotherapeutic efficacy in vivo.

A major obstacle to the effective use of adoptive immunotherapeutic treatment of cancer is the difficulty of obtaining tumor-reactive lymphocytes in either sufficient numbers or with appropriate in vivo function to make such an approach feasible. Previous studies have shown that antitumor cytotoxic T lymphocytes (CTL) with in vivo efficacy can be generated in vitro from lymphoid cells obtained from lymph nodes that drain the anatomical site of a tumor. Results presented here demonstrate that inclusion of interleukin 7 (IL-7) into the medium in which such CTL are cultured can support their growth in vitro for prolonged periods of time in the absence of repeated stimulation with either tumor stimulator cells or tumor antigen. More importantly, antitumor CTL propagated in medium containing IL-7 have retained both their antigenic specificity and their ability to reject tumors in vivo subsequent to intravenous injection. Parallel cultures of antitumor CTL similarly cultured in medium containing only IL-2 could only be maintained for 5-6 wk, after which the number and proportion of viable cells that were recoverable from such cultures progressively decreased. Phenotypic analysis of CTL maintained after extended culture (i.e., 22 mo) in medium containing IL-7 demonstrated them to be CD3+4-8+ T cells. These cells were also found to express lymphocyte function associated 1, intercellular adhesion molecule 1, and Mel-14 cell interaction molecules. The data also demonstrate that these CTL do not require the presence of antigen-presenting cell populations to mount a proliferative response to tumor stimulator cells. Cells in these cultures were also demonstrated to produce IL-2 after stimulation with irradiated tumor cells, thereby indicating that these CTL have become independent of the requirement for CD4+ helper cells to survive and function either in vitro or in vivo. Collectively, the findings that IL-7 can beneficially augment the generation, and propagate the long-term growth, of antitumor CTL from lymph nodes draining a tumor site may have profound implications for promoting the immunotherapeutic treatment of cancer in humans.

Animals↗
PubMed1994

gld/gld mice are unable to express a functional ligand for Fas.

Mice homozygous for either the lpr or gld genes develop phenotypically identical autoimmune disorders. The gene responsible for the pathology in lpr/lpr mice encodes the Fas antigen, a protein associated with the induction of programmed cell death. To determine if the defect associated with gld represents a mutation in the ligand for Fas, we have assessed the ability of lymphoid cells from homozygous gld/gld mice to lyse target cells in a Fas-dependent manner. Using an antagonistic antibody to Fas, we demonstrate that activated T cells from normal and lpr mice are capable of inducing Fas-mediated lysis of tumor target cells. In contrast, activated T cells from gld/gld mice fail to induce lysis of tumor targets, although cells from gld mice are able to lyse specific allogeneic targets following mixed lymphocyte culture. In addition, activated T cells from gld/gld homozygous animals are not capable of binding to a Fas.Fc fusion protein at high levels, whereas activated T cells from normal and lpr/lpr animals bind Fas.Fc efficiently. These data indicate that mice homozygous for gld are unable to express a functional ligand for Fas.

Animals↗
PubMed1994

The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF family gene cluster.

The gene for the mouse Fas ligand was cloned and its chromosomal position determined. Fasl was tightly linked to gld (no crossovers in 567 meiotic events) on mouse chromosome 1 and closely linked with a novel member of the same TNF family of ligands, the Ox40 ligand (Ox40l, 1 crossover in 567 meiotic events). Southern blot analysis did not reveal any difference between the Fasl gene from gld and wild-type mice and levels of Fasl mRNA transcripts were similar in PMA and ionomycin induced wild-type and coisogenic gld T cells. Sequence analysis of the gld gene indicated a single amino acid change (Phe Leu) in the COOH terminal portion of this type II transmembrane protein, and COS cells transfected with Fasl cDNA from gld mice failed to induce apoptosis of Fas-expressing target cells. Thus, the data demonstrate that the gld phenotype is the result of a point mutation in the Fasl gene and that Fasl is part of a complex of ligands structurally related to TNF mapping within a small region of mouse chromosome 1.

Amino Acid Sequence↗
PubMed1994

Differential ability of Th1 and Th2 T cells to express Fas ligand and to undergo activation-induced cell death.

Stimulation of previously activated T cells through the antigen receptor can result in the apoptotic death of the responding cell, a process referred to as activation-induced cell death (AICD). This process appears to involve Fas (CD95) and its ligand (Fas-L). The distribution of Fas and Fas-L on various T cell subsets has not been extensively characterized. We have therefore analyzed cells committed to a Th1- or Th2-type differentiation pattern for the expression and function of Fas-L. Using both a sensitive bioassay and flow cytometry, we demonstrate that cloned Th1 cells express high levels of Fas-L, whereas cloned Th2 cells express only low levels. The expression of Fas-L by Th1 and Th2 cells correlates with the relative abilities of these two cell types to undergo AICD. Whereas AICD is readily observed in cultures of cloned Th1, but not Th2 cells, Th2 cells are capable of undergoing apoptosis in the presence of Th1 cells expressing Fas-L. The ability of T cells to undergo AICD appears to be unrelated to the presence of various cytokines. Thus, the Fas/Fas-L pathway appears to be critical for the induction of AICD and this pathway is differentially regulated in cells committed to either Th1 or Th2 differentiation.

Animals↗
PubMed1994

Regulation of apoptosis and T cell activation by Fas-specific mAb.

Fas was initially described as a molecule expressed on the surface of certain cell lines that could mediate programmed cell death (apoptosis) subsequent to ligation by specific mAb. To determine whether mAb to other epitopes on the Fas molecule might mediate other functions, we generated a panel of mAb to the extracellular portion of human Fas. Significant lysis of Fas-expressing target cells was only observed when the new mAb were first bound to a solid-phase support and not when the mAb were added in solution. However, several of these mAb inhibited the killing of target cells induced by the prototypic Fas-specific mAb, CH-11. Those mAb that inhibited apoptosis of target cells mediated by the CH-11 mAb also blocked lysis of target cells mediated by cells expressing Fas ligand. Finally, some of the Fas-specific mAb were found to co-stimulate proliferation of peripheral blood T cells in the presence of immobilized CD3 mAb. Thus, the data indicate the existence of a complex set of interactions mediated by Fas in both normal and transformed lymphoid cells that may have important implications regarding the role(s) of this molecule in regulation of immune responses.

Animals↗
PubMed1994

Preparation and evaluation of peptidic aspartyl hemiacetals as reversible inhibitors of interleukin-1 beta converting enzyme (ICE).

Aspartyl aldehyde, Ac-Tyr-Val-Ala-Asp-H 1 (L-709,049), has been reported to be a potent, reversible inhibitor of interleukin-1 beta converting enzyme (ICE) [Thornberry, N.A. et al. (1992) Nature (London) 356, 768-774]. In the context of our own work, we have developed a general synthetic approach to peptidic aspartyl aldehydes. Semicarbazone derivative, H-Asp(Ot-Bu)-Sc 4, was identified as a stable, masked aspartyl aldehyde equivalent. We have used 4 to synthesize a series of mono-, di- and tripeptide aldehydes, and multigram quantities of Ac-Tyr-Val-Ala-Asp-H 1, Ac-Tyr-Val-Lys-Asp-Sc 21 and Ac-Tyr-Val-Lys-Asp-H 2. Biological evaluation of these aspartyl aldehydes and derivatives suggests that the tripeptide scaffold, Z-Val-Ala-Asp, is a peptide scaffold that retains good potency and selectivity for ICE.

Aldehydes↗
PubMed1994

Molecular cloning of mouse insulin-like growth factor binding protein 4 (IGFBP4) cDNA and expression of a fusion protein with IGF-binding activity.

The TC-1 bone marrow stromal cell line expresses a 2.3 kb IGFBP-4 mRNA transcript. Reverse transcription/polymerase chain reaction was used to amplify the complete open reading frame of the insulin-like growth factor binding protein-4 (IGFBP-4) from poly(A)+ of a murine bone marrow stromal cell line (TC-1). Sequence analysis reveals that the murine IGFBP-4 is highly homologous to the rat IGFBP-4 and less so to the human IGFBP-4. The inferred amino acid sequence has a molecular weight of 25.7 kD. An IGFBP-4/maltose binding protein fusion peptide expression in the pMal-p2 vector produced a fusion protein exhibiting both IGFBP immunoreactivity and IGF-I binding activity with specificity characteristic of IGFBPs.

Amino Acid Sequence↗
PubMed1993

Synthesis and antimalarial activity of some 9-substituted artemisinin derivatives.

Several 9-substituted derivatives of the antimalarial drug artemisinin have been prepared by functionalizing the double bond of artemisitene and related compounds. Stereochemical assignments for these compounds were made using a combination of NMR experiments, an X-ray diffraction study of one compound, and chemical correlations of several other compounds with this one compound of unambiguous structure and with its epimer. The compounds synthesized show a wide variation in in vitro antimalarial activity.

Animals↗
PubMed1993

Protective effects of recombinant human interleukin-1 alpha in doxorubicin-treated normal and tumor-bearing mice.

Experiments were performed to determine whether treatment with recombinant human IL-1 alpha (rhuIL-1 alpha) would protect C3H mice from the toxic effects of the widely used chemotherapeutic agent, doxorubicin (DXR). Pretreatment of mice with rhuIL-1 alpha was found to protect 85-90% of mice tested from the acute toxic effects of a lethal dose of doxorubicin (25 mg/kg). Late deaths (> 20 days post-DXR) were observed in a substantial proportion (40-45%) of rhuIL-1 alpha-pretreated mice. However, the data clearly demonstrate a beneficial effect of rhuIL-1 alpha pretreatment on the overall survival of mice challenged with DXR, since both the median survival (32 days) and proportion (53%) of surviving mice were significantly increased (P < 0.0001) compared to the control group (8 days and 14%, respectively). The beneficial effects mediated by rhuIL-1 alpha treatment were both dose- and schedule-dependent and were associated with decreases in the level and duration of DXR-induced neutropenia, and amelioration of the suppressive effects of DXR on myeloid progenitor cells (granulocyte/monocyte colony forming units) as evidenced by milder depressions in marrow cellularity and enhanced recovery of granulocyte/monocyte colony forming unit activity. Finally, pretreatment of mice bearing a solid tumor with rhuIL-1 alpha permitted effective dose escalation with DXR that resulted in decreased tumor growth rates and increased survival (90%) as compared to non-rhuIL-1 alpha-treated groups (20% survival). Thus, effective chemotherapeutic dose escalation is made feasible by rhuIL-1 alpha pretreatment of mice, but may ultimately be limited by nonhematological toxicities associated with DXR.

Animals↗
PubMed1993

The prevalence of hepatitis A, B and C infection among different ethnic groups in Belize.

Little is known about the prevalence of infection with hepatitis viruses in Belize, Central America. We conducted a serologic survey among members of the Belize Defence Force (BDF), which is composed of the five major ethnic groups in Belize, to estimate prevalence rates of hepatitis A, B, and C among military-aged men and women in Belize. Of approximately 600 men and women in the BDF, 492 (82%) completed a questionnaire and blood collection. Antibody to hepatitis A was found in 94%, with similar rates by age, sex, rank, and ethnicity. Antibody to hepatitis B core antigen (anti-HBc) was found in 31%. Rates of anti-HBc varied significantly among the ethnic groups with the lowest rates in Mestizo (5%) and Mayan Indians (9%), and significantly higher rates among Creoles (30%) and Garifuna (56%). Rates increased with increasing age from 28% in those 18-24 years old to 35% in those > or = 35 years old (P = 0.07, by chi-square test for trend). Hepatitis B surface antigen was found in 21 (4%) overall. Antibody to hepatitis C was found in two (0.4%). In this young healthy population, exposure to hepatitis A before the age of 18 is almost universal, while exposure to hepatitis B is related to age and ethnic origin.

Adult↗
PubMed1993

Laparoscopic management of peritoneal dialysis catheters.

Laparoscopic surgical techniques were used for peritoneal dialysis catheter placement or for revision in patients with previous extensive abdominal surgical treatment, multiple prior catheter insertions or dysfunctional catheters with outflow obstruction. Nineteen laparoscopic procedures were performed upon 16 patients between July 1990 and January 1992. All patients were chosen for the laparoscopic approach because of the complicated nature of previous incisions or in an attempt to salvage existing catheters. In five patients, open laparoscopy was performed with the blunt Hasson trocar, and in the remaining patients, closed techniques were used to establish the pneumoperitoneum. Dysfunctional catheters were revised by adhesiolysis, partial omental resection and subtotal omentectomy. New catheters were easily placed percutaneously, sometimes after extensive adhesiolysis, using direct laparoscopic guidance. All patients had functioning catheters postoperatively. Two catheters subsequently failed because of dislodgement and recurrent obstruction. The overall success rate for the entire series was 75 percent. We conclude that laparoscopy will be a useful addition to the surgical armamentarium in managing patients on peritoneal dialysis, particularly as this mode of renal replacement therapy rapidly expands.

Adult↗
PubMed1992

Pharmacokinetic parameters of recombinant mast cell growth factor (rMGF).

The gene product of the murine Steel (Sl) locus encodes an early-acting hematopoietic growth factor that is a ligand for the c-kit protooncogene. Several cDNAs for the Sl gene product, known as mast cell growth factor (MGF), stem cell factor (SCF), or kit ligand (KL), have recently been isolated, and both soluble and membrane-associated versions have been shown to be biologically active. The potential for therapeutic usage of recombinant MGF (rMGF) indicated a need for determining the biodistribution and elimination parameters of this cytokine. Pharmacokinetic studies demonstrated that radiolabeled rMGF had a distribution half-life of 2 min and an elimination half-life of 2.1 h in wild-type mice following iv injection, during which a striking localization of labeled rMGF in the lungs was noted. When administered by subcutaneous injection the elimination half-life was prolonged to 8.4 h. The primary sites of rMGF elimination appeared to be the kidneys and the liver. Pharmacokinetic analysis of labeled rMGF in mutant Sl/Sld mice, which are mast cell deficient, demonstrated similar distribution and elimination half-lives compared to wild-type mice (1.4 min and 1.8 h, respectively). In addition, the biodistribution pattern of the labeled rMGF in Sl/Sld mice was similar to that observed in wild-type mice, including the striking localization to the lungs. Binding of radiolabeled rMGF to lungs in vivo subsequent to iv injection was completely inhibited by excess unlabeled rMGF. Interestingly, mice that received an iv injection of the higher doses of rMGF (15 micrograms) demonstrated profound respiratory distress and hypotension within minutes of administration. Histologic analysis of lungs from such mice revealed extensive mast cell degranulation, which was associated with vasodilatation and pronounced hyperemia of virtually all pulmonary vessels. The respiratory distress in normal mice was probably a consequence of mast cell degranulation induced by rMGF since similar findings were not observed in Sl/Sld mice injected with identical concentrations of rMGF.

Animals↗
PubMed1992

Exercise testing for chronotropic assessment.

Cardiac chronotropic analysis has only begun to develop into a clinically relevant science. In the past, formal exercise testing was usually relegated to the assessment of ischemia or cardiac rehabilitation. The establishment of rate-responsive pacemakers as a potentially effective treatment for chronotropic incompetence forced the definition of cardiac chronotropism and assessment of the pacemaker response. Little is known about the normal chronotropic response and less has been established about patients with ventricular dysfunction or ischemia, but standards are being set and modern pacemakers have produced the ideal clinical laboratory for investigation. Advanced telemetry, including sensor and actual rate trends, histography and sensorgraphy produce previously unobtainable clinical data. Now scientific inquiry demands that chronotropic evaluations seek to match the pacemaker-augmented response of the chronotropically incompetent patient to the metabolic requirements of the body. Only with formal exercise testing will this goal be achieved.

Atrial Fibrillation↗