Zero-temperature critical behavior of the infinite-range quantum Ising spin glass.
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Journal Article↗
Biomedical subjects
J Miller
Publications and source records attributed to J Miller.
Hepatitis C virus and organ transplantation.
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Hepacivirus↗
Antitumor activity of N1,N11-bis(ethyl)norspermine against human melanoma xenografts and possible biochemical correlates of drug action.
In in vitro systems, the spermine analogue, N1,N11-bis(ethyl)norspermine (BENSPM), suppresses the polyamine biosynthetic enzymes, ornithine and S-adenosylmethionine decarboxylase (ornithine decarboxylase and S-adenosylmethionine decarboxylase, respectively), greatly induces the polyamine catabolic enzyme, spermidine/spermine N1-acetyltransferase (SSAT), depletes polyamine pools, and inhibits cell growth. Against MALME-3 M human melanoma xenografts, BENSPM and related homologues demonstrate potent antitumor activity that has been found to correlate positively with their ability to induce SSAT activity in vitro. Herein, we further evaluate the antitumor activity of BENSPM and at the same time characterize the biochemical effects of BENSPM treatment on polyamine metabolism of selected normal and tumor tissues. At 40 mg/kg 3 times/day for 6 days i.p., BENSPM suppressed growth of MALME-3 M human melanoma xenografts during treatment and for 65 days afterwards. Similar antitumor activity was obtained with 120 mg/kg once daily for 6 days and 40 mg/kg once daily for 6 days, indicating that against this tumor model, the dosing schedule can be relaxed up to sixfold without compromising antitumor activity. When MALME-3 M tumor-bearing mice were retreated with BENSPM 2 weeks after the first treatment at 40 mg/kg 3 times/day for 6 days, initial tumor volumes of 85 mm3 were reduced to < 10 mm3. Analysis of melanoma, liver, and kidney tissues from mice treated with 40 mg/kg 3 times/day for 6 days revealed relatively similar accumulations of BENSPM in all tissues at levels greater than the original total content of polyamine pools. By 2 weeks following treatment, BENSPM pools in normal tissues were almost gone, whereas in tumor tissues significant amounts (40%) were still retained. The biosynthetic enzymes, ornithine decarboxylase and S-adenosylmethionine decarboxylase, gave no indication of enzyme suppression (or increase) by the analogue as typically occurs in vitro. By contrast, SSAT was induced from an average of < 50 pmol/min/mg in control tissues to 320 pmol/min/mg in liver, 1255 pmol/min/mg in kidney, and 13,710 pmol/min/mg in MALME-3M tumor. Two weeks later, SSAT activity was still 12 times higher in tumor than in kidney. Polyamine pools (putrescine, spermidine, and spermine) were reduced after treatment in all tissues and approached near-total depletion in the tumor. Good antitumor activity and even more potent induction of SSAT (i.e., 26,680 pmol/min/mg) was also observed in PANUT-3 human melanoma xenografts. Overall, the findings reveal meaningful antitumor activity by BENSPM against 2 human melanoma xenografts and provide in vivo evidence consistent with SSAT-induced polyamine depletion playing a determining role in at least the initial phase of the antitumor response.
Acetyltransferases↗
Heparin-binding EGF-like growth factor: characterization of rat and mouse cDNA clones, protein domain conservation across species, and transcript expression in tissues.
Clones were obtained that encode the rat and mouse forms of heparin-binding EGF-like growth factor (HB-EGF), a potent mitogen for smooth muscle cells, fibroblasts and keratinocytes that is proposed to be derived from a transmembrane precursor. Within the HB-EGF precursor sequences predicted from these cDNAs, the region corresponding to the secreted ("mature") factor was found to represent one of the least well conserved areas when compared to human or monkey HB-EGF (73-76% sequence identity). Regions of high sequence conservation included the proposed juxtamembrane and transmembrane domains, as well as a proposed heparin-binding region within the "mature" factor. Northern blotting experiments using the HB-EGF clones as probes revealed HB-EGF transcript expression in multiple tissues, particularly lung, skeletal muscle, brain, and heart.
Amino Acid Sequence↗
Anergized T cell clones retain their cytolytic ability.
CD4+ T cells have been described to have both helper and lytic function. The helper function of Th1 cells in particular can be inactivated by inducing the T cell into a state of nonresponsiveness in which the T cell is no longer capable of producing IL-2 or proliferating in an autocrine way to a conventional antigenic stimulus. To determine whether the lytic ability of Th1 cells can also be rendered nonfunctional upon anergy induction, we induced Th1 clones into a nonresponsive state and tested their ability to lyse target cells in an Ag-specific and MHC class II-restricted manner. We show that cells newly induced into an anergic state were able to lyse target cells nonspecifically. This effect was short-lived and after resting in culture media, the cells regained their ability to lyse target cells in an Ag/MHC-specific manner, and this ability was comparable to normal resting T cells. In contrast, the helper function of these cells remained nonresponsive, and the cells were unable to proliferate or to secrete IL-2 in response to the same antigenic stimulus used for lysis. Therefore, the lytic pathway appears to be regulated separately from the proliferative/lymphokine pathway(s) and is not affected long-term by an anergic stimulus.
Animals↗
Chronic myelogenous leukemia: in search of the benign hematopoietic stem cell.
Donor marrow transplantation can cure chronic myelogenous leukemia (CML). Unfortunately, the procedure is associated with severe complications and is limited to the minority of potential recipients with suitably matched donors. Autologous marrow transplantation using negative selection approaches such as incubation with gamma interferon (IFN-gamma) can produce cytogenetic and clinical remissions, but they are often associated with recurrent evidence of leukemia. A primitive progenitor population can be separated from normal human marrow on the basis of morphologic characteristics and cell surface antigen expression. Cell populations with similar morphologic and phenotypic characteristics obtained by positive selection from the marrow of patients with CML appear to be benign. Benign primitive and committed progenitors selected in this fashion can be expanded ex vivo when cultured in a "Transwell" system which physically separates hematopoietic cells from stromal feeder layers. Positive selection and ex vivo cultivation of benign progenitors from CML marrow may provide a source of hematopoietic stem cells suitable for autologous marrow transplantation. Autologous natural killer (NK) cells obtained from the peripheral blood of patients with CML are of benign origin and have antileukemia activity. Interleukin 2 (IL-2) activated autologous NK cells may be used in post-transplant cellular therapy to prevent recurrence of CML.
Bone Marrow Transplantation↗
Reversible contractile dysfunction in reversible experimental cardiac allograft rejection: alterations in the beta-receptor-stimulated adenylylcyclase pathway.
Alterations in the beta-adrenergic receptor adenylylcyclase (AC) pathway are well known in heart failure. Previous studies by our group have demonstrated impaired function of the AC pathway and contractile reserve when stimulated with isoproterenol (ISO) or forskolin (F) in cardiac allografts with moderate or severe rejection. To determine if recovery of the AC pathway occurs when rejection is reversed, we used a rat heterotopic heart transplant model. Lewis (L) rats received either isografts or Lewis-Brown Norway (LBN) allografts (ALLO). The hearts were explanted on Day 4 and reimplanted into a recipient syngeneic with the original donor (L to L, LBN to LBN). Grafts were harvested 2 days later and analyzed. Receptor-mediated modulation of AC activity was investigated using ISO, F, and the metabolic inhibitor of AC, R-N6-(2-phenylisopropyl)-adenosine (R-PIA). ISO- and F-mediated stimulation of AC were significantly impaired in ALLO (see Table). CARB and R-PIA remained unchanged. [table: see text] Reimplanted hearts had no histologic evidence of rejection and had normal cAMP production in response to ISO and F. In conclusion, AC alterations are concordant with histologic changes in this reversible model of heart failure. Such alterations may be a component in the contractile dysfunction associated with rejection.
Adenylyl Cyclases↗
Elbow joint restriction: effect on functional upper limb motion during performance of three feeding activities.
This study was conducted to quantify and compare changes in upper limb joint motion during different feeding tasks when the elbow joint was restricted. Ten male and nine female volunteer subjects age 18 to 50 years participated; all were healthy, right dominant, with no upper limb pathology. A splint was used to restrict elbow joint motion. Three feeding tasks under both unrestricted and restricted conditions were randomly assigned; motion was recorded by a video-based three-dimensional motion analysis system. Elbow restriction resulted in significantly (p < .05) larger arcs of motion in shoulder flexion and internal rotation. Differences between feeding types were similar during both unrestricted and restricted conditions. Increased shoulder joint motion resulting from elbow joint restriction may require greater activity of shoulder girdle muscles increasing the risk of soft tissue problems and degenerative joint disease. Decisions regarding elbow immobilization should take into consideration potential effects upon total upper limb motion.
Activities of Daily Living↗
Necrobiotic xanthogranuloma without periorbital lesions.
Cutaneous necrobiotic xanthogranuloma is rare and closely resembles widespread necrobiosis lipoidica. It is important to recognize this skin disorder because of its strong association with paraproteinemia and, in some cases, with a hematologic malignancy. We describe two patients with necrobiotic xanthogranuloma who are unusual in that they had no periorbital involvement, a feature previously believed to be diagnostic of this condition.
Aged↗
Molecular monitoring of the immunosuppressive effects of cyclosporine in renal transplant patients by using a quantitative polymerase chain reaction.
We have developed a rapid (24 hours) quantitative PCR assay to measure the direct effect of cyclosporine on IL-2 mRNA production by activated PBMC cultures from renal transplant patients. The PBMCs were purified from normal laboratory volunteers (group A, n = 26), CsA-treated renal transplant patients with good renal function, tested between 3 and 8 weeks (group B, n = 14) or between 2 and 8 years (group C, n = 15) after surgery, and stimulated with PHA in media supplemented with either patient serum or pooled commercially obtained AB serum. The mRNA was then isolated and, using semiquantitative PCR or quantitative PCR with a competitive inhibitor, the relative levels or exact levels of IL-2 mRNA (in attomoles) could be measured. A 3-day confirmatory lymphoproliferation assay of [3H]thymidine incorporation was also performed on the samples. Kinetic analysis of the data from group A showed that the peak level of IL-2 transcription into mRNA occurred at 6 hours after mitogen stimulation. Increasing in vitro concentrations of CsA in this group resulted in lower IL-2 mRNA levels and a shift in the peak time to 12-24 hours. In the transplant recipients, there was no correlation between individual CsA blood levels and proliferation responses. However, some correlation was found between CsA blood levels and IL-2 mRNA levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
Transoral-transpharyngeal approach to the upper cervical vertebrae.
The classical operative approaches to the cervical spine include the posterior one and the anterior exposure along the sternomastoid muscle. However, neither of these are helpful in exposing the upper cervical vertebrae, especially the odontoid process, atlas, and axis. We have used the transoral-transpharyngeal exposure for lesions of the odontoid process and upper (first to third) cervical vertebrae in six patients. The pathologic processes included rheumatoid disease and fracture of the cervical vertebrae, suspected tumor with compression of the spinal cord, basilar invagination, and compression of the medulla. In all six patients, the exposure was excellent, and postoperative morbidity was minimal. Tracheostomy was performed routinely in all these patients. In five patients, vertebral stabilization was performed as a secondary procedure a few days after the initial anterior decompressive surgery. The transoral-transpharyngeal approach appears to be relatively easy. It is associated with minimal complications and provides excellent exposure of the odontoid and upper cervical vertebrae for a microneurosurgical approach. Modifications of this approach include incision of the soft palate, excision of a portion of the hard palate, and, occasionally, transmandibular median labio-mandibulo-glossotomy (Trotter's) approach. Although the technique was described initially approximately 35 years ago, this neglected anatomic approach will facilitate cooperative efforts between head and neck surgeons and neurosurgeons.
Adult↗
Laparoscopic cholecystectomy in patients admitted with acute biliary symptoms.
Laparoscopic cholecystectomy has become the standard of care for the elective management of cholelithiasis. Little information exists, however, regarding the appropriateness of this procedure in the setting of acute symptomatology. We retrospectively reviewed our experience with 516 laparoscopic cholecystectomies performed at a single institution from May 1990 to May 1991. Seventy-five (14.5%) of these patients were admitted from the emergency department with acute abdominal pain (100%), fever (4 of 75, 5%), and/or an elevated white blood cell count (22 of 75, 29%). There were 54 females and 21 males, with a mean age of 50.0 +/- 2.4 years (range: 17 to 89 years). Laparoscopic cholecystectomy was attempted in all patients, and was successful in 68 of 75 patients (91%). Seven procedures were converted to open cholecystectomy because of the difficulty in dissection precluding safe laparoscopic cholecystectomy. The time from admission to surgery (mean: 3.4 +/- 0.3 days), as well as the total hospital stay (mean: 5.5 +/- 0.6 days), was much longer than in the elective circumstance. Mean laboratory values for the group as a whole were as follows: white blood cell count (mean: 9.6 IU/L +/- 0.4 IU/L, range: 4.1 IU/L to 19.5 IU/L), alkaline phosphatase (mean: 97.0 IU/L +/- 13.7 IU/L, range: 27 IU/L to 375 IU/L), and alanine aminotransferase (mean: 78.3 IU/L +/- 13.7 IU/L, range: 15 IU/L to 701 IU/L). Patients requiring open cholecystectomy were older (mean: 61.4 +/- 4.4 versus 48.8 +/- 2.6), were more likely to be febrile (3 of 7, 42%, versus 1 of 68, 1%), and were more likely to have a significant leukocytosis (mean: white blood cell count 12.9 +/- 1.8 x 10(3) cells/mm3 versus 9.2 +/- 0.4 x 10(3) cells/mm3) than were those undergoing successful laparoscopic cholecystectomy. Laparoscopic cholecystectomy can be performed safely in the majority of patients presenting with acute biliary symptoms. Patients with a triad of acute abdominal pain, fever, and elevated white blood cell count, particularly elderly patients, are more likely to require conversion to open cholecystectomy, however.
Acute Disease↗
Immunocytologic findings in a case of Vogt-Koyanagi-Harada syndrome.
BACKGROUND: Vogt-Koyanagi-Harada (VKH) syndrome is a form of chronic panuveitis that often has a poor long-term visual outcome. To the authors' knowledge, there have been only two previous reports describing immunocytologic findings in the eyes of patients with VKH syndrome, all studied in relatively late stages of the disease. METHODS: The authors performed immunocytologic studies on the enucleated eyes of a patient with active VKH syndrome, using monoclonal antibodies to mononuclear subsets, major histocompatibility antigens, and viral and treponemal agents, to better understand the pathophysiologic mechanisms underlying the disease. Emulsified chorioretinal tissue also was processed for viral isolation in tissue culture and for Treponema pallidum by rabbit inoculation studies. RESULTS: The dense uveal infiltrates in active VKH syndrome are composed predominantly of T lymphocytes and HLA-DR+ macrophages. Scattered T cells and plasma cells were present in the retina. In addition, nondendritic-appearing CD1 (Leu-6) positive cells were localized in the choroid, in close proximity to choroidal melanocytes. No microbial agents were identified. CONCLUSION: Whereas the etiology of the VKH syndrome remains an enigma, the authors' immunocytologic findings are consistent with a T-cell-mediated disorder. In demonstrating CD1 (Leu-6) positive cells in the infiltrates, the authors propose a potential role for these cells in the etiology of VKH syndrome.
Cell Count↗
A queue-series model for reaction time, with discrete-stage and continuous-flow models as special cases.
This article presents a new reaction time model that includes both sequential-stage (discrete) and overlapping-stage (continuous-flow) models as special cases. In the new model, task performance is carried out by a series of distinct processing stages, each of which functions as a queue. A stimulus conveys 1 or more distinct components of information (e.g., features), and each stage can begin processing as soon as it receives 1 component from its predecessor. If a stimulus activates only 1 component, successive stages operate in strict sequence; if it activates multiple components, successive stages operate with temporal overlap. Within this class of models, experimental factors affecting different processing stages always have additive effects on reaction time with sequential stages but rarely do so with overlapping stages. Within this class of models, then, observations of factor additivity support discrete-stage models.
Attention↗
Ab initio theoretical study of the structures of thymine glycol and dihydrothymine.
The structures of all diastereoisomers of 5,6-dihydroxy-5,6-dihydrothymine (thymine glycol) an 5,6-dihydrothymine, two important DNA lesions, have been optimized with ab initio quantum chemical methods at a 6-31 G level of calculations. The methyl group on C5 of thymine glycol shows a strong preference for a pseudo axial orientation. In contrast, in 5,6-dihydrothymine a pseudo equatorial methyl is preferred. Consequently, the thymine glycol lesion is much more bulky than 5,6-dihydrothymine. This observation may explain the different biological consequences observed for the two lesions.
DNA↗
Production and characterization of recombinant canine interferon-gamma from Escherichia coli.
We have used the recently cloned cDNA for canine interferon-gamma (IFN-gamma) to engineer bacteria to produce large amounts of the recombinant cytokine. The resulting protein can be recognized by monoclonal and polyclonal antibodies largely species specific for canine IFN-gamma. The purified recombinant IFN-gamma (rIFN-gamma) also had biological activity in vitro in three assay systems: (i) vesicular stomatitis virus plaque inhibition, (ii) class II major histocompatibility complex antigen upregulation on canine kidney parenchymal cells, and (iii) amplification of in vitro tissue-associated lymphoproliferation, all known to be effected by native IFN-gamma (nIFN-gamma). The availability of large amounts of active canine rIFN-gamma will be an important tool in studies of the role of this cytokine in the widely used experimental canine organ transplant model and also will be of diagnostic and therapeutic veterinary interest.
Amino Acid Sequence↗
Induction of a polarized micro-environment by human T cells and interferon-gamma in three-dimensional spheroid cultures of human endometrial epithelial cells.
Expression of human leukocyte antigen (HLA)-DR molecules and proliferation of epithelium in human endometrium are polarized. We have suggested that the induction of such a polarized micro-environment is T cell and interferon (IFN)-gamma dependent. The present study was designed to demonstrate the induction of such a micro-environment around T cells and around the source of IFN-gamma. Spheroids reminiscent of endometrial glands were formed by allowing three-dimensional aggregation of endometrial epithelial cells of a cloned HLA-DR negative endometrial carcinoma cell line (ECC1) over agarose. Both HLA-DR expression and inhibition of proliferation were found to be directly dependent on the dose of IFN-gamma that was allowed to diffuse in the agarose beneath the spheroids. To show that the interaction of the epithelial cells with activated T cells also induces HLA-DR molecules in a paracrine fashion in the epithelial cells, ECC1 spheroids were co-cultured with increasing numbers of allogeneic peripheral blood T cells for various time-intervals. T cells bound to the ECC1 cells, and became activated as indicated by the expression of interleukin (IL)-2 receptor and HLA-DR molecules. A focal HLA-DR expression became apparent in the ECC1 cells adjacent to the T cells. As the number of T cells added to spheroid cultures was increased, a concomitant increase in the number of HLA-DR positive ECC1 cells occurred and HLA-DR immunoreactivity was enhanced in each cell. There was a corresponding decrease in the proliferation of the ECC1 cells in T cell-ECC1 spheroid co-cultures. Based on these data, we suggest that activation of T cells is associated with the induction of HLA-DR expression and inhibition of proliferation in a paracrine fashion in the epithelial cells and may be responsible for the creation of a polarized micro-environment in vivo.
Animals↗
Macroscopic equilibrium from microscopic irreversibility in a chaotic coupled-map lattice.
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