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Biomedical subjects

K W Jones

Publications and source records attributed to K W Jones.

At least 37 records · Page 2Linked to original sources
PubMed1997

The comorbid association of migraine with osteoarthritis and hypertension: complement C3F and Berkson's bias.

Migraine is known to have a major genetic component and has been associated with a wide variety of comorbid disorders including arthritis and heart disease. Since migraine and some of its comorbid disorders involve inflammation, complement C3, a protein involved in acute inflammation, was selected for analysis as a candidate gene in an ongoing study of the genetic basis of migraine. Polymorphism frequencies for complement C3F (0.19) and C3S (0.81) in a sample of 137 unrelated migraineurs were found to be consistent with a control group as well as previous population studies, indicating that this common polymorphism has no association with migraine susceptibility. However, C3F positive individuals with migraine were found to have an increased incidence of osteoarthritis (Chi square = 10.06; p < 0.0008) and hypertension (Chi square = 5.18; p < 0.01). Therefore, the data in the present study indicate that certain migraine comorbidities that have been reported in the literature may result from Berkson's bias as opposed to a shared pathophysiological variation in the C3 gene.

Comorbidity↗
PubMed1997

Current issues in living donor nephrectomy.

Of 96 consecutive renal transplants in 2 years, 50 (52%) were living donor grafts. Donor demographics, treatment plans, length of stay (LOS), charges, and complications were reviewed. Donors included 27 women and 23 men aged 22 to 61 (mean 42.2) years; 33 were living related and 17 living unrelated donors. Racial distribution included 1 Hispanic, 2 Asian, 8 black, and 39 white donors. Pretransplant evaluation defined renal anatomy and function (minimal creatinine clearance 75 cc/min). Hospital admission occurred the morning of donation. Nephrectomy under general anesthesia entailed an anterior flank, extra-retroperitoneal approach (no rib resection); and postoperative epidural pain control was standard. Progressive early ambulation and pulmonary self-care optimized recovery. The 50 donors were hospitalized for 2 (n = 7), 3 (n = 18), 4 (n = 15), 5 (n = 6), and 6-8 (n = 4) days (mean LOS: 3.74 +/- 0.17, range 2-8 days). The mean charge for donor hospitalization was $15,415 +/- $397 (range $10,808-$29,579). One major intraoperative hemorrhage required transfusion; 1 patient was readmitted for wound drainage and pneumonia treated medically. While 40 of 50 patients (80%) were hospitalized for 4 days or less, there was no readmission because of short hospital stay. One early graft loss (3 days) occurred from technical problems; all others gained excellent life sustaining function. Three additional kidneys failed from rejection, noncompliance, and systemic coagulopathy. One recipient died at 8 months (CVA) with normal renal function. Current strategies for successful living kidney donation are thorough patient and family education, ambulatory preoperative testing, morning of surgery admission, and discharge planning beginning before hospitalization. Excellent outcomes may be accompanied by a brief LOS, epidural pain management, and liberal use of willing and healthy related and unrelated living donors.

Adult↗
PubMed1996

Activated T hybridomas induce upregulation of B7-1 on bystander B lymphoma cells by a contact-dependent interaction utilizing CD40 ligand.

The upregulation of costimulatory molecules of antigen presenting cells (APC) resulting from interaction with activated T cells was studied in an in vitro system composed of well-characterized murine T hybridomas and B cell lymphomas. Increased B7-1 expression was induced on both MHC-matched and -mismatched (bystander) B lymphoma cells present in cultures of activated T hybridomas. Identical results were obtained with T hybridomas activated by either the appropriate peptide presented by MHC-matched APC or by mitogen stimulation in the absence of MHC/TCR cognate interactions. Soluble factors alone did not lead to upregulation of B7-1; B lymphomas cultured on the opposite side of a transwell membrane from an ongoing T cell stimulation response, or in supernatants of activated T cells, did not exhibit enhanced expression of B7-1. Antibodies to the CD40 ligand (CD40L) of T cells inhibited the increased appearance of B7-1 on B lymphomas. Significant B7-1 upregulation on the population of bystander B cells could be achieved even when they were present at a 10:1 excess over MHC-matched APC. These data indicate that B7-1 upregulation results from contact between bystander B cells and activated T hybridomas in vitro by CD40-CD40L interaction, without the requirement for TCR/MHC interaction.

Animals↗
PubMed1996

Low lead levels stunt neuronal growth in a reversible manner.

The developing brain is particularly susceptible to lead toxicity; however, the cellular effects of lead on neuronal development are not well understood. The effect of exposure to nanomolar concentrations of lead on several parameters of the developing retinotectal system of frog tadpoles was tested. Lead severely reduced the area and branchtip number of retinal ganglion cell axon arborizations within the optic tectum at submicromolar concentrations. These effects of lead on neuronal growth are more dramatic and occur at lower exposure levels than previously reported. Lead exposure did not interfere with the development of retinotectal topography. The deficient neuronal growth does not appear to be secondary to impaired synaptic transmission, because concentrations of lead that stunted neuronal growth were lower than those required to block synaptic transmission. Subsequent treatment of lead-exposed animals with the chelating agent 2,3-dimercaptosuccinic acid completely reversed the effect of lead on neuronal growth. These studies indicate that impaired neuronal growth may be responsible in part for lead-induced cognitive deficits and that chelator treatment counteracts this effect.

Animals↗
PubMed1996

Long-term results of cardiac transplantation in patients older than sixty years. UTAH Cardiac Transplant Program.

Advanced age has traditionally been a contraindication to cardiac transplantation. We have, however, offered cardiac transplantation to patients older than 60 years with end-stage heart failure if they were otherwise acceptable candidates. From 1985 to 1994, 527 patients underwent cardiac transplantation. Among these patients, 101 were older than 60 years at transplantation. The mean follow-up of this group is 6 years. Patients older than 60 years had significantly fewer rejection episodes per patient than those who were younger than 60 years at transplantation (1.9 +/- 1.3 vs 2.6 +/- 1.8, p = 0.009). No difference in the number of infectious complications per patient was detected between the two groups. Both short-term and long-term survival after transplantation were significantly lower for patients who were older than 60 years at transplantation than for younger patients (p < 0.05). The 6-year actuarial survival after transplantation for patients older than 60 years was 54% compared with 72% for patients younger than 60 years at transplantation (p < 0.05). Patients older than 60 years at transplantation were more likely to die of infectious complications or malignant disease after transplantation (p < 0.05). We believe caution is warranted in offering cardiac transplantation to patients older than 60 years. This group of patients should be carefully observed for the development of potentially life-threatening infectious complications or new malignant tumors after transplantation.

Age Factors↗
PubMed1996

Improved long-term survival after heart transplantation predicted by successful early withdrawal from maintenance corticosteroid therapy.

BACKGROUND: Short-term studies suggest that cardiac transplant immunosuppression without maintenance corticosteroids is feasible in selected patients. However, concern exists as to the long-term effects, specifically the possibility of increased morbidity and mortality because of late allograft rejection and allograft coronary artery disease. METHODS: We retrospectively reviewed the records from 441 consecutive heart transplantation procedures done in 416 patients with use of an immunosuppressive protocol that attempted corticosteroid withdrawal within 2 months of transplantation. forty-two patients died or underwent retransplantation during the first 3 months and were excluded from further analysis. Analysis focused on demographic and long-term outcome variables (including death, rejection, retransplantation, and infection). RESULTS: Thirty percent (111) of eligible patients (374) met the definition of successful early steroid withdrawal. Only male gender independently predicted successful withdrawal. Mortality, both short and long term, was significantly lower in patients in whom successful early withdrawal from corticosteroids was achieved than in patients in whom the early attempts failed (1.7% per year versus 4.7% per year; p < 0.0001). The prevalence of late acute allograft rejection (more than 1 year after transplantation) was lower in patients successfully withdrawn from steroid therapy early after transplantation (0.07 pt-yr of follow-up versus 0.15 pt-yr; p = 0.002). Multivariate analysis of the entire group identified incidence of infection (p = 0.001), older age (p = 0.001), failed early steroid withdrawal (p = 0.006), and female gender (p = 0.016) as independent predictors of mortality. CONCLUSIONS: Successful early corticosteroid withdrawal identifies a subgroup of "immunologically privileged" patients with a low risk for long-term mortality and is not associated with an increased prevalence of late rejection or clinically significant coronary artery disease.

Case-Control Studies↗
PubMed1995

Calcium, sulfur, and zinc distribution in normal and arthritic articular equine cartilage: a synchrotron radiation-induced X-ray emission (SRIXE) study.

Calcium, sulfur, and zinc content in normal and arthritic equine cartilage have been studied by synchrotron radiation-induced X-ray emission (SRIXE). Ranging from the superficial to the columnar zone of the normal tissue, calcium and zinc concentrations are increasingly higher, whereas sulfur is at its highest concentration in the transitional zone. In the arthritic tissue, calcium concentration is at its maximum in the transitional zone, whereas zinc and sulfur distributions are relatively homogeneous. Sulfur concentration in arthritic cartilage is reduced to about one-third with respect to that in normal tissue. The possibility that zinc concentration reflects the distribution of the zinc-containing enzyme alkaline phosphatase is presented.

Animals↗
PubMed1995

Cold ischemia and outcome in 17,937 cadaveric kidney transplants.

To determine if cold preservation time continues to affect renal transplant outcome, prospectively collected data from 17,937 cadaveric renal transplants performed between 1982 and 1991 were analyzed. Cold preservation intervals of 1-16, 16-32, 32-48, and greater than 48 hr were studied by multi- and univariate methods for two time periods: 1982-1989 (n = 13,800) and 1990-1991 (n = 4137). The functional one-year graft survival for kidneys stored over different intervals was significantly different (P < 0.001) only for the 1982-1989 epoch: one-year allograft survival ranged from 76% (1-16), to 72% (16-32 and 32-48) to 74% (> 48) hr. One-year graft survival ranged from 81 to 83% for the four preservation times in 1990 through 1991 (P = NS). Overall actuarial graft survival was 76% (74% prior to 1990, and 82% after 1990). Factors significantly (P < 0.0001) affecting kidney transplant outcome before and after 1990 were delayed graft function (DGF): n = 4232, 65% one-year graft survival; retransplant status: n = 3029, 67% one-year graft survival; and HLA match at three or more loci: n = 6067, 79% one-year graft survival. While DGF occurred more often with prolonged preservation, kidneys with DGF had similar survival regardless of preservation duration. Before 1990, pretransplant transfusion was associated with better and black recipient race with worse outcome; neither transfusion nor recipient race had any effect after 1990. Patients receiving kidneys preserved for longer periods demonstrate one-year graft survival comparable to kidneys preserved for shorter periods. Prolonged cold ischemic time should no longer be a principal reason for considering organ discard.

Analysis of Variance↗
PubMed1995

Characterization of nucleoside transport activity in rabbit cortical synaptosomes.

Rabbit central nervous system (CNS) preparations have been used to study the central effects of adenosine, but little is known about the specific uptake mechanisms in rabbit brain involved in the regulation of extracellular adenosine concentrations. The present study assessed the kinetic and pharmacological characteristics of the uptake of [3H]uridine (a poorly metabolized substrate for adenosine transporters) by rabbit cortical synaptosomes, to define the transporter subtypes involved and to evaluate species variability in transporter characteristics. [3H]Uridine transport into rabbit cortical synaptosomes was mediated by two saturable, facilitated diffusion systems with characteristics compatible with the es and ei transporter subtypes identified in other mammalian species. About 65% of the total transport was mediated by the es system, and Km estimates of 320 and 94 microM were determined for [3H]uridine uptake by the es and ei transporter, respectively. These results differ significantly from the subtype ratio and kinetic characteristics reported for rat and guinea pig cortical synaptosomes, where most of the transport was mediated by an ei subtype. Dipyridamole, dilazep, nitrobenzylthioinosine, R75231, soluflazine, and mioflazine were relatively more effective as inhibitors of es-mediated uptake (compared with ei), while the substrates adenosine, cytidine, and guanosine did not distinguish between the es and ei transporters in rabbit cortical synaptosomes. These results highlight the significant species-tissue variability in nucleoside transporter characteristics and subtype expression, and emphasize the need to characterize the transporters in human CNS tissue to allow the rational development of CNS-active therapeutics based on inhibition of nucleoside transport.

Animals↗
PubMed1994

Effect of cellular differentiation on nucleoside transport in human neuroblastoma cells.

The nucleoside transport characteristics of undifferentiated and differentiated LA-N-2 human neuroblastoma cells were compared through measurement of the cellular accumulation of [3H]formycin B in the absence and presence of specific nucleoside transport blockers such as dipyridamole and nitrobenzylthioinosine (NBMPR). [3H]NBMPR was also used as a high affinity probe to obtain an estimate of the number of NBMPR-sensitive nucleoside transport proteins. Undifferentiated LA-N-2 cells accumulated [3H]formycin B (25 microM) via a NBMPR/dipyridamole sensitive, Na(+)-independent, nucleoside transport system (Vi = 1.52 pmol/microliters/s; maximum intracellular concentration = 45 pmol/microliters cell water). The undifferentiated cells also had a high density of site-specific [3H]NBMPR binding sites (135,000 sites/cell; KD = 0.4 nM). When cell differentiation was induced by exposure to a serum-free defined medium, the initial rate of transporter-mediated [3H]formycin B uptake increased to 1.92 pmol/microliters/s, and the steady-state intracellular concentration of [3H]formycin B also increased significantly to 73 pmol/microliters. However, there was no concomitant change in the number of [3H]NBMPR binding sites, and the additional uptake was not Na(+)-dependent. This enhanced uptake in the differentiated cells appeared to be due, in part, to an increased functional expression of a NBMPR-resistant form of facilitated nucleoside transporter. Approximately 18% of the transporter-mediated uptake in the differentiated cells was resistant to inhibition by NBMPR at concentrations that blocked transport completely in the undifferentiated cells. This cell model may prove useful for basic studies on regulation of nucleoside transporter subtype expression in neural tissues, and for evaluation of the efficacy and potential host toxicity of cytotoxic nucleoside analogues (+/- specific transport blockers) in the treatment of neuroblastoma.

Biological Transport↗
PubMed1994

Kidney transplantation in the older patient.

To determine renal transplant outcome in older patients, 26 consecutive primary kidney allograft recipients aged 50-76 (mean 58) were followed from three to 50 months. Azathioprine, prednisone, and cyclosporine were used in all cases and OKT3 induction in cadaveric grafts. Four patients died at three, 15, 20, and 24 months from infection, hepatic cancer, trauma, and myocardial infarction respectively; each had life-sustaining graft function at final hospital admission or death (one year actuarial patient survival 96.2%). One patient lost a kidney to accelerated acute rejection (one year immunologic graft survival 96.2%) and 11 others (42.3%) experienced acute rejection episodes which were uniformly reversed. Older patients tolerate multidrug immunosuppression, demonstrate acceptable patient survival and good rehabilitation potential, have a low incidence of rejection, and maintain excellent graft function. Renal transplantation is effective and safe renal replacement therapy for patients over age 50 years.

Aged↗
PubMed1993

Interaction of the mioflazine derivative R75231 with the nucleoside transporter: evidence for positive cooperativity.

This study investigated the interaction of the mioflazine derivative R75231 with the nucleoside transport system of rabbit cortical synaptosomes, and assessed the binding of [3H]R75231 to human erythrocyte ghost membranes. R75231 was a potent inhibitor of [3H]nitrobenzylthioinosine binding and [3H]uridine uptake in synaptosomes (Ki < 10 nM). This inhibition was evident even after extensive washing of the synaptosomes, subsequent to exposure to R75231. In addition to its tight binding characteristics, R75231 was shown to be a 'mixed' type inhibitor of [3H]nitrobenzylthioinosine binding (increased KD, decreased Bmax). [3H]R75231 bound with high affinity (KD = 0.4 nM) to erythrocyte membranes with a Bmax of 44 pmol/mg protein, which is comparable to the number of [3H]nitrobenzylthioinosine binding sites in this preparation. Binding of [3H]R75231 to these membranes was reversible, but the rate of dissociation was dependent upon the displacer used. Nitrobenzylthioinosine and dipyridamole each induced a complete dissociation of site-bound [3H]R75231 at rates not significantly different from those observed using a protocol involving a 100-fold dilution with buffer (no displacer). However, R75231 and mioflazine slowed the rate of dissociation of [3H]R75231 and actually caused an initial increase in the amount of site-bound [3H]R75231. Adenosine, on the other hand, enhanced the rate of [3H]R75231 dissociation. These results indicate that R75231 binding to the nucleoside transporter is a complex reaction, which may involve multiple interacting sites demonstrating positive cooperativity.

Adenosine↗
PubMed1993

The use of mycophenolate mofetil (RS-61443) in human heart transplant recipients.

Mycophenolate mofetil is a potent inhibitor of de novo guanine nucleotide synthesis that selectively blocks lymphocyte proliferative responses. In animal models, mycophenolate mofetil has been shown to prolong allograft survival, reverse ongoing rejection, and induce strain-specific tolerance. To assess the safety and efficacy of mycophenolate mofetil in cardiac transplantation, 30 recipients with mild rejection were enrolled in an 8-week phase I trial. Mycophenolate mofetil in doses from 500 to 3000 mg/day orally was substituted for azathioprine, while baseline cyclosporine levels and corticosteroid doses were maintained. Rejection resolved in the majority of patients, with a significant decrease in mean biopsy score. By protocol, mycophenolate mofetil was discontinued in 4 patients due to persistent mild rejection, and in 4 patients due to progression to moderate rejection. The rate of progression to moderate rejection compared favorably with that observed in patients with mild rejection maintained on azathioprine without augmentation of immunosuppression. Significant increases were observed in hematocrit, total white blood cell count, and absolute neutrophil count. Absolute lymphocyte count remained unchanged. No nephrotoxicity or hepatotoxicity was observed. Gastrointestinal side effects prompted discontinuation of mycophenolate mofetil in one patient. Two major infections occurred. Mycophenolate mofetil remained well tolerated during long-term maintenance immunosuppression, with a rate of rejection similar to that in patients receiving azathioprine. We conclude that mycophenolate mofetil is safe and well tolerated in cardiac transplant recipients, is less myelosuppressive than azathioprine, and appears to be at least equipotent to azathioprine.

Adult↗