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Biomedical subjects

K W Jones

Publications and source records attributed to K W Jones.

At least 73 records · Page 4Linked to original sources
PubMed1990

Trace elemental analysis in bone using x-ray microscopy.

Following in vivo administration of gallium nitrate, the greatest concentrations of the therapeutic element gallium localized in the metaphysis and at the endosteal and periosteal surfaces of the diaphysis. These are the regions of greatest metabolic activity, where new bone formation and remodeling are occurring. The lowest levels of gallium were noted in the mid-cortical region of the diaphyseal shaft where bone turnover is least. The accumulation of gallium in the metaphysis was associated with a concomitant fall in iron and zinc. The gallium-induced change in the metaphysis may reflect a subtle modulation of metal dependent enzymes that are necessary for the active bone modeling that occurs in this bone region. X-ray microscopy has provided the first insights into the localization and possible mechanisms of action of gallium in bone.

Animals↗
PubMed1990

Distribution of trace levels of therapeutic gallium in bone as mapped by synchrotron x-ray microscopy.

Gallium nitrate, a drug that inhibits calcium release from bone, has been proven a safe and effective treatment for the accelerated bone resorption associated with cancer. Though bone is a target organ for gallium, the kinetics, sites, and effects of gallium accumulation in bone are not known. We have used synchrotron x-ray microscopy to map the distribution of trace levels of gallium in bone. After short-term in vivo administration of gallium nitrate to rats, trace (nanogram) amounts of gallium preferentially localized to the metabolically active regions in the metaphysis as well as the endosteal and periosteal surfaces of diaphyseal bone, regions where new bone formation and modeling were occurring. The amounts measured were well below the levels known to be cytotoxic. Iron and zinc, trace elements normally found in bone, were decreased in amount after in vivo administration of gallium. These studies represent a first step toward understanding the mechanism(s) of action of gallium in bone by suggesting the possible cellular, structural, and elemental "targets" of gallium.

Animals↗
PubMed1990

Functional analysis of the transcriptional promoter for the CYP1A1 gene.

In mouse hepatoma cells, the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the transcription rate of the CYP1A1 gene, which encodes a cytochrome P-450 enzyme. In this study, we analyzed the DNA region immediately upstream of the CYP1A1 gene. A domain that extends upstream to nucleotide--166 was found to function as a transcriptional promoter. The promoter was silent when uncoupled from the dioxin-responsive enhancer located farther upstream. DNase footprinting experiments indicated that nuclear proteins interact with distinct domains of the promoter in a TCDD-independent fashion. Mutational analyses indicated that the CYP1A1 promoter contains at least three functional domains, including a TATAAA sequence, a CCAAT box transcription factor/nuclear factor I-like recognition motif, and a guanine-rich G box.

Animals↗
PubMed1990

Cardiac allograft function with corticosteroid-free maintenance immunosuppression.

Potent prophylactic immunosuppressive protocols promote the safe withdrawal of corticosteroid maintenance. The benefits of corticosteroid-free maintenance immunosuppression include the absence of the cushingoid habitus, fewer infections, less obesity, and lower serum cholesterol. The incidence of allograft coronary artery disease is not increased by corticosteroid-free maintenance. To assess the long-term effects of corticosteroid-free immunosuppression on allograft function, we compared results of hemodynamic study and noninvasive evaluation over the 2-year follow-up of 57 patients on corticosteroid-free maintenance to 40 patients who required corticosteroid. Age and pretransplantation diagnoses were similar, but a greater percentage of those who required corticosteroid maintenance were female (28% versus 2%, p less than 0.001). Indexes of allograft function were similar in both groups and these indexes included ejection fraction, right atrial pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index, left ventricular end-diastolic dimension, and posterior wall thickness. Patient survival was identical in the two groups (98%). These data indicate that corticosteroids can be safely withdrawn with the subsequent early benefits and without compromising long-term allograft function.

Antibodies, Monoclonal↗
PubMed1990

Cardiac transplantation in situs inversus.

Transplantation of the heart was successfully performed in a patient with situs inversus of the viscera and atria. Anatomic constants common to all patients allowed the left atrium, pulmonary artery, and aorta to be joined as usual in the transplant operation. Systemic venous reconstruction was the crux of the operation. A composite superior vena cava was reconstructed on the right side from the recipient translocated superior vena cava, donor superior vena cava and innominate vein, and recipient in situ pericardium. The inferior vena cava was rerouted from the left side across the midline to the right through a composite conduit consisting of the recipient night atrium and in situ pericardium over the diaphragm. These reconstructed venous passageways have remained patent and unobstructed for 1 1/2 years after the operation.

Anastomosis, Surgical↗
PubMed1990

Bypass of superior vena cava. Fifteen years' experience with spiral vein graft for obstruction of superior vena cava caused by benign disease.

Nine patients had operations for obstruction of the superior vena cava with superior vena caval syndrome caused by benign disease. Three patients had fibrosing mediastinitis, four had fibrosing mediastinitis with caseous necrosis, one had thrombosis of the superior vena cava around a pacemaker electrode, and one had spontaneous thrombosis of the superior vena cava. Patients ranged in age from 25 to 68 years. All bypass operations were performed with a composite spiral vein graft constructed from the patient's own saphenous vein, split longitudinally and wrapped around a stent in spiral fashion. The edges of the vein were sutured together to form a large conduit ranging in diameter from 9.5 to 15.0 mm. Six grafts were from the left innominate vein and three grafts were from the internal jugular vein. The grafts were placed into the right atrial appendage in all except one case, in which the graft was to the distal superior vena cava. Follow-up extends from 1 to 15 years. One patient required reoperation at 4 days for thrombosis at the innominate vein-graft anastomosis. Resection of the anastomosis and reconstruction of the graft rendered the patient symptom free. Two grafts closed during the first year after operation. One patient had advancing fibrosing mediastinitis, and a second bypass graft from the external jugular veins remain patent. Another patient had recurrence of spontaneous venous thrombosis. Thus seven of nine grafts remain patent for up to nearly 15 years and all but one patient is free of superior vena caval syndrome. These data show that bypass of the obstructed superior vena cava with a spiral vein graft relieves superior vena caval syndrome and demonstrate long-term patency of the graft.

Adult↗
PubMed1989

Major abdominal complications following cardiac transplantation. Utah Transplantation Affiliated Hospitals Cardiac Transplant Program.

Serious complications involving the alimentary tract are commonly reported following cardiac transplantation, and may be associated with significant morbidity and mortality. The aim of this report was to review the incidence, severity, and outcome of abdominal complications in our heart transplant population in whom we used corticosteroid-sparing protocols for immunosuppression. From March 1985 through September 1988, 178 patients underwent 185 cardiac transplants. Twenty-six cardiac transplant recipients (15%) sustained 33 major abdominal complications, including gastrointestinal bleeding (n = 8), pancreatitis (n = 8), bowel perforation (n = 6), cholecystitis (n = 4), and miscellaneous other problems (n = 7). Operative therapy was required in 61% of cases. No deaths were caused by the gastrointestinal complications of their operative management. Corticosteroid-sparing immunosuppression may be responsible for the low incidence of abdominal morbidity, and early, aggressive surgical intervention may reduce subsequent mortality.

Adult↗
PubMed1989

Activation of transcription as a general mechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin action.

We studied the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) of mouse hepatoma cells that contain a single, integrated copy of a chimeric gene under the control of a dioxin-responsive DNA domain, which was originally associated with the cytochrome P450iA1 gene. Our findings indicate that TCDD increases the RNA polymerase II-catalyzed transcription rate of the chimeric gene and that the transcripts are initiated at the correct promoter. Therefore, the dioxin-responsive DNA operates as a bona fide transcriptional enhancer. Other studies imply that the Ah receptor mediates the transcriptional response to TCDD. Our results indicate that the Ah receptor-dependent, dioxin-responsive enhancer can activate transcription when in a regulatory context and in a chromosomal location different from those of the cytochrome P450iA1 gene. Therefore, in principle, the receptor-enhancer system represents a mechanism by which numerous genes can respond to aromatic hydrocarbons in the environment.

Animals↗
PubMed1989

Activation of cytochrome P450IA1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin in wild-type and high-activity variant mouse hepatoma cells.

We analyzed the function of a DNA domain located upstream of the cytochrome P450IA1 gene in wild-type (Hepa 1c1c7) mouse hepatoma cells and in high-activity variant (HAV) cells that overtranscribe the gene in response to the inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Transfection experiments indicated that both wild-type and HAV DNA confer responsiveness to TCDD upon the bacterial chloramphenicol acetyltransferase (CAT) gene. However, the level of CAT activity was four- to fivefold higher when the hybrid genes were expressed in the HAV cells. These findings imply that an alteration in a trans-acting function confers the HAV phenotype. Studies of mRNA accumulation imply that TCDD acts by enhancing the rate of mRNA initiation rather than by removing a block in mRNA elongation. We found that both wild-type and HAV cells used the same transcriptional promoter as that described previously for the cytochrome P450IA1 gene in C57BL/6 mouse liver. Both cell types exhibited superinduction of cytochrome P450IA1 gene expression in response to TCDD plus cycloheximide.

Animals↗
PubMed1989

Systemically administered N-methyl-D-aspartate interferes with acquisition of a passive avoidance response in rats.

The effect of several doses of systemically administered N-methyl-D-aspartate (NMDA) was studied on step-through passive avoidance (PA) retention in rats. Retention of single trial PA was significantly reduced by preacquisition (30 minutes) doses of NMDA (3, 10, 30, and 50 mg/kg SC). Preacquisition amnesia was found when NMDA (30 mg/kg SC) was administered between two and 60 minutes. At shorter and longer pretreatment times (0.5 and 180 minutes) NMDA (30 mg/kg SC) did not disrupt retention testing. Across the same dose range and pretreatment times, NMDA failed to interfere with PA retention when given after acquisition or before retention testing. The results suggest that systemic NMDA administration can interfere with the acquisition of a PA response but does not alter consolidation of information or retrieval.

Animals↗
PubMed1989

Efficacy of OKT3 retreatment for refractory cardiac allograft rejection.

Although OKT3 monoclonal antibody is a useful therapy for refractory cardiac allograft rejection, the use of OKT3 for prophylaxis may be limited by the potential of sensitization and subsequent loss of efficacy on retreatment. OKT3 was required for refractory rejection in 21 of 165 recipients transplanted between March 1985 and August 1988. Twelve of these patients had previously been exposed to OKT3, and the retreatment efficacy was evaluated. The study population averaged 42.1 +/- 15.3 years of age (mean +/- SEM) and had experienced 2 +/- 1 previous episodes of rejection. The prior episodes of rejection had been treated with pulse methylprednisolone and antithymocyte globulin, and in addition 3 patients (25%) also required a course of antilymphoblast globulin. Retreatment OKT3 for refractory rejection was required 120 +/- 94 days following transplantation. CD3+ lymphocytes were eliminated from the circulation within 24-48 hr in 11 of 12 patients, all of whom showed histologic improvement within the first week. Total resolution on the initial follow-up biopsy was noted in 9 (75%) during the course of therapy. Subsequent rejection episodes occurred in 9 (82%) of the survivors at 71 +/- 64 days. One-year survival was 83% in this vigorously rejecting patient population. Serious infections occurred within 3 months of therapy in 4 (36%). The side effects of OKT3 retreatment were similar to those seen with first exposure and did not require OKT3 discontinuation. Thus OKT3 may be administered with success in most patients who have previously been exposed to it.

Adult↗
PubMed1989

A prospective comparison of murine monoclonal CD-3 (OKT3) antibody-based and equine antithymocyte globulin-based rejection prophylaxis in cardiac transplantation. Decreased rejection and less corticosteroid use with OKT3.

To test the efficacy of murine monoclonal CD-3 antibody (OKT3) in early prophylaxis for cardiac allograft rejection, we conducted a 6-month trial, prospectively assigning 51 patients to receive either equine antithymocyte globulin-based (n = 25) or OKT3-based (n = 26) early prophylaxis. ATG patients received 8 days of ATG (10 mg/kg), with the first dose given preoperatively. OKT3 patients received 14 days of OKT3 (5 mg) beginning on the second postoperative day. Corticosteroid and azathioprine administration were similar during early prophylaxis. Cyclosporine was begun preoperatively in ATG patients and on the fourth postoperative day in OKT3 patients. In addition, patients in both groups were randomized to receive or not receive eight weekly administrations of vincristine (0.025 mg/kg). While infection rate (0.8 +/- 0.2 infections/patient in both groups [mean +/- SEM]) and mortality (1 patient in each group) did not differ, OKT3-based early prophylaxis delayed the first rejection episode (76 +/- 11 days vs. 36 +/- 8 days, P = 0.005) and decreased the risk of rejection during the 6-month follow-up (P less than 0.001, product-limit analysis). Overall, the OKT3 group manifested 1.5 +/- 0.2 episodes of rejection/patient compared with 2.2 +/- 0.2 episodes/patient in the ATG group (P = 0.036). Despite similar 6-month cumulative cyclosporine and azathioprine dosages, six month average corticosteroid administration was less in the OKT3 group (12.2 +/- 1.5 mg prednisone equivalent/m2/day versus 19.3 +/- 2.1 mg prednisone equivalent/m2/day, P = 0.008), fewer OKT3 patients subsequently required additional cytolytic therapy for rejection (2 [8%] versus 12 [48%], P = 0.001), and more patients in the OKT3 group were successfully weaned off maintenance corticosteroids (22 [88%] versus 11 [46%], P = 0.002). We conclude that, relative to an equine ATG-based protocol, OKT3-based early prophylaxis results in less rejection, permitting less chronic corticosteroid administration.

Antibodies, Monoclonal↗
PubMed1988

Restriction fragment polymorphism in the sex-determining region of the Y chromosomal DNA of European wild mice.

Using 32P-labeled probe consisting mainly of (GATA)n we have shown that a male specific Alu1 DNA blot pattern which defines the Y chromosome sex-determining locus in inbred mice is highly polymorphic in wild mice, indicating substantial sequence evolution in this region under field conditions. In all cases examined by in situ hybridization, the region concerned is paracentromeric. In contrast, the blot pattern of another probe (M 34) which detects repeated sequences specific to the mouse Y chromosome but outside the sex-determining locus, remains constant between different isolates.

Animals↗
PubMed1988

X-ray fluorescence with synchrotron radiation.

The use of synchrotron radiation for X-ray fluorescence has several advantages over the use of other conventional X-ray sources. The principles of synchrotron radiation and methods for applying synchrotron radiation to the X-ray fluorescence measurements of trace elements are discussed. The Brookhaven National Laboratory X-ray microprobe, facilities dedicated to X-ray fluorescence, and related analytical techniques are discussed. Some examples of trace element analyses in biological materials with synchrotron radiation are presented.

Electron Probe Microanalysis↗
PubMed1987

A DNA sequence which shows genomic variation in a, alpha and HO strains of Saccharomyces cerevisiae.

HindIII digested DNA from various mutant strains of Saccharomyces cerevisiae probed with a 340 bp nucleotide sequence in M13mp8 derived from a mouse liver cDNA clone p1581 showed strong hybridization to a 4.1 kb DNA fragment class. This was limited to the DNA of cells of alpha mating type but the fragments concerned apparently do not originate from chromosome III. The pattern of hybridization was modified in strains carrying the HO gene consistent with there being extra copies of the Bkm-homologous sequence in these cells. Northern analysis of RNA from cells synchronised in various stages of the mitotic and meiotic cell cycle probed with M13mp8/p1581 indicated related transcripts in meiotic cells.

Cloning, Molecular↗
PubMed1987

Age-associated decline in cardiac allograft rejection.

The influence of age on cardiac allograft rejection was studied in 57 consecutive recipients. Twenty-one subjects were 54 years of age or older (mean, 57.7 +/- 0.6 years [+/- SEM]; range, 54 to 63 years) and 36 subjects were 52 years of age or younger (mean, 39.9 +/- 1.8 years; range, 16 to 52 years; p less than 0.001). The older recipients had fewer rejection episodes during the first four months following cardiac transplantation (0.24 +/- 0.05 episodes per month versus 0.72 +/- 0.09 episodes per month; p less than 0.001) and during the total duration of follow-up (0.20 +/- 0.03 episodes per month versus 0.40 +/- 0.07 episodes per month; p = 0.045), and experienced their first rejection episode later (50.4 +/- 4.0 days versus 27.7 +/- 8.5 days; p = 0.008). Younger age was found to add significantly as a predictor of rejection in a multivariate analysis that controlled for sex, immunosuppressive agents, cause of heart failure, and pretransplantation lymphocyte cross-match status (r = 0.64, p less than 0.05). Decreased rejection frequency occurred without a concomitant increase in the serious infection rate (67 percent in both groups). The 12-month actuarial survival was 100 percent in the older group and 94 percent in the younger group (p = NS). Decreased rejection in the older recipients is likely a manifestation of an age-associated decline in immune function and might represent an advantage in transplantation for carefully selected older patients.

Actuarial Analysis↗