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J W Williams

Publications and source records attributed to J W Williams.

At least 73 records · Page 4Linked to original sources
PubMed1998

Treatment of depression--newer pharmacotherapies.

OBJECTIVES: Depressive disorders are persistent, recurring illnesses that impose enormous personal suffering on individuals and their families. Major depression alone is estimated as the fourth most important cause of worldwide loss in disability-adjusted life years and is likely to become the second most important within 20 years. A continued quest for more effective treatments has spawned newer antidepressants and herbal treatments, which have contributed to explosive growth in antidepressant prescribing, increasing pharmacy costs, and wider but sometimes confusing choices for clinicians and patients. This evidence report provides a comprehensive evaluation of the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and children. SEARCH STRATEGY: Pertinent literature from 1980 to January 1998 was identified from a specialized registry of controlled trials, meta-analyses, and experts. The registry contained trials addressing depression that had been identified from multiple electronic bibliographic databases, hand searches of journals, and pharmaceutical companies. The search, which yielded 1,277 records, combined terms "depression," "depressive disorder," or "dysthymic disorder" with a list of 32 specific "newer" antidepressant and herbal treatments. SELECTION CRITERIA: Randomized controlled trials were reviewed if they (1) were at least 6 weeks in duration; (2) compared a "newer" antidepressant with another antidepressant (newer or older), placebo, or psychosocial intervention; (3) involved participants with depressive disorders; and (4) had a clinical outcome. Two or more independent reviewers identified 315 trials that met these criteria. DATA COLLECTION AND ANALYSIS: Two persons independently abstracted data from each trial. Data were synthesized descriptively, paying attention to participant and diagnostic descriptors, intervention characteristics, study designs and clinical outcomes. Some data were analyzed quantitatively using an empirical Bayes random-effects estimator method. Primary outcomes were response rate, total discontinuation rates (dropouts), and discontinuation rates due to adverse events. Response rates were defined as a 50 percent or greater improvement in symptoms as assessed by a depression symptoms rating scale or a rating of much or very much improved as assessed by a global assessment method. MAIN RESULTS: There were 264 trials that evaluated antidepressants in patients (adults and children) with major depression. Of these, 81 compared newer agents with placebo, 150 newer with older agents, 32 newer agents with newer agents, and 1 newer agent with psychotherapy. There were 14 trials evaluating hypericum (St. John's wort), 27 trials each in primary care patients and older adults, 10 trials limited to patients with specific concomitant illnesses, 9 trials in patients with dysthymia, 3 trials each in patients with mixed anxiety depression and subsyndromal depression, 2 trials in adolescents, and 1 in the postpartum setting. Most trials were conducted in outpatients and examined only acute phase treatment of less than 12 weeks' duration. Newer antidepressants were more effective than placebo in treating major depression (risk ratio 1.6, 95% CI 1.5 to 1.7) and dysthymia (risk ratio 1.7, 95% CI 1.3 to 2.3). They were effective among older adults and in primary care patients. In general, there were no significant differences in efficacy among individual newer agents or between newer and older agents. Hypericum (St. John's wort) was more effective than placebo in treating mild to moderately severe depressive disorders (risk ratio 1.9, 95% CI 1.2 to 2.8). Whether hypericum (St. John's wort) is as effective as standard antidepressant agents given in adequate doses was not established. No significant differences were found between newer and older antidepressants in overall discontinuation rates. Selective serotonin reuptake inhibitors (SSRIs), reversi

Adult↗
PubMed1997

Modification of humoral responses by the combination of leflunomide and cyclosporine in Lewis rats transplanted with hamster hearts.

BACKGROUND: Vigorous antibody-mediated responses prevent the successful engraftment of hamster hearts transplanted into Lewis rats. Early antibody responses mediating acute rejection of the xenograft are T cell-independent and resistant to the T-cell immunosuppressant, cyclosporine (CsA). Immunosuppression with the combination of leflunomide plus CsA completely prevents xenograft rejection, but when such immunosuppression is stopped the hamster heart is rejected by a process that we term late xenograft rejection. We report here on some of the immunological features of late xenograft rejection. METHODS: Lewis rats transplanted with hamster hearts were treated with leflunomide (5 mg/kg/day by gavage) for 14-21 days and CsA (20 mg/kg/day by gavage) continuously from the day of transplant. Serum was harvested and the functional activities of the xenoreactive antibodies were quantitated by in vivo passive transfer of sera, flow cytometry, in vitro C3 deposition assays, and Western blotting. RESULTS: CsA alone prevented late xenograft rejection and the accompanying production of xenoreactive antibodies. The xenoreactive antibodies accompanying acute or late xenograft rejection were predominantly IgM, but only serum from rats undergoing acute xenograft rejection was able to induce hyperacute rejection. The ability of serum to induce hyperacute rejection correlated with its ability to induce C3 deposition on hamster lymphocytes in vitro. The repertoire of hamster antigens recognized by IgM in the serum of rats undergoing late xenograft rejection is more restricted than that of IgM in the serum of rats undergoing acute xenograft rejection. We additionally demonstrate that long-term graft survival is not dependent on graft accommodation. CONCLUSIONS: These studies demonstrate that a brief treatment with the combination of leflunomide and CsA profoundly modifies the humoral xenoreactivity in the recipient, converting it from a T-independent into a T cell-dependent response. Differences in functional activity of sera from acute or late xenograft rejection suggest that antigenic specificity defines the ability of IgM to induce complement activation and hyperacute rejection.

Animals↗
PubMed1997

Quantitation of the changes in splenic architecture during the rejection of cardiac allografts or xenografts.

BACKGROUND: The spleen plays a central role in the generation of both cellular and antibody responses during graft rejection. Although changes in lymphocyte function have been extensively analyzed in vitro, there have been limited attempts at quantitating the structural changes in the lymphoid compartments within the spleen during graft rejection. METHODS: We describe here a means of quantitating the histological changes in the spleen using immunohistochemical techniques and computerized image analysis. RESULTS: Allograft rejection at 6 days after transplant is characterized by a threefold increase in the T cell-rich areas of the periarteriolar lymphoid sheaths (PALs). The follicular areas are enlarged and germinal centers appear in 55% of the white pulp regions. Acute xenograft rejection, 4 days after transplant, is specifically accompanied by a 2.3-fold increase in the marginal zone (MZ) and an increase in the numbers of B cells in the red pulp of the spleen. The expansion of both PALs and follicular/germinal centers during xenograft rejection is comparable to that observed during allograft rejection. We also investigated the effect of two immunosuppressants, leflunomide and cyclosporine, on the spleen of rats with hamster hearts. Leflunomide, which prevents acute xenograft rejection, prevented the increase in PALs and significantly reduced the areas comprising the MZ and follicles. Cyclosporine, which does not alter the tempo of xenograft rejection and only partially inhibited xenospecific antibody production, inhibited the increase in PALs and the appearance of germinal centers, while permitting a modest increase in the area of MZ and follicles. CONCLUSIONS: These observations collectively suggest that both T cell-dependent and T cell-independent responses are stimulated by the transplanted xenograft. However, the T cell-independent responses that initiate xenograft rejection are characterized by very modest increases in the area of MZ and follicles within the white pulp of the spleen.

Animals↗
PubMed1997

Effect of anti-CD4 monoclonal antibody combined with human CTLA4Ig on the survival of hamster liver and heart xenografts in Lewis rats.

We investigated the effects of pretransplant anti-CD4 monoclonal antibody (mAb) combined with human (h) CTLA4Ig on the survival of hamster heart and liver xenografts. Pretransplant anti-CD4 mAb (5 mg/kg x 4 days) or hCTLA4Ig (0.5 mg/rat on days 1, 3, and 5 after transplantation) treatment alone prolonged the survival of hamster liver xenografts in Lewis rats (mean survival time [MST]=10.5 days, n=6, and MST=9.0 days, n=5, respectively, compared with untreated Lewis recipients of hamster liver grafts, MST=6.0 days, n=6). The same regimen could not prevent hamster heart xenorejection. Pretransplant anti-CD4 mAb (5 mg/kg x 4 days) combined with hCTLA4Ig (0.5 mg/rat x 4) treatments increased survival of hamster liver xenograft fourfold (MST=24.2 days, n=5). The current results also show that IgG in the sera from Lewis recipients of hamster liver grafts treated with anti-CD4 mAb and hCTLA4Ig was threefold reduced at 6 days after transplantation compared with untreated Lewis rats. These results suggest a synergistic effect of anti-CD4 mAb combined with hCTLA4Ig in a liver xenograft transplantation model.

Abatacept↗
PubMed1997

The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms.

The immunosuppressive metabolite of leflunomide, A77 1726, inhibits the enzymatic activity of protein tyrosine kinases and of dihydro-orotic acid dehydrogenase, an enzyme involved in pyrimidine biosynthesis. Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity. At low concentrations of A77 1726, pyrimidine biosynthesis is the target, since inhibition of proliferation correlates with a reduction in pyrimidine NTP levels and is reversed by uridine. At higher concentrations of A77 1726, uridine no longer reverses the inhibition of proliferation even though pyrimidine NTP levels are restored. This second mechanism for inhibiting proliferation is probably inhibition of protein tyrosine kinases, since these higher concentrations of A77 1726 inhibit IL-2-induced tyrosine phosphorylation of Jak1 and Jak3, the protein tyrosine kinases initiating signaling by the IL-2R. Tyrosine phosphorylation of the beta-chain of the IL-2R, which is required for IL-2-driven proliferation, is also inhibited by A77 1726. Cytotoxicity of a CTLL line that overexpresses the Lck protein tyrosine kinase is inhibited by A77 1726; this inhibition is not affected by uridine, but does correlate with inhibition of an Lck in vitro kinase reaction. These studies establish that inhibition of pyrimidine biosynthesis and that of protein tyrosine kinase both contribute to the effects of A77 1726 on CTLL cell lines.

Aniline Compounds↗
PubMed1997

In vivo mechanism by which leflunomide controls lymphoproliferative and autoimmune disease in MRL/MpJ-lpr/lpr mice.

Two activities have been identified for the immunosuppressive metabolite of leflunomide, A77 1726: inhibition of dihydroorotate dehydrogenase (DHO-DHase), an enzyme involved in the biosynthesis of pyrimidine nucleotides (PyN); and inhibition of protein tyrosine kinases. The in vitro potency of A77 1726 as a DHO-DHase inhibitor is reported to be 10- to 500-fold greater than as a tyrosine kinase inhibitor. These observations suggested that the immunosuppressive efficacy of leflunomide in vivo is related to inhibition of DHO-DHase. However, observations that patients with disorders in the PyN synthetic pathway are not overtly immunodeficient militate against this hypothesis. We investigated the effects of leflunomide in vivo and report that amelioration of lymphoproliferative and autoimmune diseases in MRL/MpJ-lpr/lpr (lpr/lpr) mice by leflunomide is not accompanied by reduced PyN concentrations in lymph node cells. Our hypothesis that lymphocytes could salvage serum uridine to counter the effects of reduced PyN synthesis in vivo was supported by in vitro studies. Finally, we observed that amelioration of disease correlated with a reduction of tyrosine phosphorylated proteins in lymph node cells of lpr/lpr mice. These observations suggest that the primary mechanism by which leflunomide prevents autoimmune and lymphoproliferative diseases in lpr/lpr mice is not depletion of PyN, but correlates with reduced tyrosine phosphorylation concentrations in lymph node cells.

Aniline Compounds↗
PubMed1997

Prolongation of rat islet allograft survival by the immunosuppressive agent leflunomide.

The purpose of this study was to investigate the effect of Leflunomide (Lef), alone or in combination with a suboptimal dose of cyclosporine (CsA), on rat allogeneic islet transplantation. Two thousands islets were transplanted under the left kidney capsule of a streptozocin-induced diabetic Lewis recipient. In the ACI to Lewis combination, the mean survival time (MST) of the untreated group was 5.2 +/- 0.8 days. Lef at 2.5, 5, and 10 mg/kg/day for 14 days significantly prolonged MSTs to 19.0 +/- 1.6, 29.8 +/- 3.7, and 29.0 +/- 5.3 days (P<0.01), respectively. CsA at 5 mg/kg/day also prolonged graft survival to 21 +/- 3.5 days. When CsA (5 mg/ kg/day) was combined with Lef (5 or 10 mg/kg/day) and administered for 14 days, the survival rate of the islet allografts was further increased to 34.8 -/+ 4.7 and 36.0 -/+ 6.6 days, respectively. When Lef or CsA monotherapy was extended to 28 days at a dose of 5 mg/kg/ day, MSTs were further increased to 45.8 -/+ 8.8 or 37.4 -/+ 4.7 days, respectively. Graft MST was 56.4 -/+ 9.9 days when Lef and CsA combination therapy was administered for 28 days. In the Brown-Norway to Lewis combination, MST of the allogeneic islets in untreated rats was 6.2 -/+ 0.8 days. When Lef or CsA alone, at 5 mg/kg/day, was administered for 28 days, two of seven Lef-treated rats remained normoglycemia for more than 100 days. Graft survival longer than 100 days occurred in one of five CsA-treated rats, and in five of eight rats treated with the combination of Lef and CsA. The graft-bearing left kidney was removed after 100 days in rats with functional islet allografts, and a second Brown-Norway islet graft was transplanted into the right kidney. In all recipients, the second graft was rejected by 9.8 -/+ 1.5 days. In summary, our findings demonstrate that Lef prolonged allogeneic islet graft survival, and its immunosuppressive effect was improved when combined with CsA.

Animals↗
PubMed1997

In vivo effects of leflunomide on normal pancreatic islet and syngeneic islet graft function.

Leflunomide (Lef) is a novel immunosuppressant that can prevent islet allograft and xenograft rejection. In this study, we investigated the in vivo effects of Lef on the function of normal pancreatic islets and syngeneic islet grafts in rats and compared its effect to cyclosporine (CsA) and FK506. Different groups of rats were treated with Lef (10 and 20 mg/kg/day), CsA (20 mg/kg/day), or FK506 (2 mg/kg/day). After 4 and 6 weeks, nonfasting blood glucose (BG) levels of all the treatment groups were not different from that of the control group. Intravenous glucose tolerance test revealed that the rate of glucose disappearance was normal in Lef-treated groups. However, the rate of glucose disappearance in the CsA- and FK506-treated rats was impaired. In contrast, long-term (7 months) treatment of rats with CsA (10 mg/kg/day) resulted in five of seven rats developing hyperglycemia. However, normal BG was observed in all rats treated for 7 months with Lef (10 mg/kg/day). In the second experimental model, streptozocin-induced diabetic ACI rats were grafted with an average of 1200 syngeneic islets into the liver or kidney capsule. Diabetes in these ACI recipients was stably reversed for 6 months, then these rats were treated with Lef (20 mg/kg/day), CsA (20 mg/kg/day), and FK506 (2 mg/kg/day). After 14 days of treatment, nonfasting BG levels were significantly increased in rats treated with CsA (before: 105 +/- 2.9 mg/ dl, after: 275.8 +/- 60 mg/dl) as well as in rats treated with FK506 (before: 108 +/- 2.4 mg/dl, after: 209 +/- 10.1 mg/dl). In contrast, the BG levels of the Lef-treated rats were indistinguishable from those of the untreated control groups. Site of transplantation, i.e., liver and kidney, did not affect the results. Our results indicating that Lef has no diabetogenic property in vivo lends support to the promise that leflunomide may be effective for clinical islet transplantation.

Animals↗
PubMed1997

A practical guide for the diagnosis and treatment of acute sinusitis.

OBJECTIVE: To develop guidelines for the diagnosis and management of acute sinusitis. OPTIONS: Diagnostic clinical criteria and imaging techniques, the role of antimicrobial therapy and duration of treatment, and the role of adjunct therapy, including decongestants, glucocorticosteroids and nasal irrigation. OUTCOMES: Improved accuracy of clinical diagnosis, better utilization of imaging techniques and rational use of antimicrobial therapy. EVIDENCE: A MEDLINE search for relevant articles published from 1980 to 1996 using the MeSH terms "sinusitis," "acute sinusitis," "respiratory infections," "upper respiratory infections," "sinusitis" and "diagnosis," "sinusitis" and "therapy," "sinusitis" and "etiology," and "antimicrobial resistance" and search for additional articles from the reference lists of retrieved articles. Papers referring to chronic sinusitis, sinusitis in compromised patients and documented nonbacterial sinusitis were excluded. The evidence was evaluated by participants at the Canadian Sinusitis Symposium, field in Toronto on April 26-27, 1996. VALUES: A hierarchical evaluation of the strength of evidence modified from the methods of the Canadian Task Force on the Periodic Health Examination was used. Strategies were identified to deal with problems for which no adequate clinical data were available. Recommendations arrived at by consensus of the symposium participants were included. BENEFITS, HARMS AND COSTS: Increased awareness of acute sinusitis, accurate diagnosis and prompt treatment should reduce costs related to unnecessary investigations, time lost from work and complications due to inappropriate treatment. As well, physicians will be better able to decide which patients will not require antimicrobial therapy, thus saving the patient the cost and potential side effects of treatment. RECOMMENDATIONS: Clinical diagnosis can usually be made from the patient's history and findings on physical examination only. Five clinical findings comprising 3 symptoms (maxillary toothache, poor response to decongestants and a history of coloured nasal discharge) and 2 signs (purulent nasal secretion and abnormal transillumination result) are the best predictors of acute bacterial sinusitis (level I evidence). Transillumination is a useful technique in the hands of experienced personnel, but only negative findings are useful (level III evidence). Radiography is not warranted when the likelihood of acute sinusitis is high or low but is useful when the diagnosis is in doubt (level III evidence). First-line therapy should be a 10-day course of amoxicillin (trimethoprim-sulfamethoxazole should be given to patients allergic to penicillin) (level I evidence) and a decongestant (level III evidence). Patients allergic to amoxicillin and those not responding to first-line therapy should be switched to a second-line agent. As well, patients with recurrent episodes of acute sinusitis who have been assessed and found not to have anatomic anomalies may also benefit from second-line therapy (level III evidence). VALIDATION: The recommendations are based on consensus of Canadian and American experts in infectious diseases, microbiology, otolaryngology and family medicine. The guidelines were reviewed independently for the advisory committee by 2 external experts. Previous guidelines did not exist in Canada.

Acute Disease↗
PubMed1997

Prediction of abstinence from ethanol in alcoholic recipients following liver transplantation.

The prediction of abstinence from ethanol may be crucial to the optimal selection of liver transplantation candidates with alcoholism. Of 84 consecutive end-stage alcoholic patients who underwent transplantation (1986-1994) at our institution, we analyzed 63 long-surviving recipients for pretransplantation variables to predict posttransplantation abstinence (follow-up: 49.3 +/- 21 mo). Thirty-three pretransplantation variables were reviewed from our transplantation data base and supplemented and confirmed with interviews with recipients. The psycho-social inclusion criteria included the following: patient recognition of alcoholism, a domicile, an occupation, and at least one close personal relationship. The incidence of abstinence from ethanol was (50/63) 79%. A logistic regression of the 33 variables in conjunction with our above inclusion criteria accurately predicted abstinence (90% accuracy, chi2 model, P < .00001) based on the absence of previous history of any illicit drug use (Drug Use: yes = 1/no = 0), the presence of an active, personal life insurance policy (Life Ins: yes = 1/no = 0), number of alcoholic sisters (ETOH-SIS), and the length of pretransplantation abstinence (PRE-TRANS-ABS, mos): Prob. of abstinence = 1/1 + e(-F), F = -0.33 +/- 0.89 (DRUG USE) -1.02 (LIFE INS) -1.68 (ETOH-SIS) +0.24 (PRE-TRANS-ABS). In contrast, receiver-operating characteristic curve analysis found that 7 and 9 months of pretransplantation abstinence were the best cut-off points in predicting subsequent abstinence, but poor utility was noted at these points with this specific value alone (sensitivity 61-84%, specificity 64-68%). A separate analysis of high-risk patients with poly-drug use (n = 15, alcohol recidivism 8/15, 53%) and the remaining low-risk group of purely alcohol dependent patients (n = 48, alcohol recidivism 5/48, 10%) found no combination of variables was predictive of abstinence in either group. The length of pretransplantation abstinence is a relatively poor predictor of posttransplantation abstinence. Variables of comorbid substance use, social function, and possibly family history are more predictive in conjunction with our standard criteria and might be useful as tools in evaluating liver transplantation candidates whose primary diagnosis is alcohol-induced cirrhosis.

Adult↗
PubMed1997

MRI in the investigation of Morton's neuroma: which sequences?

Morton's 'neuroma' is a painful focus of peri-neural fibrosis, which may affect the interdigital nerves of the feet. Clinical diagnosis and localization may be inaccurate. Computed tomography (CT), ultrasound and magnetic resonance imaging (MRI) have been used to confirm the diagnosis pre-operatively. Recently, MRI using T1-weighted sequences with fat saturation after i.v. Gadolinium DTPA has been suggested as the most effective MR sequence for depiction of Morton's neuroma of the neuroma of the forefoot. Our results show that T1-weighted axial and coronal images with an axial FSE T2-weighted sequence detect neuromata more consistently than an enhanced T1 fat suppressed sequence.

Contrast Media↗
PubMed1997

Knowledge and attitudes about depression among non-generalists and generalists.

BACKGROUND: The purpose of this study was to learn more about barriers to managing depression by comparing knowledge and attitudes about depression among physicians, internists, obstetrician-gynecologists, and a reference group of psychiatrists. Among the non-psychiatrists, we hypothesized that generalist physicians would have more favorable attitudes and greater knowledge about depression than non-generalists. METHODS: Survey questionnaires were sent to resident and faculty physicians (N = 375) of two university-affiliated medical centers. The physicians were classified as non-generalists (medicine subspecialists, transitional year interns, and obstetrician-gynecologists), generalists (general internists and family physicians), and psychiatrists. A 33-item written questionnaire assessed knowledge and three attitudinal dimensions: attitudes attributed by physicians to patients; physicians' confidence in managing depression; and physicians' psychosocial orientation. A knowledge scale and an attitudes scale were scored by adding the number of knowledge items answered correctly and the more favorable attitudinal responses. Multivariable regression was used to identify physician characteristics among non-generalists and generalists associated with higher knowledge and attitudinal scores. RESULTS: Response rate was 82%. Sixty percent of the respondents were male, 63% were resident physicians, and 14% had advanced psychosocial training. Non-generalists and generalists had similar demographic characteristics, but psychiatrists were significantly more experienced. Psychiatrists had the most favorable attitudes, followed by generalists and non-generalists. Compared with non-generalists, generalists were more confident in prescribing antidepressants (62% vs 25%), more likely to report that treating depression is rewarding (71% vs 39%), and less likely to refer to a psychiatrist (58% vs 79%). Generalist classification, increased experience, and higher levels of psychosocial training were associated with more favorable attitudes. Knowledge scores were significantly higher for psychiatrists than for non-generalists and generalists. Among non-psychiatrists, correct responses for knowledge items were: treatment efficacy (61%), treatment duration (59%), > or = 5 DSM-III-R criteria (52%), and prevalence of depression (30%). Among those with incorrect responses, both non-generalists and generalists overestimated the prevalence (52%) and underestimated the efficacy of drug therapy (30%). CONCLUSIONS: Generalists and non-generalists have similar and relatively good basic knowledge about depression. Misperceptions about treatment efficacy, and attitudinal barriers, particularly among non-generalists, may compromise the physician's ability to diagnose and manage depression.

Depression↗
PubMed1997

Control of lymphoproliferative and autoimmune disease in MRL-lpr/lpr mice by brequinar sodium: mechanisms of action.

Brequinar sodium (BQR) was originally developed as an antitumor drug and subsequently as an immunosuppressant for controlling transplant rejection. It has been widely accepted that the antitumor and immunosuppressive activities of BQR are dependent on its ability to inhibit the enzymatic activity of dihydroorotate dehydrogenase, the fourth enzyme in the de novo pyrimidine synthesis pathway. Recently, we discovered that BQR has the ability to inhibit protein tyrosine phosphorylation in anti-CD3-stimulated murine T lymphocytes and to inhibit the activity of src-related protein tyrosine kinases, p56lck and p59fyn. We examined the in vivo activities of BQR in MRL-lpr/lpr mice. We report that the dose of BQR (10 mg/kg/day) that induced anemia, controlled lymphadenopathy and inhibited autoantibody production, also selectively reduced the pyrimidine nucleotide levels in the bone marrow and in the lymph nodes. Coadministration of uridine (1000 mg/kg/day) with BQR completely normalized pyrimidine nucleotide levels in the bone marrow and lymph nodes, and prevented BQR-induced anemia. However, coadministration of uridine with BQR only partially reversed the anti-proliferative effects of BQR, and did not antagonize the inhibitory effect of BQR on autoantibody production. Finally, we report that BQR markedly reduced protein tyrosine phosphorylation in lymph nodes of MRL-lpr/lpr mice. These results collectively suggest that the control of lymphadenopathy and autoantibody production in MRL-lpr/lpr mice by BQR is only partially dependent on inhibition of pyrimidine nucleotide synthesis, and suggest a critical role for in vivo inhibition of protein tyrosine phosphorylation.

Animals↗
PubMed1996

Renal transplantation without sutures using the vascular clipping system for renal artery and vein anastomosis--a new technique.

A cadaveric renal transplant was performed on a 63-year-old woman. The donor renal artery and vein were anastomosed to the recipient external iliac vessels using the vascular clipping system. These vascular anastomoses were performed with four stay sutures and several clips for each anastomosis, without a continuous vascular suture. The time taken was 8 min for each anastomosis. There were no postoperative complications and the patient went home after 6 days in the hospital. At 1 month follow-up her serum creatinine was 1.3 mg/dl. We conclude that cadaveric renal transplantation can be performed using clips for the vascular anastomoses. This technique permits an expeditious, interrupted anastomosis. Since the arcuate legged clips are nonpenetrating, there is minimum trauma to the vascular intima. In pediatric transplantation this interrupted technique may be of special importance, since it should allow the anastomoses to grow with time. The ability to quickly perform this type of anastomosis may reduce warm ischemia time as well. The safety and technical ease of this technique should allow its application in the anastomosis of other tubular structures as well. This might further improve the currently excellent outcomes of solid organ transplantation.

Arteriovenous Shunt, Surgical↗
PubMed1996

Two activities of the immunosuppressive metabolite of leflunomide, A77 1726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation.

Previous studies have demonstrated that the active metabolite of leflunomide, A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], is capable of inhibiting the activities of tyrosine kinases and dihydroorotate dehydrogenase (DHO-DHase). In the present study, we define the relative contribution of these activities to the ability of A77 1726 to inhibit proliferation of the murine leukemia cell line LSTRA. A77 1726 inhibited LSTRA cell growth and proliferation (IC50 = 10-30 microM); this inhibition, however, could be reversed by the addition of exogenous uridine, suggesting that the anti-proliferative activity of A77 1726 may be due to inhibition of de novo pyrimidine nucleotide synthesis. Quantitation of nucleotide levels revealed that A77 1726, at an IC50 of about 10 microM, selectively inhibited pyrimidine nucleotide but not purine nucleotide synthesis. In vitro enzyme assays confirmed that A77 1726 directly inhibited the activity of DHO-DHase, the fourth enzyme in the de novo pathway of pyrimidine nucleotide synthesis (IC50 = 220 nM). LSTRA cells overexpress p56lck and have elevated levels of tyrosine phosphorylated intracellular proteins. A77 1726 reduced the intracellular levels of tyrosine phosphorylated proteins with relatively high IC50 values ranging from 50 to 100 microM. A77 1726 also inhibited p56lck activity in LSTRA membrane preparation and immunoprecipitates; the IC50 values for inhibition of immunoprecipitated p56lck autophosphorylation and exogenous substrate histone 2B were 80 and 40 microM, respectively. The anti-tyrosine phosphorylation activity of A77 1726 was not affected by uridine. These studies therefore demonstrate the two activities of A77 1726: inhibition of pyrimidine nucleotide synthesis and interference with tyrosine phosphorylation.

Animals↗