Search PubMed⌕ Search

Biomedical subjects

J W Williams

Publications and source records attributed to J W Williams.

At least 91 records · Page 5Linked to original sources
PubMed1996

Granulocyte colony-stimulating factor immunomodulation in the rat cardiac transplantation model.

Granulocyte colony-stimulating factor (G-CSF) administration decreases tumor necrosis factor(TNF) release, an important mechanism in allograft rejection. to study G-CSF's possible antirejection effects, 30 Lewis rats underwent heart transplantation using Brown-Norway donors and were assigned varying dosages of recombinant human G-CSF (0, 20, 100, 250 and 500 microgram/kg/day) for 14 days following the operation. Recipients receiving 250 microgram/kg/day experienced an improvement in graft survival (12.3+/-4 days vs. 7.0+/-0.6 days, P>0.05, Breslow). In a separate cohort, G-CSF-treated recipients (250 microgram/kg/day x 14) killed at 2,4,and 6 days after transplantation revealed improved serial allograft biopsy grading scores versus untreated controls (P<0.001 stratified Wilcoxon). Significant reduction in serum TNF levels was noted in the G-CSF-treated animals (P<0.025, analysis of variance). These data describe a moderate antirejection effect of G-CSF administration. Inhibition of circulating TNF in the G-CSF-treated recipients may describe a marker or possible mechanism of this antirejection effect.

Animals↗
PubMed1996

Regulation of B cell function by the immunosuppressive agent leflunomide.

Leflunomide is an immunosuppressive drug capable of inhibiting cellular and humoral mediated responses in vivo. The mechanism responsible for suppression of B cell antibody responses in vivo has not been identified. In this study we demonstrate that leflunomide functions to inhibit murine B cell antibody production by directly acting on the B cell. Experiments performed in vivo showed that both T cell-dependent as well as T cell-independent antigen responses were suppressed by leflunomide. Initial in vitro experiments demonstrated that leflunomide inhibited B cell antibody production by decreasing B cell proliferation. The suppression of B cell proliferation induced by a variety of stimuli that use different signal cascade components suggested that leflunomide was acting on a common component required for B cell proliferation. Kinetic studies with LPS activated B cells revealed that leflunomide retained its inhibitory activity when added as late as 24 hr after stimulation in an 88-hr assay. By analyzing the cell cycle of LPS-stimulated B cells we observed that leflunomide targets two different stages in cell cycle transition: (1) from G1 to S phase and (2) from S phase to G2/M phase. Analysis of one of the cyclin-dependent kinases, Cdk2 protein, by Western blot revealed that Cdk2 levels were decreased, in the presence of leflunomide, 48 hr after stimulation. These data further confirmed that leflunomide inhibited B cell progression through the S phase. We also present evidence that the addition of exogenous uridine reversed the antiproliferative activity of leflunomide. This indicated that leflunomide acted as a pyrimidine synthesis inhibitor, thereby inhibiting B cell proliferation and cell cycle progression.

Animals↗
PubMed1996

Effects of leflunomide and other immunosuppressive agents on T cell proliferation in vitro.

Leflunomide and its active metabolite, A771726, are structurally unrelated to immunosuppressive agents currently under investigation. Previous in vitro studies have revealed that leflunomide primarily inhibits interleukin-2-stimulated T cell proliferation. In the current study, we have extended our previous work and demonstrate that leflunomide prevents T cell progression induced by phytohemagglutinin into the S phase of the cell cycle. To discriminate further the action on T cells of leflunomide from other immunosuppressive agents, we performed kinetic studies where leflunomide was added either after the initiation of mixed lymphocyte cultures (MLC) or after interleukin-2 stimulation of CTLL-4 cell proliferation. These studies revealed that leflunomide acted comparably to rapamycin, but was distinct from brequinar sodium in the MLC, and from cyclosporine and mycophenolic acid in both MLC and CTLL-4. Although previous biochemical studies indicated that leflunomide can inhibit src-family tyrosine kinase activity, more recent studies have suggested that leflunomide can also inhibit pyrimidine synthesis. Our data demonstrate that the ability of leflunomide (25-100 microM) to inhibit MLC and CTLL-4 cell proliferation is partially antagonized by uridine (25-100 microM), and support the hypothesis that leflunomide inhibits pyrimidine synthesis in T cells. Unique molecular mechanisms of immunosuppression suggest that drug combinations may result in synergistic immunosuppression. Our in vitro studies revealed synergistic inhibition of T cell proliferation with the combinations of leflunomide with cyclosporine or with rapamycin. We have extended those studies to quantitate inhibition of MLC by the combinations of leflunomide and brequinar sodium or mycophenolic acid.

Cell Division↗
PubMed1996

Ultraviolet-B irradiation of leukapheresis. Products: dose-response relationship with the mixed lymphocyte reaction.

Ultraviolet-B (UVB) irradiation of blood constituents intensifies their anti-rejection effect in pretransplant donor-specific transfusions. UVB-induced inhibition of the mixed lymphocyte reaction (MLR) between UVB-irradiated donor cells and prospective recipient cells is a predicator of this anti-rejection effect. In order to define the dose-response relationship between the incident UVB irradiation on leukocyte concentrates and subsequent inhibition of their MLR responses, we collected 4 +/- 2 x 10(9) leukocytes (93 +/- 7% lymphocytes) in 200 ml plasma from each of three volunteers by leukapheresis and exposed them to rapid, serial doses of UVB irradiation which was delivered by a blood product irradiator (4R4440 UVB Irradiator, Baxter, Inc) with aliquots removed between doses. Lymphocytes from each aliquot were placed in MLR with panel donors and studied in three groups: 1) the panel donor cells were gamma-irradiated (1,500 rads) (i.e., only the UVB-irradiated cells could proliferate), 2) the UVB-irradiated cells were gamma-irradiated (i.e., only the panel lymphocytes could proliferate), and 3) no gamma-irradiation (i.e., both cell populations could proliferate). Each group had a similar UVB dose-related diminution in the MLR (p = .79, ANOVA). A single dose of 6 J/cm2 extinguished the MLR to baseline in all groups. This dose should theoretically prevent transfused cells from producing either graft-versus-host disease or allosensitization, and might heighten their tolerogenic effect. This dose will be employed in our study of donor-specific leukocyte transfusion in clinical renal transplantation.

Dose-Response Relationship, Radiation↗
PubMed1996

General internists influence students to choose primary care careers: the power of role modeling.

PURPOSE: To determine whether medical students supervised by general internist attendings during the third-year medicine clerkship are more likely to choose primary care careers than students supervised by subspecialist attendings. METHODS: One hundred forty-four consecutive medical students rotating on the general medicine inpatient service during the 1993-1994 academic year were surveyed about their career choice and professional expectations, both at the beginning and end of the clerkship; an additional 50 students completed a post-clerkship survey only. The cohort of students was surveyed at graduation to determine stability of their career preferences. RESULTS: Both pre- and post-clerkship surveys were completed by 138 of 144 students (96%); post-clerkship surveys were completed by 181/194 (93%); and graduation surveys were completed by 137/188 (73%). Fifty-eight students (32%) designated primary care (general internal medicine, general pediatrics, or family practice) as their career choice post-clerkship; of these, 45 students (78%) also indicated a primary care career choice at graduation. Characteristics associated with choosing primary care post-clerkship were: low income expectation, desire to interact closely with patients, desire to contribute to society, low class rank, female gender, and high educational debt. Having a physician parent was negatively associated with choosing primary care. After controlling for important demographic, academic and attitudinal characteristics, increasing exposure to a general internist attending was associated with choosing primary care (OR = 5.1, comparing highest to lowest amount). Among students choosing primary care, exposure to a general internist attending was associated with choosing general internal medicine in a dose-dependent fashion (OR = 4.2, comparing highest to lowest amount). CONCLUSIONS: Although career choice is clearly related to personal characteristics such as socioeconomic background and humanistic qualities, a high degree of exposure to general internists during the medicine clerkship is associated with choosing primary care. Exposure of students interested in primary care to general internist attendings may also influence them to consider general internal medicine over family practice and pediatrics.

Adult↗
PubMed1995

Case-finding instruments for depression in primary care settings.

OBJECTIVE: To evaluate the usefulness of case-finding instruments for identifying patients with major depression in primary care settings. DATA SOURCES: A MEDLINE search of the English-language medical literature; bibliographies of selected papers; and experts. STUDY SELECTION: Studies that were done in primary care settings with unselected patients and that compared case-finding instruments with accepted diagnostic criterion standards for major depression were selected. DATA SYNTHESIS: 9 case-finding instruments were assessed in 18 studies. More than 15,000 patients received screening with a case-finding instrument; approximately 5300 of these received criterion standard assessment. Case-finding instruments ranged in length from 2 to 28 questions. Average administration times ranged from less than 2 minutes to 6 minutes. Sensitivities and specificities for detecting major depression ranged from 67% to 99% and from 40% to 95%, respectively. No significant differences between instruments were found. Overall sensitivity was 84% (95% CI, 79% to 89%); overall specificity was 72% (CI, 67% to 77%). If a case-finding instrument were administered to 100 primary care patients with a 5% prevalence of major depression, the clinician could expect that 31 patients would screen positive, that 4 of the 31 would have major depression, and that 1 patient with major depression would not be identified. CONCLUSIONS: Several instruments with reasonable operating characteristics are available to help primary care clinicians identify patients with major depression. Because the operating characteristics of these instruments are similar, selection of a particular instrument should depend on issues such as feasibility, administration and scoring times, and the instruments' ability to serve additional purposes, such as monitoring severity or response to therapy.

Depression↗
PubMed1995

The use of granulocyte colony-stimulating factor after liver transplantation.

Granulocyte colony-stimulating factor (G-CSF) increases the number of circulating granulocytes and decreases TNF production while improving survival in sepsis models. To study the effects of G-CSF administration on sepsis and rejection, 37 primary liver allograft recipients received intravenous recombinant human G-CSF (rhG-CSF; 5-10 micrograms/kg/day) for the first 7-10 days following transplantation, targeting a blood absolute granulocyte count of between 10,000 and 20,000 cells/mm3. These recipients were monitored prospectively for sepsis and rejection, as were the previous 49 primary liver allograft recipients who did not receive G-CSF. Both groups utilized identical protocol immunosuppression and standardized diagnosis and treatment of sepsis and rejection. Univariate and logistic regression analysis of risk factors for sepsis and rejection revealed no difference between the two patient groups. G-CSF-treated patients developed an increased absolute granulocyte count over time (P < 0.0001, repeated-measures analysis of variance). G-CSF-treated patients had a decreased number of sepsis episodes per patient (0.92 +/- 1.5 vs. 2.18 +/- 2.8, P < 0.02, t test), and a lower percentage of sepsis-related deaths (8% vs. 22%, P < 0.04, chi-square test). The incidence of acute rejection was decreased in the G-CSF-treated group (22% vs. 51%, P < 0.01, chi-square test). These pilot data support further investigation into G-CSF's favorable effects on sepsis and rejection.

Analysis of Variance↗
PubMed1995

Inhibition of protein tyrosine phosphorylation in T cells by a novel immunosuppressive agent, leflunomide.

Leflunomide, a novel immunosuppressive drug, is able to prevent and reverse allograft and xenograft rejection in rodents, dogs, and monkeys. It is also effective in the treatment of several rodent models of arthritis and autoimmune disease. In vitro studies indicate that leflunomide is capable of inhibiting anti-CD3- and interleukin-2 (IL-2)-stimulated T cell proliferation. However, the biochemical mechanism for the inhibitory activity of leflunomide has not been elucidated. In this study, we characterized the inhibitory effects of leflunomide on Src family (p56lck and p59fyn)-mediated protein tyrosine phosphorylation. Leflunomide was able to inhibit p59fyn and p56lck activity in in vitro tyrosine kinase assays. The IC50 values for p59fyn (immunoprecipitated from either Jurkat or CTLL-4 cell lysate) autophosphorylation and phosphorylation of the exogenous substrate, histone 2B, were 125-175 and 22-40 microM respectively, while the IC50 values for p56lck (immunoprecipitated from Jurkat cell lysates) autophosphorylation and phosphorylation of histone 2B were 160 and 65 microM respectively. We also demonstrated the ability of leflunomide to inhibit protein tyrosine phosphorylation induced by anti-CD3 monoclonal antibody in Jurkat cells. The IC50 values for total intracellular tyrosine phosphorylation ranged from 5 to 45 microM, with the IC50 values for the zeta chain and phospholipase C isoform gamma 1 being 35 and 44 microM respectively. Leflunomide also inhibited Ca2+ mobilization in Jurkat cells stimulated by anti-CD3 antibody but not in those stimulated by ionomycin. Distal events of anti-CD3 monoclonal antibody stimulation, namely, IL-2 production and IL-2 receptor expression on human T lymphocytes, were also inhibited by leflunomide. Finally, tyrosine phosphorylation in CTLL-4 cells stimulated by IL-2 was also inhibited by leflunomide. These data collectively demonstrate the ability of leflunomide to inhibit tyrosine kinase activity in vitro, and suggest that inhibition of tyrosine phosphorylation events may be the mechanism by which leflunomide functions as an immunosuppressive agent.

Animals↗
PubMed1995

Randomized controlled trial of 3 vs 10 days of trimethoprim/sulfamethoxazole for acute maxillary sinusitis.

OBJECTIVE: To compare 14-day outcomes and relapse and recurrence rates among patients with acute maxillary sinusitis randomized to 3-day (3D) vs 10-day (10D) treatment with trimethoprim/sulfamethoxazole (TMP/SMX). SETTING: University-affiliated Veterans Affairs general medical and acute care clinics. PATIENTS: Consecutive patients with sinus symptoms and radiographic evidence of maxillary sinusitis (complete opacity, air-fluid level, or > or = 6 mm of mucosal thickening). Patients were excluded for antibiotic use within the past week, TMP/SMX allergy, symptoms for more than 30 days, or previous sinus surgery. METHODS: All subjects (n = 80) received oxymetazoline nasal spray 0.05%, two sprays twice daily for 3 days. Subjects were randomly assigned to TMP/SMX double strength: one tablet twice daily for 10 days or one tablet twice daily for 3 days followed by 7 days of placebo. At 7 and 14 days, patients rated their overall sinus symptoms on a Likert scale. Radiographs were scored at baseline and 14 days by radiologists masked to clinical symptoms and treatment assignment. The primary outcome was number of days to "cure" or "much improvement" in sinus symptoms. Patients who were clinical successes by day 14 were assessed for symptomatic relapse or recurrence at 30 and 60 days, respectively. RESULTS: Groups were comparable at randomization: male, 100%; black, 53%; median age, 48 years (interquartile range, 41 to 63 years); symptom duration, 10 days (interquartile range, 6 to 17 days); bilateral maxillary disease, 51%; and radiograph score, 4 (interquartile range, 2 to 4). Outcome assessment was completed in 95% of patients at day 14 (n = 76). Medication side effects and use of nonstudy sinus medications were equal between groups. By 14 days, 77% of 3D subjects and 76% of 10D subjects rated their sinus symptoms as cured or much improved (95% confidence interval for difference, -15% to 17%). Median days to cure/much improvement were 5.0 and 4.5 for the 3D and 10D groups, respectively; distributions of time to cure were not different (P = .34). Radiograph scores improved in both groups compared with baseline (2 points; P < .001), but improvement did not differ between groups (P = .31). Eight percent of 3D subjects and 13% of 10D subjects missed work due to sinus symptoms. Of the 52 patients who were clinical successes at 14 days and completed follow-up, three (11%) of 27 3D subjects and one (4%) of 25 10D subjects relapsed symptomatically by day 30; one (4%) of 27 3D subjects and one (4%) of 25 10D subjects suffered symptomatic recurrence between days 30 and 60 (P = .45 for the relapse and recurrence rates combined). CONCLUSION: At the 2-week follow-up, clinical symptoms and radiograph scores improved equally following 3 or 10 days of TMP/SMX plus oxymetazoline nasal spray. Symptomatic relapse and recurrence were similar between groups. Three days of antibiotics were as effective as 10 days and, because of the high disease prevalence, hold the potential for substantial cost savings.

Acute Disease↗
PubMed1995

Usual care and outcomes in patients with sinus complaints and normal results of sinus roentgenography.

OBJECTIVE: To describe the usual care and outcomes of patients with sinus symptoms and normal sinus roentgenograms. DESIGN: Prospective cohort with 60-day follow-up. SETTING: Medical outpatient clinics at a university-affiliated Veterans Affairs medical center. PATIENTS: Consecutive patients (n = 126, 88% follow-up rate) with rhinorrhea (88%), facial pain (65%), or self-suspected sinusitis (24%) and normal four-view sinus roentgenography (median age, 47 years; 90% male; 56% white). MAIN OUTCOME MEASURE: Fourteen-day self-reported symptom status. RESULTS: Sixteen history and five physical examination items were recorded by clinicians who were blinded to the results of sinus roentgenography; clinical diagnoses and treatment plans were formulated by clinicians with knowledge of the results of sinus roentgenography. Clinical diagnoses included allergic rhinitis (27%), sinusitis (22%), viral respiratory tract infection (14%), and bronchitis (11%). Treatments included administration of antibiotics (40%), decongestants (32%), antihistamines (25%), and nasal steroids (9%). Forty-nine percent achieved 14-day clinical success (13.5% were cured and 36% were much improved). Improvement was more likely among patients who presented with cough (odds ratio, 3.0; 95% confidence interval, 1.3 to 6.9) but was less likely among those with itchy eyes (odds ratio, 0.18; 95% confidence interval, 0.07 to 0.43). Patients with cough and without itchy eyes had significantly shorter clinical courses (P = .003). Of patients who achieved clinical success on day 14, 30% relapsed or recurred by day 60. CONCLUSION: With usual medical care, the syndrome of sinus symptoms and normal results of sinus roentgenography persists for at least 14 days in many patients; however, patients with cough but without itchy eyes may have shorter clinical courses.

Adult↗
PubMed1995

Depressive disorders in primary care: prevalence, functional disability, and identification.

OBJECTIVES: To assess the relative prevalence of subsyndromal depression (SubD) and major depression (MDD) in primary care patients and describe their associated functional impairments, and to define the operating characteristics of a short depression screen (SDS). SETTING: Three primary care clinics: a university-affiliated Veterans Affairs clinic, a county general internal medicine clinic, and a community health center. SUBJECTS: Randomly selected adult patients (n = 221), aged > or = 30 years, with no history of psychiatric comorbidity, current substance abuse, major depressive disorder, chronic pain disorder, or dementia. MEASUREMENTS: The SDS and the Medical Outcomes Study Short Form 36 (SF-36) were interviewer-administered by an experienced bilingual research assistant to all subjects in the language of their choice. A physician administered independently the Structured Clinical Interview for DSM-III diagnosis (SCID) and the Hamilton Depression Rating Scale (HDRS) to all patients who exceeded a minimum threshold on the SDS and to a randomly selected sample of patients who had subthreshold scores. MDD was defined by DSM-III criteria and SubD was defined as two to four DSM-III criteria, of which one had to be depressed mood or anhedonia. RESULTS: Demographic and clinical characteristics of the patients were: Mexican American 53%, non-Hispanic white 38%, and African American 9%; men 68%; mean age 60 +/- 12.7 years; mean level of education 9.5 +/- 4.4 years; and hypertension 57%, diabetes mellitus 51%, and arthritis 45%. The prevalences of MDD and SubD (adjusted for sampling strategy) were 4% and 16%, respectively. For the patients who had MDD, the median HDRS score was 17 (interquartile range, 10-18), and for those who had SubD, the median HDRS score was 9 (interquartile range, 8-14). Compared with the patients who did not have depressive symptoms, those who had either MDD or SubD were significantly impaired in multiple domains of self-reported function. The sensitivity and specificity of the SDS for MDD were 100% (95% CI 57-100) and 72% (95% CI 63-81), respectively. For depressive disorders (MDD or SubD), the sensitivity was 66% (95% CI 49-83) and the specificity was 79% (95% CI 69-89). CONCLUSIONS: SubD was more prevalent than MDD in these primary care settings. Both MDD and SubD were associated with significant functional impairment. The sensitivity of the SDS was lower for identifying depressive disorders (MDD or SubD) than it was for identifying MD.

Adult↗
PubMed1995

Pronephric carcinoma: chromosomes of cells rescued from apoptosis by an oncogenic herpesvirus detected with a polymerase chain reaction.

The amphibian pronephros is fated to die during early development. Pronephric cells undergo apoptosis and their function is replaced by the mesonephros, which becomes the functional kidney of the adult frog. Tadpoles of the northern leopard frog, Rana pipiens, were inoculated with a Lucké tumour herpesvirus (LTV) preparation. Most of the animals developed typical Lucké renal carcinomas at metamorphosis. Fewer developed carcinomas of the pronephric cell type. A pronephric carcinoma, rescued from apoptosis by the herpesvirus, was harvested from a post-metamorphic frog. The tumour was judged to be pronephric by its anatomical location (in the anterior part of the body) and because both mesonephric kidneys were intact and tumour-free upon removal of the tumour mass. A tumour fragment was fixed for histological examination, which confirmed that the tissue was a renal carcinoma. A further fragment was subjected to short-term culture in order to produce metaphase cells for cytogenetical analysis. Based upon silverstained nucleolar organizing region numbers, 14 of 15 metaphase cells were estimated to have the diploid number (2N = 26) of chromosomes and a karyotype was constructed which did not appear to differ from that of normal cells. A single cell was estimated to be tetraploid (4N = 52). This is the first report of chromosomes of a pronephric Lucké carcinoma. LTV replicates only in tumour tissue maintained in the cold. Because the frog in this study had been maintained in the laboratory at 22 degrees C for about 10 months, no viruses would have been detectable with electron microscopy. However, the presence of Lucké herpesvirus DNA was detected in tumour homogenates by polymerase chain reaction amplification of a 1.2 kbp Hind III restriction fragment of the LTV DNA. The presence of LTV DNA provided assurance that the rescued pronephric tumour was indeed a Lucké carcinoma.

Animals↗