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Background: Elevated expression of platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta have been observed in a number of fibrotic diseases, including systemic sclerosis (SSc). This suggests a possible interaction between these factors in establishing a profibrotic programme in dermal fibroblasts., Objectives: To examine the effects of PDGF isoforms on the expression of TGF-beta receptors in human dermal fibroblasts., Methods: Steady-state mRNA levels of TGF-beta receptor I and II (TbetaR-I and TbetaR-II) were analysed by northern blot. TbetaR-I protein levels were analysed by immunoprecipitation of 35S metabolically labelled cells. TbetaR-II protein levels were analysed by western blot., Results: Steady-state mRNA levels of TbetaR-I and TbetaR-II were induced in response to PDGF isoforms. PDGF-AA and PDGF-AB stimulated both receptors with similar potency, whereas PDGF-BB was less potent. The MEK1 (mitogen-activated protein kinase [MAPK] or extracellular signal regulated kinase) inhibitor, PD98059, abrogated the stimulatory effect of PDGF-AB. In contrast to mRNA levels, only TbetaR-II protein levels were elevated in response to PDGF., Conclusions: These data suggest that PDGF receptor alpha and MAPK mediate stimulation of TGF-beta receptors by PDGF. Furthermore, TGF-beta receptor protein levels are discordantly regulated by PDGF.

Anti-CD4 antibodies, which cause CD4(+) T-cell depletion, have been shown to increase susceptibility to infections in mice. Thus, development of anti-CD4 antibodies for clinical use raises potential concerns about suppression of host defense mechanisms against pathogens and tumors. The anti-human CD4 antibody keliximab, which binds only human and chimpanzee CD4, has been evaluated in host defense models using murine CD4 knockout-human CD4 transgenic (HuCD4/Tg) mice. In these mice, depletion of CD4(+) T cells by keliximab was associated with inhibition of anti-Pneumocystis carinii and anti-Candida albicans antibody responses and rendered HuCD4/Tg mice susceptible to P. carinii, a CD4-dependent pathogen, but did not compromise host defense against C. albicans infection. Treatment of HuCD4/Tg mice with corticosteroids impaired host immune responses and decreased survival for both infections. Resistance to experimental B16 melanoma metastases was not affected by treatment with keliximab, in contrast to an increase in tumor colonization caused by anti-T cell Thy1.2 and anti-asialo GM-1 antibodies. These data suggest an immunomodulatory rather than an overt immunosuppressive activity of keliximab. This was further demonstrated by the differential effect of keliximab on type 1 and type 2 cytokine expression in splenocytes stimulated ex vivo. Keliximab caused an initial up-regulation of interleukin-2 (IL-2) and gamma interferon, followed by transient down-regulation of IL-4 and IL-10. Taken together, the effects of keliximab in HuCD4/Tg mice suggest that in addition to depleting circulating CD4(+) T lymphocytes, keliximab has the capability of modulating the function of the remaining cells without causing general immunosuppression. Therefore, keliximab therapy may be beneficial in controlling certain autoimmune diseases.

Keliximab and clenoliximab are monkey/human chimeric CD4 monoclonal antibodies (mAbs) of the IgG1 and IgG4 isotypes, respectively. The pharmacokinetics (PK) and pharmacodynamics (PD) of these mAbs were evaluated in transgenic mice bearing human CD4 molecules on their T cells after a single i.v. administration at three dose levels (5-125 mg/kg). The PK of keliximab and clenoliximab were similar, dose-dependent, and adequately described by a two-compartment model with saturable elimination from both compartments. The enumeration of circulating CD4(+) T cells and density of CD4 on their surface were determined as the PD effects. An indirect response model was proposed to characterize the PD effects. With the increase in mAb dose, the maximum intensity (R(max)) of PD effects was increased, and the time to reach R(max) shifted to later times. At all three dose levels, keliximab caused a relatively rapid decline in the number of circulating CD4(+) T cells, which then recovered gradually. In contrast, clenoliximab at the lowest dose (5 mg/kg) did not produce a significant effect on CD4(+) T cell counts compared with the placebo group. At high doses, clenoliximab caused a significant decrease in the number of CD4(+) T cells. Keliximab appeared to be more potent and efficient in depleting CD4(+) T cells. Both mAbs produced similar down-modulation of CD4 at corresponding dose levels. The findings of this study are consistent with the results of a recent clinical trial that emphasize the importance of this transgenic mouse model for evaluating PK/PD to support clinical development of anti-human CD4 mAbs.

Alopecia areata is a common skin disease in which proinflammatory cytokines such as IL-1beta may play a pathogenic role. In this study, we examined the distribution of genotypes of an IL-1beta single base change polymorphism at position +3953 in patients with alopecia areata. The distribution of immunoglobulin kappa light chain (KM) genotypes was similarly examined. The data obtained showed that the IL-1beta and KM loci act cooperatively to significantly increase susceptibility to alopecia areata.

Azaspiranes are novel macrophage-targeting agents with activity in preclinical animal models of autoimmune disease and transplantation. The purpose of this work was to determine the effects of atiprimod (SK&F 106615), an azaspirane being developed for the treatment of rheumatoid arthritis, on rat pulmonary alveolar macrophage (AM) function and immunocompetance in Candida-infected mice. AM from rats treated with 20 mg/kg/day of atiprimod for 15 days demonstrated enhanced killing of Candida albicans ex vivo. Concentration-dependent increases in candidacidal activity were also observed as early as one hour after exposure in vitro in AM from untreated normal rats. Treatment of AM with atiprimod in vitro did not increase particulate-stimulated superoxide production or phagocytosis of Candida but decreased their ability to concentrate acridine orange, indicating an increase in lysosomal pH. Increased candidacidal activity was inhibited by superoxide dismutase and catalase, suggesting a role for reactive oxygen intermediates (ROI). Atiprimod also increased free radical-mediated killing of Candida in the presence of H2O2, iron and iodide in a cell-free system. These findings indicated that treatment with atiprimod increased the candidacidal activity of rat AM in a free radical-dependent manner. The data also suggested that atiprimod did not increase ROI production by AM, but rather increased the efficiency of radical-mediated killing. This increase may be caused by cyclization of atiprimod, facilitating electron transfer and peroxidation of lipid membranes. In vivo studies in Candida-infected CBA mice showed that atiprimod (10 mg/kg/day), did not compromise immune function in the infected mice and could be differentiated from prototypical immunosuppressive compounds used for treatment of autoimmune diseases.

Novel biomarkers are often required in the preclinical development of biopharmaceuticals in order to characterize pharmacologic and toxicologic effects and to establish pharmacodynamic and pharmacokinetic relationships. Flow cytometry is uniquely suited for measurement of these biomarkers. Large numbers of single cells in a heterogeneous population can be rapidly identified and characterized with high accuracy and reproducibility. Cells are not damaged by the detection system and can be subsequently sorted for further morphologic or functional analysis. The availability of clinical instruments and a wide range of fluorescent probes have made this technology applicable for use in toxicologic clinical pathology. Flow cytometry has played an integral role in the development of a monoclonal antibody to human CD4 (keliximab, IDEC-CE9.1, SB 210396). Lymphocyte subset analysis and assays for expression, coating, and modulation of human CD4 were used for sequential assessment of the pharmacologic activity of keliximab in transgenic mice expressing human CD4.

Adult periodontitis is a complex multifactorial disease whose etiology is not well defined. The pro-inflammatory and bone resorptive properties of interleukin-1 beta (IL-1beta) strongly suggest a role for this cytokine in the pathogenesis of periodontal disease. In the study reported here, the frequency of IL-1beta genotypes including allele 2 of the IL-1beta+3953 restriction fragment length bi-allelic polymorphism was significantly increased in patients with advanced adult periodontitis compared to those with early and moderate disease. Furthermore, allele 2 was associated with increased production of IL-1beta by activated peripheral blood polymorphonuclear cells of patients with advanced disease, although this increase failed to reach statistical significance. Finally, the data obtained revealed significant linkage disequilibrium between allele 2 of the IL-1beta+3953 polymorphism and allele 2 of the bi-allelic IL-1alpha-889 polymorphism in both patients and orally healthy controls. These findings provide new insight into the possible role of IL-1alpha and beta gene polymorphisms in the susceptibility to adult periodontitis.

Purpose: This study was undertaken to evaluate long-term pulmonary function changes in patients undergoing bone marrow transplantation (BMT), to assess their clinical significance, and to identify factors influencing these changes., Methods and Materials: Pulmonary function tests (PFT) were evaluated before and after BMT in 111 adult patients undergoing BMT between 1985 and 1991. Forced expiratory volume at 1 s (FEV1), forced vital capacity (FVC), diffusing capacity (DLCO), and total lung capacity (TLC) were evaluated. One hundred and three patients (92.8%) received total body irradiation (TBI) to a total dose of 14 Gy in nine equal fractions. The lung dose was restricted to < 6.5 Gy in 95% of patients with partial transmission lung shielding. Seventy-eight percent of patients had acute graft-versus-host disease (aGVHD), 69% chronic graft-vs.-host disease (cGVHD), and 63% posttransplant pulmonary infection. Effects of GVHD, TBI, radiation dose to the lungs, dose rate of TBI, posttransplant pulmonary infection, Busulfan use for conditioning, age, and history of smoking were evaluated for their influence on pulmonary function., Results: Posttransplant FEV1, FVC, and TLC were lower than pretransplant values (p < 0.05) at 6 months and 1 year posttransplant with subsequent recovery. DLCO was significantly lower at all posttransplant intervals. FEV1 did not fall significantly in patients without acute or chronic GVHD and recovered earlier than in patients without posttransplant pulmonary infection. Recovery of FVC, TLC, and DLCO was also delayed in patients with acute and chronic GVHD and posttransplant pulmonary infection. Multiple regression analysis revealed an association between a higher radiation dose to the lungs, and decreased FVC at 2 years (p = 0.01). Progressive obstructive pulmonary disease was not observed., Conclusion: An initial decline in PFTs with subsequent recovery was observed. Factors associated with delayed recovery and incomplete recovery of PFTs were GVHD, posttransplant pulmonary infection, and higher radiation dose to the lungs. The conditioning regimen used at Medical College of Wisconsin, including relatively high TBI doses with partial transmission pulmonary shielding, appears to be well tolerated by the lungs in long-term survivors. No progressive decline in PFTs or symptomatic decline in pulmonary function was observed during the time interval studied.

Background: There is a clear national mandate to increase the proportion of generalist physicians within the medical community and to increase their numbers within rural and underserved urban locations. Little is known, however, about the geographic and temporal career patterns of family physicians or about how these patterns differ by sex and graduation cohort., Methods: Using information from a follow-up survey of the University of Washington Family Practice Residency Network, we analyzed the characteristics of 358 graduate physicians and their 493 practices, including data on geographic practice locations., Results: Two thirds of graduates began their practices in urban locations, and one third initially settled in rural communities. Female graduates were much less likely than their male peers to choose rural practice locations. Few physicians left practices after they had practiced in them for 5 or 6 years. The majority of graduates were still in the practice where they started as long as 18 years earlier., Conclusions: The most important career decision made by the graduate of a family medicine residency involves practice location. Because women are less likely to practice in rural areas, the increasing proportion of women graduating from family practice residencies might presage shortages of rural physicians in the future.

This study describes how graduates of the University of Washington Family Medicine Residency Network who practice in rural locations differ from their urban counterparts in demographic characteristics, practice organization, practice content and scope of services, and satisfaction. Five hundred and three civilian medical graduates who completed their residencies between 1973 and 1990 responded to a 27-item questionnaire sent in 1992 (84% response rate). Graduates practicing outside the United States in a specialty other than family medicine or for fewer than 20 hours per week in direct patient care were excluded from the main study, leaving 116 rural and 278 urban graduates in the study. Thirty percent of graduates reported practicing in rural counties at the time of the survey. Rural graduates were more likely to be in private and solo practices than urban graduates. Rural graduates spent more time in patient care and on call, performed a broader range of procedures, and were more likely to practice obstetrics than urban graduates. Fewer graduates in rural practice were women. A greater proportion of rural graduates had been defendants in medical malpractice suits. The more independent and isolated private and solo practice settings of rural graduates require more practice management skills and support. Rural graduates' broader scope of practice requires training in a full range of procedures and inpatient care, as well as ambulatory care. Rural communities and hospitals also need to develop more flexible practice opportunities, including salaried and part-time positions, to facilitate recruitment and retention of physicians, especially women.

The age at which paediatricians and family practitioners first spend private time with child patients was investigated. An anonymous survey which included both hypothetical clinical situations and direct questions about the age at which patients are usually seen alone was sent to 380 physicians, 47.6% of whom responded. A privacy index, computed from the responses to the hypothetical situations, had a significant positive correlation with the age at which physicians said they usually see children alone for routine situations, for chronic disease, and for compliance problems. The results indicated that family practitioners may see children alone in more situations and at younger ages than do paediatricians. The rationale for affording child patients an opportunity for some private discussion with their primary care physician and the impediments to this are discussed.

Olivocerebellar pontine degeneration of the Wadia type is characterized by progressive symmetrical cerebellar ataxia, slow eye movements, absent deep tendon reflexes, autosomal dominant inheritance, and onset between the second and fourth decades. The only available treatments are genetic counseling, social and psychological support, and physiotherapy. This article presents a case of this subtype of hereditary ataxia and a review of the literature.

Predictors of outcome in pediatric submersion victims treated by Seattle and King County's prehospital emergency services were studied. Victims less than 20 years old were identified from hospital admissions and paramedic and medical examiners' reports. The proportion of fatal or severe outcomes in patients were compared with various risk factors. Of 135 patients, 45 died and 5 had severe neurologic impairment. A subset of 38 victims found in cardiopulmonary arrest had a 32% survival rate, with 67% of survivors unimpaired or only mildly impaired. The two risk factors that occurred most commonly in victims who died or were severely impaired were submersion duration greater than 9 minutes (28 patients) and cardiopulmonary resuscitation duration longer than 25 minutes (20 patients). Both factors were ascertained in the prehospital phase of care. Submersion duration was associated with a steadily increasing risk of severe or fatal outcomes: 10% risk (7/67) for 0 to 5 minutes, 56% risk (5/9) for 6 to 9 minutes, 88% risk (21/25) for 10 to 25 minutes, 100% risk (4/4) for greater than 25 minutes. None of 20 children receiving greater than 25 minutes of cardiopulmonary resuscitation escaped death or severe neurologic impairment. Our rates for saving all victims, particularly victims in cardiopulmonary arrest, are considerably higher than has been reported before the children. Prompt prehospital advanced cardiac life support is the most effective means of medical intervention for the pediatric submersion victim. Prehospital information provided the most valuable predictors of outcome.

This article summarizes the practice content and continuity for 35 senior residents in six family medicine residency model teaching units utilizing a computerized information management system. Comparisons are drawn with the content of family practices in the National Ambulatory Medical Care Survey (NAMCS), showing that family medicine third-year residents provide a large proportion of pregnancy care and general medical examinations and treat a smaller number of chronic illness patients compared with family physicians in practice. Third-year residents performed few surgical procedures in the model teaching units. Continuity of care, though espoused by family medicine residencies in principle, was deficient in the model teaching units studied. Intensive training to compensate for these deficiencies is recommended.

We compared pediatric residents' psychosocial attitude, personality, and in-training examination (American Board of Pediatrics) scores with faculty evaluations of the residents' clinical performance (clinical skills, medical knowledge, interpersonal skills and relationship with other staff) in inpatient, outpatient, and intensive care settings. We found no relationship between psychosocial attitudes and the in-training examination scores or among aggregate faculty ratings, attitudes, and examination scores, but faculty ratings grouped by setting yielded more discriminating results. On inpatient rotations, cognitive knowledge (as reflected by in-training examination scores) was positively correlated with faculty ratings. On intensive care and outpatient rotations, knowledge did not correlate with faculty ratings. Residents' attitudes favoring a psychosocial approach to medical practice were associated with positive evaluations on outpatient rotations but with negative evaluations on intensive care rotations. Psychosocial attitudes seemed to be determined by the social orientation of the resident's personality styles. Our results emphasize the importance of clinical setting to faculty rating and suggest that valued resident characteristics vary by setting. These findings have significant implications for both improving the clinical evaluation of residents and creating a better understanding of the interaction of personality, attitude, and cognitive variables in rated clinical performance.

Childhood encopresis is discussed in terms of problems of definition, approaches to management in relation to symptoms and underlying mechanisms, and efficacy of treatment. Case histories of six intractable clinic cases are examined and an intensive team intervention programme described. Difficulties in carrying through a consistent plan are outlined: the key worker providing an essential motivational role towards participant staff, parents and child.

The factors associated with submersion events among less than 20-year-old persons that occurred in King County from 1974 to 1983 were studied to focus prevention efforts. Near-drowning (n = 103) and drowning (n = 96) victims were identified from medical examiners' reports, paramedics' reports, and hospital discharge registers. Annual incidence was 5.5; the mortality rate was 2.6 per 100,000 children. Although preschool-aged children had the largest incidence (12.8), followed by older adolescents (4.9), adolescents had the largest case fatality rate, 77%. Lake and river victims had the largest incidence, mortality, and case fatality rate; swimming pools, the smallest case fatality rate (25%). A total of 89% of all victims had absent or no supervision; victims supervised by lifeguards had a 42% case fatality rate. Prior seizures were part of the history of 7.5% of all victims; 25% of fatal submersions by adolescents were associated with alcohol. Bathtub submersions were associated with child abuse in three of 16 preschool-aged children and epilepsy in four of five older children. Certain age groups and sites combined had the greatest incidence: preschool-aged children in swimming pools, infants in bathtubs, teenagers in lakes and rivers. Incidence decreased in public and semipublic pools coincident with fencing regulations. These findings suggest prevention strategies: extending fencing requirements to private pools, discouraging alcohol consumption during water sports, changing bathing practices of epileptics, and improving lifeguard efficacy.

In the design of projected transparencies, aesthetics usually govern color selection. However, the perceptual consequences of color use should be considered as well. Studies on the effects of color on visual perception and attention to them in the psychological literature are reviewed. The findings are discussed and applied to the problem of selecting color for projected transparencies.

We sought to define objective indicators of the resolution of Pseudomonas aeruginosa endobronchial infection in patients with cystic fibrosis. We prospectively studied 75 patients admitted for treatment of a pulmonary exacerbation and quantitated sputum bacterial density, DNA content, and the concentration of albumin and total protein in sputum, and compared these values with clinical evaluation. Eleven of the 75 patients had systemic signs, fever, and leukocytosis, which we arbitrarily defined as due to endobronchial infection. At the end of hospitalization, these 11 patients were afebrile, had peripheral leukocyte counts in the normal range, and were judged improved. Sputum P. aeruginosa density, DNA content, and total protein content on admission were similar in the two illness groups. Hospitalization and parenteral antibiotic administration for an average of 14.6 days were associated with improved pulmonary function in all 75 subjects (P values for forced vital capacity, forced expiratory volume at 1 second, and peak expiratory flow rate were all less than 0.001). With improvement, there was a decrease in sputum P. aeruginosa density (mean of both groups decreased from 10(7.80) CFU/g on admission to 10(5.96) CFU/g; P less than 0.001), and a decreased DNA concentration (overall mean 4.73 +/- 4.75 on admission to 2.76 +/- 2.49 mg/g; P less than 0.002). The decrease in sputum total protein concentration for both groups was not significant (overall mean 60.5 +/- 48.4 to 43.9 +/- 38.2 mg/g; P = 0.06). Sputum albumin concentrations did not change in either group. We conclude that in cystic fibrosis subjects with a pulmonary exacerbation, bacterial density, sputum DNA and protein content decrease with hospitalization and parenteral antibiotic therapy. At the end of treatment, these indices of sputum infection and inflammation correlate with improved pulmonary function and clinical improvement. These changes are independent of the presence or absence of fever on admission.

We examined, in a 2-year prospective study, the frequency of respiratory viral infections in 19 school-age patients with cystic fibrosis and their unaffected siblings. At 2-month intervals throughout the study period, pulmonary function tests, oropharyngeal cultures, and serologic tests for respiratory viruses were performed in all subjects. Quantitative sputum cultures for bacteria were performed in subjects with cystic fibrosis. The same laboratory specimens were also collected at the time of all acute respiratory illnesses. Over the 2-year period, 398 viral cultures and serum samples were collected, 210 from patients with cystic fibrosis and 188 from their siblings. The frequency of culture-documented and seropositive viral infections was not significantly different between patients with cystic fibrosis and their siblings. The patients with the highest frequency of viral infection were younger and had the lowest rate of decline in lung function and severity score. We conclude that school-age patients with cystic fibrosis are no more susceptible to viral infections than their unaffected siblings. We were unable to demonstrate any significant adverse effect of respiratory viral infections on pulmonary function in 19 patients with cystic fibrosis aged 5 to 21 years.

To determine the potential toxicity of prolonged aerosol tobramycin administration, 22 patients with cystic fibrosis were monitored while receiving inhaled tobramycin three times a day for 12 weeks. Prior to, four times during administration and approximately 6 weeks after discontinuation of treatment, we assessed pulmonary function, weight, height, body temperature, eighth cranial nerve function, serum creatinine, blood urea nitrogen, urinary creatinine clearance, plasma iothalamate clearance, urinary beta-2 microglobulin concentration, and Pseudomonas aeruginosa density in sputum. There was no detectable laboratory evidence of nephrotoxicity. Neither a decrease in auditory acuity (range 250-20,000 Hz) nor vestibular dysfunction was detected. Pulmonary function tests significantly improved during the first month in all subjects (P less than 0.05) but returned to enrollment values by the end of the 12th week of administration of tobramycin aerosol. Sputum P. aeruginosa density initially decreased from a mean of 10(7) cfu/gm to a mean of 10(4) cfu/gm after 2 weeks of aerosol tobramycin administration and remained significantly below the enrollment value throughout. Coincident with the reduced bacterial density, a reduction in cough frequency and sputum production, as well as a weight gain was observed. Seventy-three percent of the patients with sputum P. aeruginosa isolates susceptible to tobramycin on enrollment yielded resistant organisms during aerosol administration. However, 1 year later all sputum P. aeruginosa isolates obtained from patients were susceptible to tobramycin. We conclude that thrice daily aerosol tobramycin administration for 3 months is not associated with detectable eighth cranial nerve or renal toxicity. Transient emergence of tobramycin resistant P. aeruginosa may occur.

This report describes a study of the content and uses of the University of Washington Affiliated Residency Network documentation system for future hospital privileges. The selected procedures and problems considered important to document for future hospital privileges were validated by means of a graduate survey conducted in 1985. Fifty percent of the 43 graduates responding used their personal documentation when applying for hospital privileges. Intermediate-sized hospitals of 50 to 199 beds were significantly more likely to require documentation than either small (fewer than 50 beds) or large (more than 200 beds) hospitals. However, 84 percent of the hospitals where graduates are located either require documentation or would find it helpful for privilege application. The three-year cumulative experiences of the 1986 cohort of graduating residents are also presented. Thirty-six of the residents (71 percent) participated actively in the voluntary network documentation system. None of the items selected as important to document for future hospital privileges were recorded by 100 percent of the residents. Obstetric procedures and problems were the items most commonly documented.

This paper describes an evaluation of the University of Washington family practice project to document resident experiences in training. The production of aggregate reports using clustering techniques and peer group comparisons were well received by residents and faculty. A questionnaire survey and personal interview with a sample of faculty and residents analyzed attitudes toward the usefulness of such a documentation system as well as the actual uses of the reports produced. Documentation of inpatient and outpatient procedures was the most highly regarded application, but an overview of the scope and content of a resident ambulatory practice experience was also considered useful. Physician behavior was altered in subtle ways as a result of the feedback.