Studies of multidrug transport proteins in cells derived from human lung samples.
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ATP Binding Cassette Transporter, Subfamily B, Mem↗
Biomedical subjects
S Stewart
Publications and source records attributed to S Stewart.
Association between blood eosinophil counts and acute cardiac and pulmonary allograft rejection.
BACKGROUND: Peripheral blood eosinophilia is a particularly early and specific marker of both renal and hepatic allograft rejection. Therefore we evaluated the relationship between blood eosinophil counts and cardiac and pulmonary allograft rejection. METHODS: Differential blood counts were available within 3 days before 383 endomyocardial biopsy specimens in 56 heart transplant recipients. Blood counts were also available before 84 treated rejection episodes and 28 transbronchial biopsy specimens showing no rejection in 58 lung transplant recipients. RESULTS: Cardiac allograft rejection: There was a significant association between the mean maximum blood eosinophil count and treated acute rejection (p < 0.01) and a linear relationship between this eosinophil count and the histologic grade of rejection (p < 0.01). The first increase in eosinophils occurred at a median of 4 days before treated rejection. Pulmonary allograft rejection: The mean maximum blood eosinophil count was 0.14 x 10(9)/L (95% confidence interval = 0.10, 0.18) preceding treated rejection, and this was significantly greater than the mean maximum blood eosinophil count of 0.07 x 10(9)/L (confidence interval = 0.05, 0.09) measured when there was no rejection or during infection (p = 0.01). The first increase in eosinophil occurred at a median of 5 days before treated rejection. There was no relationship between blood neutrophil counts and either cardiac or pulmonary allograft rejection. CONCLUSIONS: An increase in peripheral blood eosinophils but not neutrophils is a specific and early marker of clinically significant rejection of both cardiac and pulmonary allografts. Furthermore, the maximum blood eosinophil count measured in the 3 days before rejection is linearly related to the severity of cardiac allograft rejection.
Adolescent↗
Bronchiolitis obliterans syndrome: incidence, natural history, prognosis, and risk factors.
BACKGROUND: In lung transplantation, obliterative bronchiolitis is the major factor limiting long-term survival. Bronchiolitis obliterans syndrome (BOS), defined as staged decline in pulmonary function has proved a reproducible and sensitive marker of obliterative bronchiolitis. METHODS: The incidence of, and risk factors for, BOS were investigated in 230 lung transplant recipients who underwent transplantation from April 1984 to December 1995 and who survived at least 3 months after operation. Progression and prognosis was investigated in the 109 cases with development of BOS. RESULTS: Actuarial BOS-free probability at 5 years was 36%. Post-BOS onset survival was 51% at 3 years. BOS onset conferred increased risk of death (hazard ratio [HR], 5.96; 95% confidence interval [CI], 3.61, 9.83). Donor and recipient characteristics such as sex, age, underlying disease, type of transplant, and graft ischemic time did not affect BOS onset, progression, or prognosis. Cytomegalovirus serologic status and early acute rejection were risk factors for BOS onset in multivariate modeling. In univariate analysis, other risk factors were lung infection, cytomegalovirus episodes, organizing pneumonia, and human leukocyte antigen mismatch. Later transplantation era (1991 to 1995) was associated with decreased risk of BOS (HR, 0.64; 95% CI, 0.44, 0.92). Acute rejection affected post-BOS progression (HR, 1.28/episode; 95% CI, 1.12, 1.45) and survival (HR, 1.20/episode; 95% CI, 1.05, 1.37). Post-BOS lung infection was an independent prognostic factor (HR, 1.12/episode; 95% CI, 1.01, 1.24). BOS onset in the later half of the series (1992 to 1997) was associated with decreased risk of progression (HR, 0.52; 95% CI, 0.33, 0.82). CONCLUSIONS: This study confirms that BOS is a major problem in lung transplantation, with a high incidence, rapid progression, and poor survival. It affects all modes of lung transplantation, regardless of sex, age, or underlying diagnosis. Acute rejection is a major prognostic factor. Lung infections after BOS onset worsen survival rates.
Actuarial Analysis↗
Intrapersonal and maternal correlates of aggression, conflict, and externalizing problems in toddlers.
Research has shown that 2-year-olds engage in peer-directed aggression and initiation of conflict. However, there has been little consideration of the factors associated with variability in toddlers' aggression. One hundred and four toddlers (52 females) were observed for 35 min of free play with a same-sex peer, with both mothers present. Experience in early out-of-home care was not related to aggression. Toddlers' observed and mother-rated dysregulated temperament, and mothers' use of warmth and negative dominance during interactions with their children, were used to predict toddlers' aggression and maternal ratings of externalizing difficulties. Boys were observed to be more aggressive than girls. Regression analyses showed that, after controlling for main effects, the interaction of child gender, temperament, and maternal negative dominance predicted both outcomes. Observed aggression and mother-reported externalizing problems were associated significantly with dysregulated temperament only for boys with mothers who demonstrated relatively high levels of negative dominance.
Adult↗
The calcium/calmodulin-dependent protein phosphatase calcineurin is the major Elk-1 phosphatase.
The transcription factor Elk-1 is a component of ternary complex factor and regulates gene expression in response to a wide variety of extracellular stimuli. Phosphorylation of the C-terminal domain of Elk-1, especially at serine 383, is important for its transactivation activity. Recently mitogen-activated protein kinases, such as extracellular signal-regulated kinase, stress-activated protein kinase, and p38 mitogen-activated protein kinase have been demonstrated to be Elk-1 kinases. However, negative regulators of Elk-1, such as protein phosphatases, still remain to be identified. Here we report that COS cell lysates were able to dephosphorylate an extracellular signal-regulated kinase-phosphorylated glutathione S-transferase-Elkc fusion protein, including serine 383. The phosphatase activity was inhibited by cyclosporin A (a calcineurin inhibitor) but not by okadaic acid (a PP1 and PP2A inhibitor). Purified calcineurin also could efficiently dephosphorylate glutathione S-transferase-Elkc in vitro. Pretreatment of COS cells with cyclosporin A significantly enhanced epidermal growth factor-induced serine 383 Elk-1 phosphorylation whereas ionomycin inhibited the Elk-1 phosphorylation. These data provide both in vitro and in vivo evidence that calcineurin is the major Elk-1 phosphatase and plays a critical role in Elk-1 regulation. The identification of calcineurin as the major Elk-1 phosphatase may provide a mechanism for Elk-1 regulation by Ca2+ signals as well as a possible biochemical basis for the neurotoxicity and nephrotoxicity of the immunosuppressant drug cyclosporin A.
Animals↗
Trust accountability. Going public.
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Communication↗
Tobacco use in Vietnam. Prevalence, predictors, and the role of the transnational tobacco corporations.
OBJECTIVE: To describe tobacco use in Vietnam and the impact of transnational tobacco corporations there. DESIGN: In cities, a multistage cluster design; in communes, a systematic sample design, using face-to-face interviews in all sites. SETTING: Hanoi, Ho Chi Minh City, and 2 rural communes in Vietnam. PARTICIPANTS: Random samples totaling 2004 men and women aged 18 years or older. MAIN OUTCOME MEASURES: Prevalence and correlates of tobacco smoking, amount and duration of smoking, age at initiation, quitting behavior, knowledge of health hazards of and attitudes toward smoking, and cigarette brand smoked, preferred, and recognized as most widely advertised. RESULTS: Smoking prevalence among men (n=970) was 72.8% and 4.3% among women (n=1031). Male smokers had smoked a mean of 15.5 years; the median age at initiation was 19.5 years. Among male smokers, 16% smoked non-Vietnamese cigarettes. More than twice as many (38%), however, said that they would prefer to smoke a non-Vietnamese brand if they could afford the cost. Among those who recalled any cigarette advertising (38%), 71% recalled a non-Vietnamese brand as the most commonly advertised. Male smokers who were significantly more likely to smoke non-Vietnamese brands lived in the south, were engaged in blue collar or business/service occupations, earned higher incomes, and lived in urban areas. CONCLUSIONS: Vietnam has the highest reported male smoking prevalence rate in the world. Unless forceful steps are taken to reduce smoking among men and prevent the uptake of smoking by youth and women, Vietnam will face a tremendous health and economic burden in the near future. Implementation of a comprehensive national tobacco control campaign together with international regulation will be the keys to the eradication of the tobacco epidemic in Vietnam and throughout the developing world.
Adult↗
Clinical value of ACE genotyping in diagnosis of sarcoidosis.
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Adult↗
Characterization of a unique OpMNPV-specific early gene not required for viral infection in tissue culture.
opep-2 is an Orgyia pseudotsugata multicapsid nucleopolyhedrovirus (OpMNPV) early gene in the ie1-ie2 gene region for which there is no homolog in either the archetype virus, Autographa californica MNPV, or Bombyx mori NPV. opep-2 is transcribed immediately upon infection as three mRNAs which initiate from a early gene motif (TATA-N27-CAGT). The expression of multiple transcripts at very early times postinfection has only been previously described for the baculovirus early gene ie1, which produces spliced mRNAs. However, distinct from ie1, the multiple mRNAs of opep-2 are due to multiple termination sites and not splicing. Western blot analysis of steady-state levels of OPEP-2 showed that in OpMNPV-infected Ld652Y cells maximum levels are obtained at 8-12 hr postinfection (p.i.) prior to DNA replication. By 48 hr p.i. OPEP-2 is shut off and is undetectable. To aid in elucidating the function of this OpMNPV-specific gene an opep-2 deletion mutant was generated and was compared to wild-type virus to determine if its absence affects viral growth in Ld652Y tissue culture cells.
Amino Acid Sequence↗
A pilot study of protracted low dose cisplatin and etoposide with concurrent thoracic radiotherapy in unresectable stage III nonsmall cell lung cancer.
PURPOSE: A Phase II study to evaluate the response rate and toxicity of daily protracted cisplatin and etoposide with concurrent chest irradiation in patients with locally advanced, unresectable nonsmall cell lung cancer (NSCLC). METHODS AND MATERIALS: Twenty-one patients with histologically confirmed locally advanced inoperable NSCLC (Stage IIIA or IIIB) were entered on study. Radiotherapy consisted of 50.4 Gy in 1.8 Gy fractions followed by a 10 Gy boost in 2 Gy fractions. Chemotherapy included the following: Cisplatin was given at 5 mg/m2 i.v. Monday-Friday before RT weeks 1-6. Etoposide was given at 25 mg/m2 i.v. M-F weeks 1, 2, 5, and 6, with 50 mg/m2 p.o. daily on the same weekends. Because of severe myelosuppression in the first two patients, etoposide only was subsequently changed to 20 mg/m2 i.v. M-F weeks 1, 2, 5, and 6. RESULTS: Twenty patients were eligible and evaluable. The overall response rate was 65% (95% confidence interval 41-85%). The median progression-free survival was 43 weeks. The median overall survival was 50.2 weeks with a 1-year survival rate of 45%. Five patients (25%) developed severe radiation pneumonitis, leading to early closure of the study. CONCLUSIONS: Combining daily protracted cisplatin and etoposide with concurrent thoracic irradiation in patients with locally advanced unresectable NSCLC yields a high overall response rate and a median survival that is at least comparable to other combined modality trials. However, future studies using protracted radiosensitizing chemotherapy should be approached cautiously in light of the high incidence of severe radiation pneumonitis encountered in this trial.
Aged↗
Factors influencing patients' decision not to repeat IVF.
Women who did not pursue a second in vitro fertilization cycle after a failed cycle were surveyed. The major reason for not pursuing a second cycle was financial.
Adult↗
Gating strategy for immunophenotyping of leukemia and lymphoma.
Clinical specimens of blood, bone marrow, lymph node, extranodal tissue, and body fluid were collected from 67 cases of hematologic neoplasms (including chronic lymphoid leukemias, T- and B-cell lymphomas, and acute lymphoblastic and myelogenous leukemias) for comparison between the right-angle light scatter (RALS)/CD45 and the forward-angle light scatter (FALS)/RALS gating combinations. One to three diagnostic markers were selected from each case, yielding 124 paired results for comparison. We found that the percentage of tumor cell isolation and the total cell count in the tumor cell gate were higher in RALS/CD45 than in FALS/RALS. When 20% was used as a cutoff point, 30 markers in FALS/RALS failed to identify the tumor population, while only 3 markers in RALS/CD45 failed to do so. The discriminative factor in the RALS/CD45 gating was mainly the CD45 intensity, whereas all cases except 3 showed low RALS. Although T-cell neoplasms showed a higher proportion of high CD45 intensity, other groups shared similar ranges of CD45 intensity, which is therefore of limited value for differential diagnosis. The RALS/CD45 combination produces higher recovery and purity for tumor cell isolation than the FALS/RALS combination and should replace the latter for routine immunophenotyping of lymphoma and leukemia.
Biomarkers, Tumor↗
Benign pulmonary lymphocytic infiltration and amyloidosis: computed tomographic and pathologic features in three cases.
The clinical radiologic, and pathologic features of three patients with a combination of pulmonary lymphocytic infiltration and amyloid deposition are presented. We report the distinctive high-resolution computed tomography features that are common to these cases.
Adult↗
A rationale for family therapy specialization in early intervention.
Over the past two decades, professionals providing intervention to families with children with disabilities have witnessed a philosophical shift from individually oriented care to family-centered care. Although the relevance of family therapy to these families has been formally acknowledged through the Individuals with Disabilities Education Act (IDEA), the integration of the fields of family therapy and developmental disabilities has not yet occurred to any significant degree. Awareness of critical issues associated with developmental disabilities and the potential impact on the family system is vital to the process of family-centered intervention. In this paper we address the need for family specialists to become knowledgeable about early intervention considerations relevant to young children with disabilities and their families.
Child↗
Human androgen receptor expression in prostate cancer following androgen ablation.
OBJECTIVE: Metastatic prostate cancer kills patients because their tumor cells fail to respond to combined androgen blockade (CAB) or respond and then relapse. To understand the molecular basis of androgen-insensitive growth of prostate tumor cells, we evaluated changes in human androgen receptor gene (hAR) mRNA levels in patients with prostate cancer treated with CAB. METHODS: The study was carried out using quantitative reverse-transcriptase polymerase chain reaction analysis. The level of hAR mRNA were compared to serum prostate-specific antigen and the mutant status of p53 in the tumor. RESULTS: hAR was expressed in 44 of 46 tumors from untreated patients, as opposed to 30 of 45 from those who had received CAB (p = 0.001). These 30 were from 8 of 9 stage D patients and from 22 of 36 patients on downsizing CAB therapy prior to radical prostatectomy. Expression was most often seen in high stages (56% of stage B vs. 89% of stage D) and high grades (52% of Gleason 3-7 vs. 92% of Gleason 8-10, p = 0.015). No tumor with a missense p53 mutation had hAR expression following CAB. Twenty-two patients following CAB were found to have undetectable serum prostate-specific antigen levels, while their tumor expressed hAR. CONCLUSIONS: hAR expression after CAB is seen preferentially in high-grade, high-stage tumors, the type of prostate carcinomas that fail to have a durable remission. Undetectable serum prostate-specific antigen from tumors that remain hAR positive may predict relapse after hormonal ablative therapy.
Androgen Antagonists↗
Bronchiolitis obliterans syndrome in heart-lung transplantation: surveillance biopsies.
Transbronchial biopsies (TBBs) are useful to diagnose acute rejection and infection in patients with lung transplants. The value of routine surveillance biopsies (S-TBBs) is not known, and such biopsies with a clinical indication are not without risk and are expensive. One hundred twenty-six 6-mo survivors of heart-lung transplantation (HLT) were studied to determine the effect of stopping S-TBBs on the development of bronchiolitis obliterans syndrome (BOS) and subsequent survival. Fifty-one received transplants while S-TBB was part of routine care (group A), and 75 received transplants after this practice was stopped (group B). There was no difference in patient characteristics. Group A had shorter graft ischemia (p < 0.01) and longer postoperative ventilation (p < 0.01). Maintenance immunosuppression was similar, but group A had more steroid pulses in the second 6 mo after HLT (p < 0.01). The number of patients free from any functional deterioration at 49 to 60 mo after HLT declined to 39% in group A and 64% in group B. The risk of developing BOS grade 1 in group A relative to group B was 1.63 (95% confidence intervals: 0.96-2.79, p = 0.07). Patient survival was similar in the two groups. A total of 86 TBBs were taken in the absence of any signs or symptoms and had low diagnostic yield. In summary, there was no increased incidence of BOS after stopping S-TBBs.
Actuarial Analysis↗
Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial.
PURPOSE: A multicenter phase II study to determine the activity and toxicity of Caelyx (Doxil; Sequus Pharmaceuticals Inc, Menlo Park, CA) in patients with metastatic breast cancer. PATIENTS AND METHODS: Seventy-one patients with stage IV breast cancer were treated with Caelyx at doses of 45 to 60 mg/m2 every 3 to 4 weeks for a maximum of six cycles. Twenty-eight patients had received prior chemotherapy with a nonanthracycline regimen. Fifty-two patients had disease at multiple sites. Hepatic and pulmonary disease were the predominant metastatic site in 50 patients. Response was assessable in 64 cases. RESULTS: Sixteen patients achieved a partial response and a complete response (overall response rate, 31%; (95% confidence interval, 20% to 43%). Twenty patients (31%) had stable disease on treatment. Neutropenia > or = grade 3 occurred in 10% of cycles (27% of patients) and mucositis > or = grade 3 in 10% of cycles (32% of patients). Significant alopecia was rare and routine prophylactic antiemetics were not required. At doses of 60 mg/m2 every 3 weeks, seven of 13 patients had > or = grade 3 skin toxicity; overall, this toxicity complicated 25% of treatment cycles. The incidence of > or = grade 3 skin toxicity was greatly reduced at doses of 45 mg/m2 every 4 weeks, occurring in five of 32 patients and affecting only 5% of 126 treatment cycles. CONCLUSION: Caelyx is an active agent in advanced breast cancer with a safety profile that differs markedly from nonliposomal doxorubicin. A regimen of 45 mg/m2 every 4 weeks was well tolerated in this cohort of women with advanced poor-prognosis breast cancer. The mild myelosuppression seen with this regimen would favor its use in combination chemotherapy.
Antibiotics, Antineoplastic↗
Vasculitis and bronchiectasis in a patient with antibodies to bactericidal/permeability-increasing protein and alpha1-antitrypsin deficiency.
A patient with alpha1-antitrypsin deficiency is reported herein; this subject developed aggressive bronchial disease and recurrent cutaneous vasculitis after pulmonary infection with Pseudomonas aeruginosa. Autoantibodies to neutrophil cytoplasmic antigens were detected, which produced granular cytoplasmic staining by indirect immunofluorescence with specificity for a newly characterized antigen: bactericidal/permeability-increasing protein (BPI). The bronchial disease and vasculitis improved, and the IgA anti-BPI titer fell after antipseudomonal treatment. This raises the possibility that anti-BPI antibodies contributed to both the bronchial disease and vasculitis.
Antibodies, Antineutrophil Cytoplasmic↗