Comparison of roflumilast, an oral anti-inflammatory, with beclomethasone dipropionate in the treatment of persistent asthma.

BACKGROUND: Roflumilast is an oral, once-daily phosphodiesterase 4 inhibitor with anti-inflammatory activity in development for the treatment of asthma. Roflumilast was compared with inhaled beclomethasone dipropionate (BDP) in patients with asthma. METHODS: In a double blind, double-dummy, randomized, noninferiority study, 499 patients (forced expiratory volume in 1 s [FEV1] = 50-85% predicted) received roflumilast 500 microg once daily or BDP 200 microg twice daily (400 microg/day) for 12 weeks. Lung function and adverse events were monitored. RESULTS: Roflumilast and BDP significantly improved FEV1 by 12% (270 +/- 30 ml) and 14% (320 +/- 30 ml), respectively (P < 0.0001 vs baseline). Roflumilast and BDP also significantly improved forced vital capacity (FVC) (P < 0.0001 vs baseline). There were no significant differences between roflumilast and BDP with regard to improvement in FEV1 and FVC. Roflumilast and BDP showed small improvements in median asthma symptom scores (-0.82 and -1.00, respectively) and reduced rescue medication use (-1.00 and -1.15 median puffs/day, respectively; P < 0.0001 vs baseline). These small differences between roflumilast and BDP were not considered clinically relevant. Both agents were well tolerated. CONCLUSIONS: Once daily, oral roflumilast 500 microg was comparable with inhaled twice-daily BDP (400 microg/day) in improving pulmonary function and asthma symptoms, and reducing rescue medication use in patients with asthma.

Expression of alpha(v)beta3 integrin is less frequent in ovarian epithelial tumors of low malignant potential in contrast to ovarian carcinomas.

Ovarian tumors of low malignant potential (LMPs) histologically lack invasion and have excellent prognosis in contrast to invasive carcinomas. Integrins are heterodimeric adhesion molecules thought to play a role in cell migration and tumor progression. The alpha(v)beta3 integrin in particular mediates melanoma invasion in vitro and promotes neoplastic angiogenesis, facilitating breast cancer metastasis. In addition, alpha(v)beta3 expression has been detected in ovarian cancer cell lines and in a limited number of human ovarian cancer samples. The distribution pattern of this integrin in LMPs is not known. We examined tissue sections from 19 LMPs and 31 ovarian carcinomas for alpha(v)beta3, in addition to alpha5beta1 and alpha2beta1 integrins, which have been shown to be expressed in ovarian cancer cell lines. Variable immunoreactivities of alpha5beta1 and alpha2beta1 were detected in both LMPs and ovarian carcinomas. Most (74.2%) ovarian carcinomas were alpha(v)beta3 positive, whereas only 36.8% of LMPs were positive, which is statistically significant (P = .009). These results establish the distribution pattern of alpha2beta1, alpha5beta1, and alpha(v)beta3 integrins in LMPs. The biological significance of the less frequent expression of alpha(v)beta3 in LMPs compared with carcinomas of the ovary needs further elucidation.

A multifaceted approach to changing handwashing behavior.

BACKGROUND: Few interventions to influence handwashing have had measurable effects. This prospective quasi-experimental study was designed to address predisposing, enabling, and reinforcing factors to improve frequency of handwashing. METHODS: Over a 12-month time period, a multifaceted intervention including focus group sessions, installation of automated sinks, and feedback to staff on handwashing frequency was implemented in one intensive care unit; a second unit served as a control. Dependent variables observed were handwashing frequency and self-reported practices and opinions about handwashing. Study phases included baseline, three phases of about 2 months each in duration in which sink automation was incrementally increased, and follow-up 2 months after intervention. RESULTS: During 301 hours of observation, 2624 handwashings were recorded. Proportion of times hands were washed varied by indication, ranging from 38% before invasive procedures to 86% for dirty-to-clean procedures (p < 0.00001). Although there were some significant differences between experimental and control units in handwashing during the study, these differences had returned to baseline by the 2-month follow-up. There were no significant differences in self-reported practices and opinions from before to after intervention nor between units. CONCLUSIONS: Intensive intervention, including feedback, education, and increased sink automation, had minimal long-term effect on handwashing frequency.

Evaluation of the Neer system of classification of proximal humeral fractures with computerized tomographic scans and plain radiographs.

The intraobserver reliability and inter-observer reproducibility of the Neer classification system were assessed on the basis of the plain radiographs and computerized tomographic scans of twenty fractures of the proximal part of the humerus. To determine if the observers had difficulty agreeing only about the degree of displacement or angulation (but could determine which segments were fractured), a modified system (in which fracture lines were considered but displacement was not) also was assessed. Finally, the observers were asked to recommend a treatment for the fracture, and the reliability and re-producibility of that decision were measured. The radiographs and computerized tomographic scans were viewed on two occasions by four observers, including two residents in their fifth year of postgraduate study and two fellowship-trained shoulder surgeons. Kappa coefficients then were calculated. The mean kappa coefficient for intraobserver reliability was 0.64 when the fractures were assessed with radiographs alone, 0.72 when they were assessed with radiographs and computerized tomographic scans, 0.68 when they were classified according to the modified system in which displacement and angulation were not considered, and 0.84 for treatment recommendations; the mean kappa coefficients for interobserver reproducibility were 0.52, 0.50, 0.56, and 0.65, respectively. The interobserver reproducibility of the responses of the attending surgeons regarding diagnosis and treatment did not change when the fractures were classified with use of computerized tomographic scans in addition to radiographs or with use of the modified system in which displacement and angulation were not considered; the mean kappa coefficient was 0.64 for all such comparisons. Over-all, the addition of computerized tomographic scans was associated with a slight increase in intraobserver reliability but no increase in interobserver reproducibility. The classification of fractures of the shoulder remains difficult because even experts cannot uniformly agree about which fragments are fractured. Because of this underlying difficulty, optimum patient care might require the development of new imaging modalities and not necessarily new classification systems.

The role of tumor necrosis factor receptors in tumor necrosis factor-alpha-mediated cytolysis of ovarian cancer cell lines.

OBJECTIVE: Our purpose was to define the expression of tumor necrosis factor receptors on ovarian cancer cells and determine what role these receptors play in tumor necrosis factor-alpha-mediated cytolysis. STUDY DESIGN: Cell surface expression of tumor necrosis factor-alpha receptors was determined on ovarian cancer cell lines Caov-3, SK-OV-3, NIH:OVCAR-3, and A2780 by a tumor necrosis factor-alpha-binding assay that used iodine 125-labeled tumor necrosis factor-alpha. Monoclonal antibodies specific for the 55 to 60 kd (TR60) and 75 to 80 kd (TR80) tumor necrosis factor receptors were used to determine the relative density of each receptor type. To elucidate which receptor(s) was responsible for mediating the signal for cytolysis, 24-hour MTT cytolytic assays that used tumor necrosis factor-alpha and emetine were performed in the presence or absence of receptor-specific monoclonal antibodies. RESULTS: The four ovarian cell lines expressed a similar number of surface receptors, 4500 to 7000 per cell, had similar dissociation constants, 0.3 to 0.6 nmol/L, and expressed predominately the TR60 receptor subtype. Receptor function studies showed that the presence of the monoclonal antibody to the TR60 receptor completely inhibited tumor necrosis factor-alpha-mediated cytolysis, whereas the monoclonal antibody to the TR80 receptor only partially blocked cytolysis. CONCLUSIONS: Ovarian cancer cell lines express both tumor necrosis factor receptors, with the TR60 receptor being the dominant subtype. Tumor necrosis factor-alpha-mediated cytolysis appears to be dependent on the presence of a functional TR60 receptor. The TR80 receptor does not appear requisite for cytolysis; however, a complementary role cannot be excluded. Manipulation of tumor necrosis factor receptor subtypes on ovarian cancer cells may enhance the cytotoxic effects, thus improving the therapeutic efficacy of tumor necrosis factor-alpha.

Potential of cervical electrosurgical excision procedure for diagnosis and treatment of cervical intraepithelial neoplasia.

The aim of this study was to evaluate the diagnostic potential, treatment efficacy, specimen adequacy, and acute complication rate associated with electrosurgical excision procedure (EEP) of the cervix for the management of cervical intraepithelial neoplasia (CIN). Analysis was performed retrospectively on 153 consecutive patients who underwent EEP under colposcopic guidance. Patients with negative endocervical curettage (ECC), adequate colposcopy, and biopsy-proven CIN were considered candidates for therapeutic EEP, whereas patients with a positive ECC, inadequate colposcopy, or cytology two or more grades discordant from the biopsy results underwent diagnostic EEP. Histopathologic specimens were graded as adequate, suboptimal, or inadequate. Diagnostic EEP was performed in 85 cases, and the remaining 68 procedures were performed primarily for treatment. Specimens were graded as adequate in 83%, suboptimal in 13%, and inadequate in 4% of the diagnostic EEP's. Specimen adequacy correlated most strongly with operator experience (P < 0.05). Four patients were found to have microinvasive or invasive cervical carcinoma. Complications occurred in 7% of the EEPs performed. Most consisted of immediate or delayed hemorrhage. In conclusion, EEP is a safe, well-tolerated procedure which is acceptable as both a therapeutic and diagnostic tool in the management of CIN when performed by an experienced operator. We recommend that initial EEP procedures should be performed for therapeutic indications, since adequacy of EEP specimens correlated with the level of operator experience.

Analysis of exposure times and dose escalation of paclitaxel in ovarian cancer cell lines.

BACKGROUND: Paclitaxel (Taxol, Bristol-Myers Squibb, Princeton, NJ) is a promising drug for the treatment of ovarian cancer. Exposure times and dose-response relationships should be explored to optimize future clinical applications of this drug. METHODS: The cytotoxic effects of paclitaxel on four human ovarian cancer cell lines (Caov-3, SK-OV-3, NIH: OVCAR-3, and A2780) were analyzed using chromium-51 release assays and tetrazolium-based colorimetric assays. Cells were exposed to paclitaxel for 4 and 24 hours at concentrations ranging from 10(-10)-10(-4) M. Two paclitaxel preparations were compared: paclitaxel in DMSO and paclitaxel in cremophor EL, the carrier used in pharmacological preparations. Cell cycle analysis compared cells exposed to 10(-5) M paclitaxel in dimethyl sulfoxide for 4 hours to those exposed for 24 hours. RESULTS: No difference in cell proliferation was demonstrated after 4 hours of treatment when compared with 24 hours of treatment with paclitaxel in dimethyl sulfoxide at 24, 48 and 72 hours after treatment in any of the cell lines tested, over all concentrations tested. When paclitaxel in cremophor was used, there was a significant decrease in cell proliferation only at 10(-4) M of paclitaxel. Similar results were seen with 10(-4) M equivalent concentration of the carrier alone. A cell cycle shift to G2/M was the same after 4 or 24 hours of exposure when assessed at 24 hours. CONCLUSIONS: A dose escalation from 10(-10) M to 10(-4) M of paclitaxel in dimethyl sulfoxide did not inhibit cell proliferation significantly in any of these cell lines. Moreover, shorter exposure times did not appear to alter the cellular response to paclitaxel. Consequently, administration of smaller dosages over shorter time periods may not compromise the cytotoxic effect of this agent. Clinical studies must be performed to validate these observations.

Bilateral compartment syndrome after a long gynecologic operation in the lithotomy position.

Compartment syndrome occurred after a tubal anastomosis in a prolonged lithotomy position. This syndrome carries the risk of permanent neuromuscular and kidney damage. The pathophysiologic features of the syndrome are reviewed. Specific guidelines for the prevention and management of this syndrome in patients undergoing gynecologic procedures are presented.

Movement of personnel and wound contamination.

We studied the association between the movement of operating room personnel and bacterial contamination of the operative field during 12 clean operations. Settle plates placed on the patient's chest and instrument table were exposed during the operation. As a control, settle plates were exposed in the same locations when no personnel and patients were in the room. Bacterial contamination of the aseptic field was categorized as disseminating (Group A: greater than 42 combined movements) and nondisseminating (Group B: less than 42 combined movements). There were 24 persons in each group. There was a highly significant difference between the two groups in the colony counts on settling plates. More vigorous movement was associated with increased bacterial contamination of the operative field. Low bacterial colony counts were found in the control plates, ruling out environmental sources of contamination. Bacterial fallout correlated with the movement of personnel. Measures to reduce excessive movement in the OR are recommended.

Well-being of cancer survivors.

One hundred and four cancer survivors 3 years past their last cancer treatment reported a significantly lower sense of self-control and more general health worries than a matched sample of healthy controls. The two groups did not differ on variables of anxiety, depression, positive well being, and vitality or on two composite scores of mental and general well-being. The well-being scores of the survivors from three geographically distinct cancer centers revealed no significant differences among centers on the composite or any of the individual subscores. Sociodemographic and treatment variables revealed only marriage and no change in job were significantly related to the amount of general well-being experienced.

Development of brief measures of psychological adjustment to medical illness applied to cancer patients.

The interrater reliability and validity of brief interview rated measures of psychosocial adjustment were examined in four sequential studies. A total of 25 videotaped interviews with cancer patients were rated by 105 social workers, nurses, physicians, and specialists in psychosocial oncology. The Rating of Psychosocial Function (RPF), Coping Adequacy Rating (CAR), and Global Adjustment to Illness Scale (GAIS) were used by various rating groups with an indication of interrater agreement. Agreement on ratings was not influenced by the length of interview (15 vs. 30 minutes) but appeared to the affected by the structure of the interview and profession of the raters. All three instruments showed a measure of matching with clinical impressions in addition to demonstrating a measure of both convergent and divergent construct validation. The GAIS was chosen as most adequately reflecting their clinical impression by a majority of raters. With a degree of training, any of the three instruments could be used to assess psychosocial adjustment with some measure of confidence in the validity of the rating.

A survey of psychotropic drug prescriptions in an oncology population.

The present study examined the prescription practices concerning psychotropic drugs in 5 major oncology centers over a 6 month period. During the survey period 1579 patients were admitted to the collaborating institutions, and 51% of them were prescribed at least one psychotropic medication. Hypnotics were the most frequently prescribed drugs, accounting for 48% of total prescriptions, followed by anti-psychotics at 26% and anti-anxiety agents at 25%. Anti-depressant drugs accounted for only 1% of psychotropic prescriptions. Analysis of prescription rationales revealed that 44% of the psychotropic prescriptions were written for sleep, while 25% were given for nausea and vomiting; approximately 17% were attributed to psychological distress, and 12% were associated with diagnostic medical procedures. The overall rate of prescription was approximately 2 psychotropic drugs per patient per admission, with only 2% of prescriptions resulting in chart-documented side effects. At the level of individual compounds, 3 distinct drugs accounted for 72% of total prescriptions--flurazepam (33%), prochlorperazine (21%), and diazepam (17%).

Granulocyte transfusion therapy: experimental basis and clinical applications.

Granulocyte replacement therapy for the infected patient with severe neutropenia is effective in improving the short-term and possibly the long-term prognosis. The best methods of procuring and administering granulocytes still are under investigation, and no reliable method for predicting compatibility has been developed. At present granulocyte transfusion therapy is indicated for severely neutropenic patients with documented infection as an adjunct to antibiotic therapy. It should be used only at institutions that offer the necessary professional and technical skills to minimize danger and discomfort to both donor and recipient as well as the expense of the treatment.