Persistence of sputum eosinophilia in children with controlled asthma when compared with healthy children

We aimed to describe induced sputum cell counts in healthy nonasthmatic children, and to compare these to children with controlled and uncontrolled asthma. Following clinical assessment and spirometry, ultrasonically nebulized hypertonic saline was used to induce sputum from children with asthma (n=50) and without asthma (n=72). Sputum was dispersed and cell counts performed to yield total and differential cell counts. Specific stains were used for eosinophil and mast cell counts. All of the children with asthma were receiving inhaled and/or oral corticosteroids. Current asthma control was assessed in terms of symptoms and lung function. Children were classified as controlled on inhaled corticosteroids (no current symptoms, normal lung function n=15), current symptomatic asthma (n=16) and asthma exacerbation (n=11). It was found that eosinophils comprised a median 0.3% (interquartile range (IQR): 0, 1.05) of cells in sputum from healthy children. Sputum eosinophils (4.3% (IQR: 15, 14.1) p=0.0005) and epithelial cells (14% (IQR: 6, 19.4) p=0.0005) were significantly higher in children with asthma than in nonasthmatic children. Children whose asthma was controlled, as well as those with symptoms, had more sputum eosinophils and epithelial cells than the nonasthmatics. Mast cells were found in the sputum of only four of the 42 children with asthma. This study demonstrates that eosinophilic airway inflammation and epithelial damage can occur in children with asthma. Airway inflammation persists even in those children who are receiving inhaled corticosteroids, have normal lung function and good symptomatic control of their disease.     

p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site

We initiated a retrospective study to determine whether p53 status and thymidylate synthase (TS) protein expression in primary colon tumors influence recurrence and survival for patients with stage II colon cancer. Tumor specimens from 45 consecutive untreated patients with stage II colon cancer were examined for p53 and TS protein expression using immunohistochemistry. The median follow-up was 5.1 years. Eighteen patients had left-sided tumors, and 27 had right-sided tumors. Fourteen of 45 patients (31%) developed recurrence. p53 overexpression was detected in the tumors of 18 patients (40%); 10 patients (55%) with p53 overexpression recurred; and 4 of 27 (15%) without evidence of p53 overexpression recurred (P = 0.002). High TS expression was detected in the tumors of 16 patients (36%): 8 patients (50%) with high TS expression recurred, and 6 patients (21%) with low TS expression recurred (P = 0.027). Patients with p53 overexpression had a significantly poorer survival than did those patients without p53 overexpression (P < 0.001). High TS expression was associated with poor survival (P = 0.004). p53 overexpression and high TS expression were significantly associated with left-sided tumors (P = 0.003 and P = 0.022). Thirteen of 16 patients (81%) with high TS expression also overexpressed p53, and 24 of 29 patients (81%) with low TS expression did not manifest p53 overexpression (P < 0.001). p53 and TS expression in primary stage II colon cancer are associated and appear to influence recurrence and survival. In this pilot study, left-sided tumors demonstrate significantly more p53 overexpression and significantly higher TS expression than do right-sided tumors, which may explain the significantly poorer survival for patients with left-sided tumors.     

Survival after relapse in childhood acute lymphoblastic leukemia: impact of site and time to first relapse--the Children''s Cancer Group Experience

After cardioversion from atrial fibrillation (AF) many patients develop early recurrence of the arrhythmia. While these patients may be appropriate for immediate prophylaxis against AF recurrence their identification at the time of cardioversion is not possible. Since the signal-averaged P wave (SAPW) is abnormal in individuals with atrial arrhythmia, we assessed its utility for predicting early AF recurrence after cardioversion. Seventy-five cardioversions in 31 patients were evaluated. The mean age was 59 (range 28-79) years; 26 were male. Fifty-eight cardioversions were internal using low energy biphasic DC shocks delivered via electrodes placed in the right atrial appendage and coronary sinus. P wave specific signal averaging was performed at 3 and 24 hours after each cardioversion to estimate filtered P wave duration and energy from 20, 40, and 60 to 150 Hz. Follow-up was by regular clinic visits and transtelephonic ECG monitoring. Early recurrence of AF (prospectively defined as sinus rhythm duration < 1 week) occurred after 30 cardioversions. No differences were found in any P wave variable measured at 3 hours between these cardioversions and those that resulted in a longer duration of sinus rhythm. Paired 3- and 24-hour signal-averaged data were available in 47 cardioversions. There were significant falls in P wave energy from 3 to 24 hours after 31 cardioversions that resulted in sinus rhythm for > 1 week, (P40: 3 hours 11.2 [+/- 1.5] micro V2.s, 24 hours 8.6 [+/- 1.2] micro V2.s, P < 0.001), but not following the 16 after which AF returned within 1 week (P40: 3 hours 9.0 [+/- 1.2] micro V2.s, 24 hours 8.5 [+/- 1.2 micro V2.s, P = NS). A fall in P40 of > 25% had a positive predictive accuracy for maintenance of sinus rhythm of 87%; negative predictive accuracy was only 37%. Similar falls in P wave energy occurred after cardioversions that resulted in longer term (> 4 weeks) sinus rhythm, but not in those that did not. However, the predictive accuracy of a fall in P40 was less (positive predictive accuracy 38%, negative predictive accuracy 62%). Patients with relapsing permanent AF who remain in sinus rhythm for at least 1 week after cardioversion show a fall in P wave energy within the first 24 hours. However, in these patients the technique does not predict recurrent AF within 1 week nor sinus rhythm > 4 weeks. These observations suggest persistent disordered atrial activation as a mechanism for early recurrence of AF after cardioversion.     

Measuring sexual harassment: development and validation of the Sexual Harassment Inventory

Recent studies have suggested that intravenous infusion of fenoldopam, a selective dopamine-1 receptor agonist, elevates intraocular pressure (IOP) in man. This study evaluated the effect of intravenous fenoldopam on IOP, aqueous humor outflow facility and gonioscopy in 12 healthy human subjects. Three doses (0.2, 0.5 and 1.0 microg/kg/min) were infused for 120 minutes in a double masked, placebo controlled, four-way crossover design. IOP was measured every 20 minutes in the supine position and every 40 minutes while sitting during the drug and placebo infusions. Tonography and gonioscopy were performed at baseline and after 120 minutes of infusion. Compared to placebo, IOP increased by 3.5 mm Hg (32%) for the lowest dose, 5.8 mm Hg (46%) for the intermediate dose, and 6.9 mm Hg (55%) for the highest dose (p<0.05 for all three doses). IOP returned to baseline within 30 minutes of stopping the infusion. The outflow facility decreased from baseline by 26% after 120 minutes of infusion for all drug doses. In contrast, outflow facility increased from baseline by 11% during placebo infusion. Compared to placebo, the fenoldopam induced changes in outflow were statistically significant (p<0.05). There was no change in the gonioscopic appearance of the anterior chamber angle during the infusion. This study shows that systemic administration of a selective dopamine-1 receptor agonist causes a significant dose-dependent increase in IOP that can be explained in part by diminished outflow facility. These results support a role for the dopamine-1 receptor in the modulation of IOP in general and suggest modulation of aqueous humor outflow by dopaminergic receptors.     

Physicochemical properties correlated with drug resistance and the reversal of drug resistance in Plasmodium falciparum

At high molar excess, verapamil can selectively increase the accumulation and cytotoxicity of structurally dissimilar natural product drugs in many multidrug-resistant tumor cell lines. Such concentrations of verapamil are also capable of increasing the accumulation and activity of chloroquine in chloroquine-resistant strains of the human malaria parasite Plasmodium falciparum. Despite such similarities, it is not clear why chloroquine-resistant P. falciparum is often susceptible to closely related compounds such as amodiaquine, whereas cancer cells are cross-resistant to many structurally unrelated drugs. For 13 aminoquinoline and aminoacridine compounds, relative drug resistance was negatively correlated with lipid solubility at physiological pH (r2 = 0.90, p < 0.0001). The ability of verapamil (5 microM) to reverse drug resistance was also negatively correlated with lipid solubility (r2 = 0.88, p < 0.0001). Furthermore, molar refractivity was weakly correlated with relative drug resistance (r2 = 0.46, p < 0.05) and reversal of drug resistance (r2 = 0.52, p < 0.005). Verapamil increases chloroquine accumulation by resistant parasites, a mechanism suggested to account for its selective chemosensitization effect. We show that the initial rate of chloroquine accumulation by resistant parasites is increased by verapamil. This effect of verapamil is abolished when deoxy-glucose is substituted for glucose. Therefore, verapamil produces an energy-dependent increase in the permeability of resistant parasites to chloroquine. For a panel of four chloroquine-resistant and two chloroquine-susceptible isolates, the effect of verapamil on the accumulation of chloroquine and monodesethyl amodiaquine was found to be correlated (r2 = 0.96, p < 0.001). Verapamil chemosensitization was also correlated for the two drugs (r2 = 0.92, p < 0.005), suggesting a common mechanism. In summary, the degree of drug resistance and the extent of verapamil chemosensitization for a particular drug seem to be dependent on general physical features such as lipid solubility and molar refractivity rather than on closely defined structural parameters. These studies provide insight into this important resistance mechanism of malaria parasites and may provide direction for the development of new drugs that are effective against resistant parasites.     

Cytopathological analysis of sputum in patients with airflow obstruction and significant smoking histories

Advances in the understanding of lung cancer biology have led to observations that specific genetic changes occur in premalignant dysplasia. These observations have occurred predominantly in molecular studies of resected lung tumors and consequently, they may not be fully representative of those biological abnormalities characterizing premalignant lesions in individuals without overt lung cancer. Studies of premalignant epithelial cell biology and chemoprevention are needed in this patient subgroup. Such an initiative is now underway through the lung cancer Specialized Program of Research Excellence (SPORE) grant awarded to the University of Colorado Cancer Center (and affiliated institutions) by the National Cancer Institute. To identify participants for the early detection and chemoprevention trials of the Colorado SPORE, we initiated a sputum cytology screening program targeting persons with chronic obstructive pulmonary disease and smoking histories of 40 or more pack-years. During the first 26 months after activation of the screening program, sputum samples from 632 participants were evaluated. Of these, 533 (84%) of the subjects submitted specimens deemed adequate for cytopathological interpretation; 99 (16%) provided sputum samples unsuitable for cytodiagnosis. Of those participants who submitted adequate samples, 48% had cytodiagnoses of mild dysplasia, 26 % had moderate to severe dysplasia, and 2% presented with carcinoma in situ or invasive carcinoma. Logistic regression modeling was pursued to determine whether selected demographic and/or clinical status variables could be identified as statistically significant predictors of the specific cytological outcome to be expected (mild dysplasia, moderate dysplasia, and so forth). The only apparent associations found from both univariate and multivariate analyses were that the total number of pack-years of smoking history decreased with severity of cytodiagnosis and that those individuals with mild or moderate dysplasia were more likely to be ex-smokers than those with grades of regular metaplasia or lower. Based on the initial results of the Colorado SPORE sputum cytology screening program, we conclude that persons with chronic obstructive pulmonary disease and 40 or more pack-years of smoking history have a high prevalence of premalignant dysplasia detectable through sputum cytology and should be targeted for research programs focusing on lung cancer prevention, early detection, and exploratory biomarker studies.