Fenoterol: clinical trial of a new long acting bronchodilator.

The bronchodilator and side effects of fenoterol and isoproterenol were evaluated in 19 asthmatic adults in a double-blind study. The study demonstrated that fenoterol has an onset of action which is just as rapid as isoproterenol and a duration of action that is markedly superior. Side effects were minimal.     

The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body model

RATIONALE: In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t(1/2)). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation:C=Ae(-alpha t)+Be(-beta t), where A and B are concentration unit-coefficients and alpha and beta are exponential coefficients. The relationships between t(1/2) and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t(1/2). METHODS: In the current paper new equations have been developed that describe the relationships between the terminal t(1/2) (or t(1/2 beta)) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input). RESULTS: A critical value (CV) equals to the quotient of (1-ln2) and (1-beta/alpha) (CV=(1-ln2)/(1-beta/alpha)=0.307/(1-beta/alpha)) has been derived and was compared with the fraction (f(1)) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f(1)=A/alpha/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1-ln2) and infinity. As long as f(1)t(1/2) and vice versa, and when f(1)=CV, then MRT=t(1/2). Following i.v. infusion and oral administration the denominator of the CV equation does not change but its numerator increases to (0.307+beta T/2) (T-infusion duration) and (0.307+beta/ka) (ka-absorption rate constant), respectively. Examples of various drugs are provided. CONCLUSIONS: For every drug that after i.v. bolus shows two-compartment disposition kinetics the following conclusions can be drawn (a) When f(1)<0.307, then f(1)t(1/2). (b) When beta/alpha>ln2, then CV>1>f(1) and thus(,) MRT>t(1/2). (c) When ln2>beta/alpha>(ln4-1), then 1>CV>0.5 and thus, in order for t(1/2)>MRT, f(1) has to be greater than its complementary fraction f(2) (f(1)>f(2)). (d) When beta/alpha<(ln4-1), it is possible that t(1/2)>MRT even when f(2)>f(1), as long as f(1)>CV. (e) As beta gets closer to alpha, CV approaches its maximal value (infinity) and therefore, the chances of MRT>t(1/2) are growing. (f) As beta becomes smaller compared with alpha, beta/alpha approaches zero, the denominator approaches unity and consequently, CV gets its minimal value and thus, the chances of t(1/2)>MRT are growing. (g) Following zero and first order input MRT increases compared with i.v. bolus and so does CV and thus, the chances of MRT>t(1/2) are growing.     

Time-resolved,light scattering measurements of cartilage and cornea denaturation due to free electron laser radiation

Light scattering is used to monitor the dynamics and energy thresholds of laser-induced structural alterations in biopolymers due to irradiation by a free electron laser (FEL) in the infrared (IR) wavelength range 2.2 to 8.5 microm. Attenuated total reflectance (ATR) Fourier-transform IR (FTIR) spectroscopy is used to examine infrared tissue absorption spectra before and after irradiation. Light scattering by bovine and porcine cartilage and cornea samples is measured in real time during FEL irradiation using a 650-nm diode laser and a diode photoarray with time resolution of 10 ms. The data on the time dependence of light scattering in the tissue are modeled to estimate the approximate values of kinetic parameters for denaturation as functions of laser wavelength and radiant exposure. We found that the denaturation threshold is slightly lower for cornea than for cartilage, and both depend on laser wavelength. An inverse correlation between denaturation thresholds and the absorption spectrum of the tissue is observed for many wavelengths; however, for wavelengths near 3 and 6 microm, the denaturation threshold does not exhibit the inverse correlation, instead being governed by heating kinetics of tissue. It is shown that light scattering is useful for measuring the denaturation thresholds and dynamics for different biotissues, except where the initial absorptivity is very high.     

A model for tracking concentration of chemical compounds within a tank of an automatic film processor

A simple kinetic model that describes the time evolution of the chemical concentration of an arbitrary compound within the tank of an automatic film processor is presented. It provides insights into the kinetics of chemistry concentration inside the processor's tank; the results facilitate the tasks of processor tuning and quality control (QC). The model has successfully been used in several troubleshooting sessions of low-volume mammography processors for which maintaining consistent QC tracking was difficult due to fluctuations of bromide levels in the developer tank.     

T(H)2 cytokine expression in atopic children with otitis media with effusion

BACKGROUND: The long-term effects of reducing exposure to latex in subjects with latex-induced asthma remain unknown. OBJECTIVE: The purpose of this study was to compare the health and socioeconomic outcomes of subjects with latex-induced asthma before and after reduction or cessation of exposure to latex. METHODS: Thirty-six subjects with latex-induced asthma as ascertained by specific inhalation challenges were investigated after a median follow-up of 56 months (range, 12 to 92 months). Initial and follow-up visits included use of a detailed questionnaire and measurement of the concentration of histamine causing a 20% fall in FEV(1) (PC(20)). At follow-up, information on employment, financial status, and quality of life was collected. RESULTS: At follow-up, 16 subjects were no longer exposed to latex, whereas 20 subjects had reduced exposure. In the subjects who avoided exposure, asthma severity decreased from a median score of 8.5 to 3.5 (P =.001) and the median histamine PC(20) value increased from 0.4 mg/mL to 2.3 mg/mL (P =.002). In the subjects who reduced their exposure, asthma-severity score improved from 6.5 to 2.5 (P <.001) and PC(20) values rose from 0.5 mg/mL to 2.4 mg/mL (P <.001). Cessation of exposure to latex was associated with asthma-related work disability (69%) and loss of income (62%) more frequently than was reduction of exposure (35% and 30%, respectively). CONCLUSION: Reduction of exposure to latex should be considered a reasonably safe alternative that is associated with fewer socioeconomic consequences than removal from exposure.     

Effects of delaying FK506 administration on neuroregeneration in a rodent model

FK506 is an immunosuppressant drug that has been shown experimentally to stimulate nerve growth and speed functional recovery, when administered immediately after peripheral nerve injury. However, the clinical scenario of a peripheral nerve injury is often associated with either a delayed diagnosis or reconstruction. The purpose of this study was to determine the efficacy of FK506 on neuroregeneration with delayed administration. Thirty-two Lewis rats underwent tibial nerve transection with immediate repair. Animals were left untreated, or were treated with daily injections of FK506 (2 mg/kg), started on the day of surgery, postoperative day 3, or postoperative day 5. Animals underwent walking track analysis to assess functional nerve recovery. Nerves were harvested for histomorphometric analysis on postoperative days 21, 28, and 42. Histomorphometry demonstrated that all treatment groups, regardless of the time of drug initiation, demonstrated evidence of enhanced neuroregeneration, compared to the untreated group. Histomorphometric data from groups harvested on day 21 demonstrated a statistically significant improvement in neuroregeneration in the immediate and 3-day delay groups. Therefore, the beneficial effects of FK506 on neuroregeneration are not restricted to immediate administration, but these effects significantly diminish when FK506 is administered 3 days after nerve injury.     

Effects of AT1 receptor block begun late in life on normal cardiac aging in rats

The goal of this study was to determine how short-term (12 weeks) angiotensin type I (AT1) block begun late in life affects aspects of myocardial biology and physiologic function altered by normal aging. Exercise capacity, myocardial morphology, histopathology, and coronary vascular function (degree of coronary vasodilation in response to adenosine) were evaluated in 53 Fischer 344 rats. Adult (6 months of age) and old (21 months of age) rats were studied after 12 weeks of either control drinking water, a low dose of candesartan that did not significantly lower blood pressure (1 mg/kg/d), or a high dose of candesartan (10 mg/kg/d). Significant age-associated changes in exercise capacity (38% decrease), coronary dilation in response to adenosine (41% decrease), and histopathology occurred but were not affected by candesartan treatment. Age-associated myocardial hypertrophy occurred as indicated by an increase in heart weight-to-tibia length ratio from 0.27 g/cm +/- 0.01 in the adult controls to 0.34 g/cm +/- 0.02 in the old controls (P < 0.05). This hypertrophy in the aged hearts was significantly attenuated by both low-dose (0.30 g/cm +/- 0.01) and high-dose (0.29 g/cm +/- 0.01) candesartan (P < 0.05). Echocardiographic measurements indicate that the candesartan-induced decrease in hypertrophy occurred concomitantly with slight decreases in septal wall thickness and left ventricular (LV) chamber diameter. It is concluded that short-term AT1 block, even when initiated late in life, can decrease age-associated LV hypertrophy independent of blood pressure-lowering effects.     

Base excision repair deficiency caused by polymerase beta haploinsufficiency: accelerated DNA damage and increased mutational response to carcinogens

The base excision repair pathway (BER) is believed to maintain genomic integrity by repairing DNA damage arising spontaneously or induced by oxidizing and alkylating agents. To establish the role of DNA polymerase beta (beta-pol) in BER and beta-pol-dependent BER in maintaining genomic stability, we have measured the impact of a gene-targeted disruption in the beta-pol gene on DNA repair capacity and on in vivo sensitivity to carcinogens. We have extensively phenotyped the DNA beta-pol heterozygous (beta-pol(+/-)) mouse as expressing approximately 50% less beta-pol mRNA and protein and as exhibiting an equivalent reduction in the specific activity of beta-pol. We measured BER activity by in vitro G:U mismatch and (8-OH)G:C repair and find that there is a significant reduction in the ability of extracts from beta-pol(+/-) mice to repair these types of DNA damage. In vivo, the beta-pol(+/-) mice sustain higher levels of DNA single-strand breaks as well as increased chromosomal aberrations as compared with beta-pol(+/+) littermates. Additionally, we show that reduction in beta-pol expression and BER activity results in increased mutagenicity of dimethyl sulfate as evidenced by a 2-fold increase in LacI mutation frequency. Importantly, the beta-pol(+/-) mice do not exhibit increased sensitivity to DNA damage induced by N-nitroso-N-ethylurea, ionizing radiation, or UV radiation, which induce damage processed by alternative repair pathways, demonstrating that this model is specifically a BER-deficient model.     

Increased expression of interleukin-9, interleukin-9 receptor,and the calcium-activated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis

OBJECTIVES/HYPOTHESIS: Mucus overproduction is commonly found in airway disease in patients with cystic fibrosis. Interleukin-9 (IL-9) has been shown to mediate airway hyper-responsiveness and mucus overproduction. Recently, the calcium-activated chloride channel hCLCA1 has been described to be upregulated by IL-9 and has been thought to regulate the expression of soluble gel-forming mucins. We sought to examine the expression of IL-9, interleukin-9 receptor (IL-9R), and hCLCA1 in the upper airway of patients with cystic fibrosis in comparison to healthy control subjects and to demonstrate the relationship of IL-9, IL-9R, and hCLCA1 expression with mucus production. STUDY DESIGN: Prospective design. METHODS: Biopsy samples from nasal polyps of four patients with cystic fibrosis, nasal mucosa of six patients with cystic fibrosis, sinus mucosa of eight patients with cystic fibrosis, and nasal mucosa of six healthy control subjects were stained with periodic acid-Schiff (PAS) to identify mucus glycoconjugates. IL-9, IL-9R, and hCLCA1 expression was determined by immunocytochemical study. RESULTS: We demonstrated significant increases in IL-9, IL-9R, and hCLCA1 immunoreactivity in the mucosa of patients with cystic fibrosis compared with that found in control subjects (P <.05). There were no significant differences between the different locations (nasal polyps, nasal mucosa, and sinus mucosa) in the patient group (P >.05). We also observed a significant increase in the number of mucus-producing cells in biopsy specimens from patients with cystic fibrosis in comparison to control subjects. A positive correlation was found between hCLCA1-positive cells and IL-9-positive cells (correlation coefficient [r] = 0.79, P <.05) or IL-9R-positive cells (r = 0.92, P <.05). Moreover, a positive correlation was also present between PAS-positive (mucus-producing) cells and hCLCA1-positive cells (r = 0.64, P <.05) or IL-9R-positive cells (r = 0.64, P <.05). CONCLUSIONS: Increased expression of IL-9 and IL-9R, as well as upregulation of hCLCA1, in mucus-overproducing epithelium of patients with cystic fibrosis supports the hypothesis that IL-9 contributes to mucus overproduction in cystic fibrosis. Expression of hCLCA1 may also be responsible, in part, for the overproduction of mucus. These preliminary findings suggest that hCLCA1 might be an interesting new therapeutic target to control mucus overproduction in airway disease in patients with cystic fibrosis.     

Women's attitudes toward preventive strategies for hereditary breast or ovarian carcinoma differ from one country to another: differences among English, French, and Canadian women

BACKGROUND: The authors investigated the acceptability to women of the preventive strategies available for dealing with hereditary breast/ovarian carcinoma in France, the United Kingdom, and Canada, countries selected because of their cultural differences. The authors aimed to discover the existence of specific factors that may affect acceptability of these preventative measures. METHODS: A cross-sectional, multicenter survey was conducted in Marseilles, France (n = 141), in Manchester, England (n = 130), and in Montreal, Quebec (n = 84). All of the women attending cancer genetic clinics for the first time because of a family history of breast-ovarian carcinoma completed a self-administered questionnaire before their clinic consultation. RESULTS: Variations in responses to different preventative options presented on the questionnaire were seen within the sample of patients considered as a whole. The highest levels of acceptability were obtained for mammographic screening (87%) and chemoprevention (58%). In contrast, prophylactic oophorectomy and prophylactic mastectomy were thought to be acceptable at an early age (before 35 years), an age associated with the highest prophylactic efficacy, by only 19% and 16% of the respondents, respectively. After multivariate adjustment, the statistical data showed that the British respondents were more in favor of oophorectomy (P < 0.0001) and more in favor of chemoprevention than the French (P < 0.001) and the Canadian respondents (P < 0.001). The British (overall adjusted response [OR(adj)] = 3.9; P < 0.001) and Canadian respondents (OR(adj) = 3; P < 0.01) were more in favor of prophylactic mastectomy than the French. The cumulated acceptability of mammography before the age of 40 years was found to be greater in the French (OR(adj) = 2.8; P < 0.01) and Canadian (OR(adj) = 3.1; P < 0.05) samples than in the British sample. CONCLUSION: These results demonstrated the existence of international variations in the acceptability of the preventive strategies available for women at risk for hereditary breast/ovarian carcinoma. Therefore, these results suggested that when establishing medical recommendations or planning public health interventions, physicians must integrate the population's perception of advantages and drawbacks with the patient's individual decision making.