Effects of selective phosphodiesterase inhibitors on platelet-activating factor- and antigen-induced airway hyperreactivity, eosinophil accumulation, and microvascular leakage in guinea pigs

There is currently interest in the potential use of selective inhibitors of cyclic nucleotide phosphodiesterases (PDE) in the treatment of asthma. In this study we examined the effects of three selective PDE inhibitors, milrinone (PDE III), rolipram (PDE IV) and zaprinast (PDE V), on the broncoconstriction produced by antigen and histamine, the airway hyperreactivity and microvascular leakage after aerosol exposure to platelet-activating factor (PAF) and antigen, and the antigen-induced eosinophil infiltration in guinea-pig lung. Inhaled rolipram (0.01–10 mg ml^–1) inhibited dose dependently the bronchospasm produced by aerosol antigen (5 mg ml^–1) an anaesthetised, ventilated guinea-pigs. Rolipram (10 mg ml^–1) produced maximal inhibition of antigen-induced bronchoconstriction but only partial inhibition of the response to aerosol histamine (1 mg ml^–1). Milrinone and zaprinast (each 10 mg ml^–1) showed weak, or no, inhibitory effects against bronchoconstriction produced by aerosol antigen or histamine. Pretreatment with rolipram (10 mg kg^–1, i.p.) prevented airway hyperreactivity to histamine which develops 24 h after exposure of conscious guinea-pigs to aerosol PAF (500 g ml^–1) or antigen (5 mg ml^–1). The pulmonary eosinophil infiltration obtained with 24 h of antigen-exposure was inhibited by rolipram. In contrast, milrinone and zaprinast (each 10 mg kg^–1, i.p.) failed to reduce either the airway hyperreactivity of the eosinophil accumulation in these animals. Rolipram (1–10 mg ml^–1) reduced the extravasation of Evans blue after aerosol PAF (500 g ml^–1) at all airway levels while a lower dose (0.1 mg ml^–1) was only effective at intrapulmonary airways. Rolipram (0.01–1 mg ml^–1) markedly reduced airway extravasation produced by inhaled antigen (5 mg ml^–1). Zaprinast (1–10 mg ml^–1) was also effective against airway microvascular leakage produced by aerosol PAF or antigen while milrinone (10 mg ml^–1) had no antiexudative effect. These data support previous suggestions that pharmacological inhibition of PDE IV results in anti-spasmogenic and anti-inflammatory effects in the airways and may be useful in the treatment of asthma.     

Situational management

In this paper, the organizational theory of situational planning is used to establish a decentralized management model for complex health units. Because of cultural limitations imposed on a perspective of change and rationalization, considerations are made in relation to a given form of dealing with culture, keeping in mind the feasibility of the management model. A particular type of communicative management emerges as a general need revealed by the analysis of the object at issue: the management of professional organizations.     

Radiosensitive populations and recovery in X-ray-induced apoptosis in the developing cerebellum

Sprague-Dawley rats received a single dose of 2 Gy X-rays at the age of 1 or 3 days and were killed at different intervals. Dying cells with the morphological characteristics of apoptosis appeared in the external and internal granular layers (EGL and IGL) and white matter (WM) of the cerebellum, mainly 3–6 h after irradiation, and decreased thereafter to reach normal values between 48 h and 5 days later. This process was curbed by the injection of cycloheximide at a dose of 1 g/g body weight. In addition, the number of mitoses in EGL rapidly decreased after irradiation and did not reach normal values until a few days later. Proliferating cell nuclear antigen (PCNA)-immunoreactive cells, which were chiefly found in EGL but also in IGL and WM, dramatically decreased in number from 3 to 48 h after irradiation. PCNA-immunoreactive cells reappeared and reached age-matched values in the following days. Hu (considered as an early neuronal marker) and vimentin immunocytochemistry disclosed that Hu-nonreactive cells in the upper level of EGL, Hu-immunoreactive cells in the inner level of EGL, Bergmann glia and many astrocytes in WM, as well as many non-typified cells in WM, were radiosensitive populations, whereas Purkinje cells were not. The present results indicate that irradiation at P1 or P3 blocks mitosis in EGL and kills sensitive cells mainly in the late G1 and S phases of the cell cycle, probably by apoptosis through a protein synthesis-mediated process. Radiosensitive cells are germinal cells and neuroblasts in EGL, Bergmann glia, astrocytes in WM, and non-typified cells, probably glial cell precursors, in WM. Surviving cells in EGL and PCNA-immunoreactive cells in other cortical layers and white matter reconstitute the cerebellum following a single dose of X-rays.This work was supported in part by CEC project FI3P-CT92-0015 and FIS grant 93-131. M. Olivé is the recipient of a grant from the Pi i Sunyer Foundation. R. Rivera has a grant from the CIRIT     

Safety effectiveness of closed-transfer,mixing-loading,and application equipment in preventing exposure to pesticides

Blood cholinesterase (CHE) activities and urinary dialkyl phosphate levels of five mixer-loaders and four mixer-loader applicators, using a closed-transfer system in conjunction with mixing-loading and application equipment, were monitored over a period of 18 weeks. Airborne pesticide residues in the breathing zone during mixing-loading and the transfer of concentrated liquid pesticide from their original container to mix and spray tanks were determined along with airborne residues during ground application. Blood ChE activities of the majority of the workers increased slightly during the study with increased use of toxic organophosphates and carbamates. Urinary dialkyl phosphate levels varied between 0.02 and 2.4 ppm. During the study, the blood ChE activities of two mixer-loaders decreased and dialkyl phosphate levels of 2.4 ppm were found in the urine of one worker. An investigation indicated that the workers had failed to use the provided closed-transfer system. Airborne residues from liquid pesticides during closed transfer and mixing-loading averaged 5.8g/m³, while residues from dusty powders averaged 152g/m³. Airborne residues during ground application averaged 3.7/m³ during the workday. Mevinphos residues on cloth patches averaged 0.2g/cm².     

Hypotension induced by sodium nitroprusside administered via an automatic-adaptive dose regulating system. Experimental development

Sodium nitroprusside (NPS) is a potent vasodilator which is frequently administered for the control of arterial blood pressure and peripheral resistances. Manual regulation of the dose is difficult and requires a permanent surveillance of patients under treatment. Several attempts have been made to develop an automatized system able to safely control the dose of the drug in clinical practice. However, since now the results have not been completely satisfactory. The aim of our study was to develop of a new automatic-adaptative system able to continuously control the dose of NPS. The system consists of a high precision infusion pump controlled by a microprocessor. Arterial blood pressure is continuously monitorized and according to its values NPS is automatically regulated to maintain blood pressure within a preselected range. A control "fuzzy logic" algorithm was used. We have assessed the efficacy, adaptability, and safeness of the system. The system was tested in 15 mongrel dogs. The protocol was divided into two parts. During the first part a 25% to 30% reduction in blood pressure from baseline values lasting for a period of 4 hours was attempted. The second part was devoted to test the adaptability of the control unit during induced unstable hemodynamic situations. Group I dogs were subjected to volume overload. Group II were treated with noradrenaline to increase blood pressure, and group III underwent a venous bleeding to produce arterial hypotension. Control of arterial blood pressure was achieved after a minimum of 5 min and a maximum of 19 min (mean values = 13.3 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

精子异常症:治疗篇

众所周知，有47%的不育是由于精子异常引起的。尽管医学发展迅速，仍有40%的不育患者存在病因不明的精液异常使临床疗效受限。另一方面，有报道显示中医疗法治疗精索静脉曲张、前列腺炎和精子异常疗效满意。我们尝试通过盲法对照试验观察针灸对精子异常不育患者的精子浓度、形态和活力是否有改善作用。     

Pilot study evaluating the pharmacokinetics, pharmacodynamics, and safety of the combination of exemestane and tamoxifen.

PURPOSE: We conducted a pilot study assessing the effects of the selective estrogen receptor modulator, tamoxifen, on the pharmacokinetics, pharmacodynamics, and safety of the steroidal, irreversible aromatase inhibitor (AI), exemestane, when the two were coadministered in postmenopausal women with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with documented or unknown hormone receptor sensitivity were eligible. Patients received oral exemestane at 25-mg once daily. Starting day 15, oral tamoxifen at 20-mg once daily, was added. We measured plasma concentrations of exemestane, estrone, estrone sulfate, and estradiol after 14 days of exemestane monotherapy and after approximately 4 weeks of combination therapy. The incidence and severity of adverse events were assessed by physical examination and patient reporting. RESULTS: We treated 18 patients. All had received prior chemotherapy and/or hormonal therapy, eight and six, respectively, with single-agent selective estrogen receptor modulators or irreversible aromatase inhibitors; no hormonal therapy was given within 30 days of study entry. Plasma exemestane concentrations and estrone, estrone sulfate, and estradiol suppression were unchanged after approximately 4 weeks of tamoxifen coadministration. All drug-related adverse events were grades 1 or 2; none was unexpected. Although not a formal study end point, antitumor activity was noted, with two partial responses and four cases of stable disease among 17 evaluable patients after a 9-month median follow-up (range, 2.5-19 months). CONCLUSIONS: This pilot study provides evidence that coadministration of tamoxifen does not affect exemestane pharmacokinetics or pharmacodynamics and that the combination is well-tolerated and active. Further clinical investigation is warranted.     

Incomplete DJH rearrangements as a novel tumor target for minimal residual disease quantitation in multiple myeloma using real-time PCR.

The hypervariable regions of immunoglobulin heavy-chain (IgH) rearrangements provide a specific tumor marker in multiple myeloma (MM). Recently, real-time PCR assays have been developed in order to quantify the number of tumor cells after treatment. However, these strategies are hampered by the presence of somatic hypermutation (SH) in VDJH rearrangements from multiple myeloma (MM) patients, which causes mismatches between primers and/or probes and the target, leading to a nonaccurate quantification of tumor cells. Our group has recently described a 60% incidence of incomplete DJH rearrangements in MM patients, with no or very low rates of SH. In this study, we compare the efficiency of a real-time PCR approach for the analysis of both complete and incomplete IgH rearrangements in eight MM patients using only three JH consensus probes. We were able to design an allele-specific oligonucleotide for both the complete and incomplete rearrangement in all patients. DJH rearrangements fulfilled the criteria of effectiveness for real-time PCR in all samples (ie no unspecific amplification, detection of less than 10 tumor cells within 10(5) polyclonal background and correlation coefficients of standard curves higher than 0.98). By contrast, only three out of eight VDJH rearrangements fulfilled these criteria. Further analyses showed that the remaining five VDJH rearrangements carried three or more somatic mutations in the probe and primer sites, leading to a dramatic decrease in the melting temperature. These results support the use of incomplete DJH rearrangements instead of complete somatically mutated VDJH rearrangements for investigation of minimal residual disease in multiple myeloma.