Exercise for rheumatoid arthritis

The approach to treating rheumatoid arthritis is changing. Greater emphasis on the exercise component of physical therapy can improve patients' muscle strength, endurance, and emotional well-being, and may even result in decreased joint inflammation.     

The Effects of IB4, a Monoclonal Antibody to the CD18 Leukocyte Integrin on Phorbol Myristate Acetate (PMA)-Induced Polymorphonuclear Leukocyte (PMN) Accumulation and Endothelial Injury in Rabbit Lungs

A model of acute lung injury induced by intravenous phorbol myristate acetate (PMA) is described. The model is characterized by the accumulation of polymorphonuclear leukocytes (PMNs) and a hemorrhagic edema in bronchoalveolar lavage (BAL) fluid when measured 6 h following the administration of PMA (60 g/kg, i.v.). It was also determined that PMA induces acute leukopenia and neutropenia which were maximal at 5 min following the injection of PMA and were sustained for at least 6 h, with circulating leukocyte numbers returning to control values by 24 h. The extents to which the inflammatory and systemic changes induced by PMA were dependent on the surface expression on leukocytes of the 2-integrins was assessed by comparing responses to PMA in control animals and animals pretreated with the anti-CD18 monoclonal antibody IB4. The administration of IB4 (1 mg/kg, i.v.) 15 min before PMA did not alter the time course or extent of PMA-induced leukopenia and neutropenia. In contrast IB4 administration (0.1 to 1 mg/kg) produced a dose dependent inhibition of PMN accumulation and plasma extravasation measured in BAL fluid. IB4 (1 mg/kg) completely inhibited PMA evoked increases in plasma extravasation (94.5 ± 1.7%, N = 4) and hemorrhage (95.2 ± 2.1%, N = 4) whereas PMN accumulation in BAL fluid was inhibited by 77.8 ± 3.8% (mean ± SEM, N = 4). Thus, a small, but reproducible, component of the PMA-induced PMN accumulation was not inhibited using this regimen of IB4 administration. If IB4 administration was delayed for 3 h post injection of PMA and bronchoalveolar lavage performed 3 h later, the extents of PMN accumulation and edema formation were similar to those observed 3 h following PMA challenge in control animals not dosed with IB4. This suggests that administration of IB4 during an ongoing inflammatory response is capable of preventing the further development of inflammatory changes and further supports the therapeutic potential of CD18 blockade in conditions such as adult respiratory distress syndrome.     

Single-channel and whole-cell analysis of ethanol inhibition of NMDA-activated currents in cultured mouse cortical and hippocampal neurons

The effects of 0.1 to 500 mM ethanol on NMDA-activated currents were studied in primary cultures of mouse cortical and hippocampal neurons. In whole-cell recordings the IC₅₀S for inhibition of NMDA-activated currents by ethanol were 129 mM ± 20 mM in hippocampal neurons and 126 ± 18 mM in cortical neurons. In single-channel recordings from excised outside-out patches of cortical neurons, ethanol inhibited total charge per minute with an IC₅₀ of 174 ± 23 mM, which was not significantly different from the IC₅₀S for inhibition of whole-cell current. The reduction in mean open channel lifetime by ethanol was fit by the logistic equation with an apparent IC₅₀ of 340 ± 28 mM. Analysis of single-channel data indicated that ethanol inhibition of NMDA currents did not involve substantial changes in fast closed state kinetics, changes in open channel conductance, or block of the open channel. At the whole-cell IC₅₀, of ethanol, mean open channel lifetime would decrease by 28% and frequency of opening would decline by 31% to account for the reduction in current. Single-channel data were consistent with ethanol being an allosteric modulator of gating which reduces agonist efficacy.     

Use of plasma cytotoxic activity to model cytotoxic pharmacodynamics of anticancer drugs

Summary We have developed a pharmacokinetic/pharmacodynamic approach that integrates the disposition, cytotoxic activity and interaction of anticancer drugs. Fundamental to this approach is the measurement of the cytotoxicity, against a target cell line, of patient plasma collected at different times after administration of the anticancer agent(s). To illustrate this approach, we have studied the plasma cytotoxic activity (PCA), against HL-60 cells, of plasma from 11 acute myeloblastic leukemic patients treated with daunorubicin (DNR). Plasma, obtained before and serially for 24 h after DNR treatment, was assayed by HPLC for DNR and daunorubicinol (DNRol), its active metabolite. The corresponding observed PCA values (PCA_obs) against HL-60 cells were also measured with a flow-cytometric cell-survival assay that we had developed previously. The pharmacodynamics, i.e. PCA, were co-modeled (dual Hill equation with an interaction term to allow synergism or antagonism) with the pharmacokinetics. The intergration of the PCA profile provided the area under the observed PCA versus time curve (AUC_obs). For each patient, we also generated an interaction panel, by adding known amounts of DNR and DNRol to his or her pretreatment plasma. The corresponding cytotoxicities were measured, and then applied to the pharmacodynamic model. This provided a standard surface from which the PCA of each sample obtained after therapy was predicted (PCA_prd), on the basis of assayed concentrations of DNR and DNRol in that sample. For plasma samples obtained after treatment, the model simultaneously fit all three outputs, i.e. PCA and DNR/DNRol concentration, very well. We observed substantial interpatient variability in HL-60 growth rate in medium containing patient pretreatment plasma, in DNR activity in pretreatment plasma, and in the in vitro activity (PCA) of plasma obtained after DNR treatment. We also compared the AUC_prd to the AUC_obs for each patient, and we identified a subset of 4/11 acute myeloblastic leukemic patients who had developed much more PCA after DNR administration than could be explained by the measured concentrations of DNR and DNRol. This may be due to unidentified active metabolites or to factors produced in the plasma in response to the treatment. This pharmacokinetic/pharmacodynamic model is promising to describe pharmacodynamics and interactions of anticancer drugs in cancer patients.This work was presented, in part, at the 31st annual meeting of the American Society of Hematology, Atlanta, Ga., December 1989, and at the 91st Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, San Francisco, Calif., March 1990. Supported in part by grant RO-1-CA40 188 from the National Institutes of Health, National Cancer Institute, a grant from the Scientific Committee of NATO, Brussels, Belgium, and a grant from the Oeuvre Belge du Cancer, Brussels, Belgium     

Multicenter study of general anesthesia. III. Predictors of severe perioperative adverse outcomes.

Little information is available about the incidence of severe adverse outcomes, and even less information is available about the identification and quantification of independent predictors of severe perioperative adverse outcomes. The purpose of this study was to identify and quantitate independent predictors of severe perioperative adverse outcomes in a prospective randomized clinical trial of general anesthesia in 17,201 patients. Twenty-nine prognostic variables for 15 severe outcomes in 847 patients were tested by multiple stepwise logistic regressions from which 20 significant (P less than 0.05) predictors were identified. A history of cardiac failure or myocardial infarction less than or equal to 1 yr; ASA physical status 3 or 4; age greater than 50 yr; cardiovascular, thoracic, abdominal or neurologic surgery; and the study anesthetics were significant predictors of "any severe outcome, including death." There were 17 significant predictors for 10 severe cardiovascular outcomes in 608 patients, including a history of ventricular arrhythmia, hypertension, cardiac failure, myocardial ischemia, myocardial infarction less than or equal to 1 yr or myocardial infarction greater than 1 yr, and smoking; ASA physical status; age; cardiovascular, thoracic, abdominal, eyes-ears-nose-throat/endocrine, neurologic, musculoskeletal, or gynecologic surgery; and the study anesthetics. There were 9 significant predictors for 4 severe respiratory outcomes in 163 patients, including a history of cardiac failure, myocardial ischemia, or chronic obstructive pulmonary disease; obesity; smoking; male gender; ASA physical status; abdominal surgery; and the study anesthetics. Colinearity between related prognostic variables (such as disease and ASA physical status) was assessed using progressively segregated groups of variables in eight stepwise logistic regressions. We conclude that the comprehensive stepwise logistic regression of 29 prognostic variables reported here provides a valid estimate of the risks of severe perioperative outcomes associated with general anesthesia.     

Reports by anaesthetists to procurators-fiscal: analysis of "anaesthetic deaths" over 10 years in four Scottish teaching hospitals.

Review of 489 "anaesthetic deaths" reported to procurators-fiscal over 10 years disclosed only 30 that were thought to justify such reporting. Most of the remainder occurred in patients so desperately ill at the time of operation that death was expected. Postmortem examinations ordered by the Crown authorities in nearly all cases were probably largely unrewarding and mostly unnecessary. The results suggest that the present regulation on reporting should be revised to focus more attention on the few deaths that occur in patients who have no apparent contraindication to anaesthesia or operation.     

Safety, efficacy and pharmacokinetics of linezolid for treatment of resistant Gram-positive infections in cancer patients with neutropenia.

BACKGROUND: Linezolid is a recently approved oxazalidinone with extended activity against Gram-positive bacteria. We evaluated the results of linezolid therapy in neutropenic cancer patients with Gram-positive bacterial infections from a compassionate-use program. PATIENTS AND METHODS: This was a prospective, multicenter, open-label, non-comparative, non-randomized compassionate-use treatment program in patients with serious Gram-positive infections. To qualify for enrollment patients were required to have an infection resistant to available antimicrobial agents, or in whom available agents had failed or to which they were intolerant. Patients with absolute neutrophil counts (ANC) <500 cells/mm(3) or <1000 cells/mm(3) and expected to decrease to <500 cells/mm(3), and who received linezolid 600 mg twice daily were included. Plasma samples for population pharmacokinetic analysis were collected. Clinical and microbiological assessments of outcomes were made at the end of therapy and at short-term follow-up. RESULTS: Of the patients in the compassionate-use trial, 103 were neutropenic. The mean [standard deviation (SD)] age was 50.1 (17.5) years, 47% were female, and 47.6% had a baseline ANC 相似文献