Cyclosporine A in the treatment of early rheumatoid arthritis. A prospective, randomized 24-month study

OBJECTIVE: To investigate the efficacy, tolerability and safety of cyclosporine A (CSA) in early rheumatoid arthritis (RA) patients. METHODS: Patients with an early diagnosis of RA, a disease duration of less than 3 years, and without prior disease modifying antirheumatic drug (DMARD) treatment were studied. They randomly received oral CSA (3 mg/kg/day) or oral methotrexate (MTX) (0.15 mg/kg/week). In addition, all patients in both groups received oral prednisone (7.5 mg/day). RESULTS: Fifty-two patients were assigned to the CSA group and 51 to the MTX group. After 24 months of treatment, 48 patients from the CSA group and 48 from the MTX group showed significant clinical improvement. This was evaluated by the duration of morning stiffness, grip strength, the total joint count, joint swelling, and joint tenderness and pain, compared to pre-treatment values. The clinical improvement was also associated with a significant decrease in ESR and CRP values in both groups. No significant radiological deterioration was observed in the CSA patients compared to those treated with MTX after 24 months. Four patients from the CSA group dropped out of the study, two because of a synovitis flare, one because of severe hypertrichosis and one because of severe gingival hyperplasia. Three patients from the MTX group withdrew, one because of disease flare-up and two because of gastrointestinal disturbances. CONCLUSION: Early immunointervention in RA patients appears to be crucial to limit the development of joint damage. Cyclosporine A appears to be effective, well tolerated and safe in the long-term treatment of RA and can therefore be used as a first immunomodulatory drug in the armamentarium for the treatment of RA.     

The influence of gender on cough reflex sensitivity

BACKGROUND: The more common occurrence in women of cough due to angiotensin-converting enzyme inhibitors raises the possibility of gender-related differences in the sensitivity of the cough reflex. Of two recent studies that evaluated cough response to inhaled capsaicin in normal subjects, one demonstrated heightened sensitivity of the cough reflex in women compared with men, while the other revealed no gender-related differences. To further investigate this question, we reviewed our experience with cough challenge testing in normal volunteers. STUDY OBJECTIVE: To compare cough reflex sensitivity in healthy adult female and male subjects. DESIGN: Retrospective data analysis. SETTING: Academic medical center. PARTICIPANTS: One hundred healthy volunteers (50 male, 50 female). Interventions: Subjects inhaled capsaicin in ascending, doubling concentrations until the concentration inducing five or more coughs (C5) was reached. In addition, the concentration inducing two or more coughs (C2; cough threshold) was measured. Results: Mean log C5 was significantly lower in women than in men: 1.02+/-0.09 (SEM) microM vs 1.41+/-0.08 microM, respectively (p=0.002). Log C2 (cough threshold) was also significantly lower in female subjects: 0.534+/-0.068 microM vs 0.870+/-0.065 microM in male subjects (p=0.00058). CONCLUSION: Healthy women have a more sensitive cough reflex than do healthy men. The reasons for this significant gender difference remain to be elucidated, but may involve a heightened sensitivity, in women, of the sensory receptors within the respiratory tract that mediate cough.     

Parallel airways inhomogeneity and lung tissue mechanics in transition to constricted state in rabbits

To investigate whether changes of tissue resistance (Rti) during methacholine (MCh)-induced constriction correspond to an intrinsic mechanism or are an artifact of increased airways inhomogeneity, rabbits were studied after exposure to air (n = 7) or 1.5 parts/million O3 (n = 6). Animals were anesthetized and mechanically ventilated. Tracheal flow and pressure (Ptr) and four alveolar capsule pressures (Pcap) were measured during 3 min after administration of an intrajugular bolus of 0.8 mg/ml MCh. By adjustment of the equation of motion [P(t) = E . V(t) + R . dV(t)/dt + P0] [where P(t), V(t), and dV(t)/dt are pressure, volume, and flow as a function of time, respectively, E is elastance, R is resistance, and P0 is end-expiratory pressure] to Ptr, lung resistance (RL) and dynamic elastance (EL) were determined breath by breath. Rti and airways resistance (Raw) were determined from Pcap in phase with rate of change of pulmonary expansion. Hysteresivity (eta) was calculated. Parallel inhomogeneity was estimated from the coefficients of variation (CV) of every Pcap at end inspiration and end expiration. Increase in CV significantly lagged Rti, RL, and eta. A linear relationship between EL and Raw was observed. Our results suggest that changes in tissue mechanics during the transition to the constricted state are not artifactual.     

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.     

Compatibility problems after intravenous immunoglobulin--a case report

The purpose of this study was to determine whether there are changes in anterior and posterior glenohumeral translation after arthroscopic, nonablative, thermal capsuloplasty with a laser. Two anteriorly and two posteriorly directed loads were sequentially applied to the humerus of nine cadaveric glenohumeral joints, and anterior and posterior translation of the humerus on the glenoid was measured. The glenoid was rigidly fixed, and the glenohumeral joint was positioned simulating 90 degrees of shoulder abduction and 90 degrees of external rotation. Using the holmium:yttrium-aluminum-garnet laser, thermal energy was then applied to the anterior capsuloligamentous structures and anterior and posterior translation measurements were then repeated. The results showed a significant reduction in anterior and posterior translation after laser anterior capsuloplasty. Anterior translation decreased from 10.9 +/- 2.0 mm (mean +/- SEM) to 6.4 +/- 1.5 mm with the 15-N load; and from 13.4 +/- 2.1 mm to 8.9 +/- 1.8 mm with the 20-N load. Posterior translation decreased from 7.2 +/- 1.2 mm to 4.4 +/- 0.6 mm with the 15-N load and from 10.4 +/- 1.4 mm to 6.5 +/- 0.9 mm with the 20-N load. These results indicate that the holmium:yttrium-aluminum-garnet laser can be used to decrease glenohumeral joint translation and may be an effective treatment for glenohumeral joint instability.     

Mechanism of activation for Zap-70 catalytic activity

There is a growing body of evidence, including data from human genetic and T-cell receptor function studies, which implicate a zeta-associated protein of M(r) 70,000 (Zap-70) as a critical protein tyrosine kinase in T-cell activation and development. During T-cell activation, Zap-70 becomes associated via its src homology type 2 (SH2) domains with tyrosine-phosphorylated immune-receptor tyrosine activating motif (ITAM) sequences in the cytoplasmic zeta chain of the T-cell receptor. An intriguing conundrum is how Zap-70 is catalytically activated for downstream phosphorylation events. To address this question, we have used purified Zap-70, tyrosine phosphorylated glutathione S-transferase (GST)-Zeta, and GST-Zeta-1 cytoplasmic domains, and various forms of ITAM-containing peptides to see what effect binding of zeta had upon Zap-70 tyrosine kinase activity. The catalytic activity of Zap-70 with respect to autophosphorylation increased approximately 5-fold in the presence of 125 nM phosphorylated GST-Zeta or GST-Zeta-1 cytoplasmic domain. A 20-fold activity increase was observed for phosphorylation of an exogenous substrate. Both activity increases showed a GST-Zeta concentration dependence. The increase in activity was not produced with nonphosphorylated GST-Zeta, phosphorylated zeta, or phosphorylated ITAM-containing peptides. The increase in Zap-70 activity was SH2 mediated and was inhibited by phenylphosphate, Zap-70 SH2, and an antibody specific for Zap-70 SH2 domains. Since GST-Zeta and GST-Zeta-1 exist as dimers, the data suggest Zap-70 is activated upon binding a dimeric form of phosphorylated zeta and not by peptide fragments containing a single phosphorylated ITAM. Taken together, these data indicate that the catalytic activity of Zap-70 is most likely activated by a trans-phosphorylation mechanism.     

PV in Japan: Improving energy security?

Japan currently imports nearly 80% of its primary energy. Almost half of this comes from politically unstable parts of the world. The country is increasingly looking for alternative sources of energy to improve energy security and reduce greenhouse gas emissions. Towards this end, Japan is currently the world's leader when it comes to PV manufacturing capability and installed capacity. With a cumulative total of 300MW of installed PV, we take a closer look at the current developments that are driving this growth in the country.     

Water in Betelgeuse and Antares

Absorption lines of hot water have been identified in the infrared spectra of Betelgeuse (alpha Orionis) and Antares (alpha Scorpii) near 12.3 micrometers (811 to 819 wavenumbers). The water lines originate in the atmospheres of the stars, not in their circumstellar material. The spectra are similar in structure to umbral sunspot spectra. Pure rotation water lines of this type will occur throughout the spectra of cool stars at wavelengths greater than 10 micrometers. From the water spectra, the upper limit for the temperature in the line formation region in both stars is 2800 kelvin. The water column density in both stars is (3 +/- 2) x 10(18) molecules per square centimeter, yielding an abundance relative to atomic hydrogen of n(H2O)/n(H) approximately 10(-)7.     

Platelet and neutrophil distributions in pump oxygenator circuits. III. Influence of nitric oxide gas infusion

The authors used quantitative gamma scintigraphy to evaluate the influence of nitric oxide gas on platelet and neutrophil deposition in Cobe Duo microporous oxygenators during cardiopulmonary bypass (CPB). The effects of nitric oxide gas on circulating platelet and neutrophil counts and platelet function also were assessed. Animals were prepared by standard methods. Cells were harvested, labeled (111 In platelet and 99mTc neutrophil), infused, and recirculated. Nitric oxide gas, a guanylate cyclase pathway promoter, was infused int he Duo gas port at 500 ppm (t = 0-60 min), increased to 1,000 (t = 60-80 min), and stopped (final, 10 min). Images were taken at 10-15 min intervals during CPB. Standard isotope image corrections were made. No differences between nitric oxide gas and control experiments were observed for flow, pressure, hematocrit, or replacement volume. Nitric oxide gas infusion significantly (p < 0.05) reduced both platelet adherence to the oxygenator and in vitro platelet aggregation. Neutrophil adhesion tended to be lower, and circulating platelet and neutrophil counts tended to be higher with nitric oxide gas infusion. Results of in vitro aggregometry studies using rabbit platelets indicate that the class V phosphodiesterase inhibitor zaprinast can strongly enhance the inhibitory effects of nitric oxide. The authors conclude nitric oxide gas is a promising platelet sparing agent in the setting of CPB.