Mercury in alligators (Alligator mississippiensis) in the southeastern United States

Mercury methylation may be enhanced in wetlands and humic-rich, blackwater systems that crocodiles and alligators typically inhabit. Given their high trophic level and long life-spans, crocodilians could accumulate significant burdens of Hg. Our objectives were to survey Hg concentrations in alligators from several areas in the southeastern United States to test their utility as sentinels of Hg contamination, to examine relationships among Hg concentrations in various tissues and to look for any differences in tissue Hg concentrations among locations. We measured total Hg concentrations in alligators collected in the Florida Everglades (n = 18), the Okefenokee National Wildlife Refuge, Georgia (n = 9), the Savannah River Site (SRS), South Carolina (n = 49) and various locations in central Florida (n = 21), sampling tissues including blood, brain, liver, kidney, muscle, bone, fat, spleen, claws and dermal scutes. Alligators from the Everglades were mostly juvenile, but Hg concentrations in tissues were high (means: liver 41.0, kidney 36.4, muscle 5.6 mg Hg/kg dry wt.). Concentrations in alligators from other locations in Florida were lower (means: liver 14.6, kidney 12.6, muscle 1.8 mg Hg/kg dry wt.), although they tended to be larger adults. Alligators from the Okefenokee were smallest and had the lowest Hg concentrations (means: liver 4.3, kidney 4.8, muscle 0.8 mg Hg/kg dry wt.). SRS alligators had the greatest size range and intermediate Hg levels (means: liver 14.9, muscle 4.8 mg Hg/kg dry wt.). At some locations, alligator length was correlated with Hg concentrations in some internal organs. However, at three of the four locations, muscle Hg was not related to length. Tissue Hg concentrations were correlated at most locations however, claw or dermal scute Hg explained less than 74% of the variation of Hg in muscle or organs, suggesting readily-obtained tissues, such as scutes or claws, have limited value for non-destructive screening of Hg in alligator populations.     

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.