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Joint immobility is a debilitating complication of articular trauma that is characterized by thickening and stiffening of the joint capsule and the formation of fibrotic lesions inside joints. Capsule release surgery can temporarily restore mobility, but contraction often recurs due to the contractile activities of fibroblasts, which exert tension on the capsule ECM via nonmuscle myosin II. Based on these findings we hypothesized that blebbistatin, a drug that reversibly inhibits the activity of this protein, would relax ECM tension imposed by fibroblasts and reduce fibrosis. In this study, we characterized the effectiveness of blebbistatin as an anticontractile treatment. Given that sustained suppression of contractile activity may be required to achieve capsule release and reduce fibrosis, we compared the effects on fibroblast-mediated collagen ECM displacement of blebbistatin-loaded poly(lactide-co-gylcolide) (PLGA) particles versus bolus blebbistatin dosing. Time-lapse imaging of fluorescent microspheres embedded in collagen gels confirmed that PLGA/blebbistatin inhibited force generation and reduced both gel displacement and rate of displacement. In addition, collagen production at 10 days was significantly reduced. Taken together, these data indicate that blebbistatin-loaded PLGA particles can be used to inhibit fibroblast force-generation and reduce collagen production and lay the foundation for optimization of drug delivery technology for treating arthrofibrosis.

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Cardiopulmonary exercise testing (CPET) is the most comprehensive investigation for understanding the mechanisms responsible for dyspnea in patients with chronic respiratory disease. The two observations presented here illustrate how CPET can contribute to the management of patients with interstitial lung diseases. A 60-year-old woman had been followed for 20 years for non-progressive pulmonary sarcoidosis, untreated for many years. CPET led to the diagnosis of an atrial septal defect. A 76-year-old man was treated for idiopathic pulmonary fibrosis. Before pulmonary rehabilitation, CPET was performed which revealed significant aortic valve stenosis, which had been to that point asymptomatic. In these two observations, CPET determined the presence of an associated disease, distinct from the interstitial lung disease.

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Amiodarone-induced thyroid dysfunction (AITD) is a common complication of amiodarone therapy and its prevalence varies according to iodine intake, subclinical thyroid disorders and the definition of AITD. There is no consensus about the frequency of screening for this condition. We evaluated 121 patients on chronic regular intake of amiodarone (mean intake = 248.5 +/- 89 mg; duration of treatment = 5.3 +/- 3.9 years, range = 0.57-17 years) and with stable baseline cardiac condition. Those with no AITD were followed up for a median period of 3.2 years (range: 0.6-6.7) and the incidence rate of AITD, defined by clinical and laboratorial findings as proposed by international guidelines, was obtained (62.8 per 1000 patients/year). We applied the Cox proportional hazard model to adjust for potential confounding factors and used sensitivity analysis to identify the best screening time for follow-up. We detected thyroid dysfunction in 59 (48.7%) of the 121 patients, amiodarone-induced hypothyroidism in 50 (41.3%) and hyperthyroidism in 9 (7.5%). Compared with patients without AITD, there was no difference regarding dosage or duration of therapy, heart rhythm disorder or baseline cardiac condition. During the follow-up of the 62 patients without AITD at baseline evaluation, 11 developed AITD (interquartile range, IR: 62.8 (95%CI: 31.3-112.3) cases per 1000 patients/year), 9 of them with hypothyroidism - IR: 11.4 (95%CI: 1.38-41.2), and 2 hyperthyroidism - IR: 51.3 (95%CI: 23.4-97.5). Age, gender, dose, and duration of treatment were not significant after adjustment. During the first 6 months of follow-up the incidence rate for AITD was 39.3 (9.2-61.9) cases per 1000 patients/year. These data show that AITD is quite common, and support the need for screening at 6-month intervals, unless clinical follow-up dictates otherwise or further information regarding the prognosis of untreated subclinical AITD is available.

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Amiodarone-induced thyroid dysfunction (AITD) is a common complication of amiodarone therapy and its prevalence varies according to iodine intake, subclinical thyroid disorders and the definition of AITD. There is no consensus about the frequency of screening for this condition. We evaluated 121 patients on chronic regular intake of amiodarone (mean intake = 248.5 ± 89 mg; duration of treatment = 5.3 ± 3.9 years, range = 0.57-17 years) and with stable baseline cardiac condition. Those with noAITD were followed up for a median period of 3.2 years (range: 0.6-6.7) and the incidence rate of AITD, defined by clinical and laboratorial findings as proposed by international guidelines, was obtained (62.8 per 1000 patients/year). We applied the Coxproportional hazard model to adjust for potential confounding factors and used sensitivity analysis to identify the best screening time for follow-up. We detected thyroid dysfunction in 59 (48.7%) of the 121 patients, amiodarone-induced hypothyroidism in50 (41.3%) and hyperthyroidism in 9 (7.5%). Compared with patients without AITD, there was no difference regarding dosage or duration of therapy, heart rhythm disorder or baseline cardiac condition. During the follow-up of the 62 patients without AITD at baseline evaluation, 11 developed AITD (interquartile range, IR: 62.8 (95%CI: 31.3-112.3) cases per 1000 patients/year), 9 of them with hypothyroidism - IR: 11.4 (95%CI: 1.38-41.2), and 2 hyperthyroidism - IR: 51.3 (95%CI: 23.4-97.5). Age, gender,dose, and duration of treatment were not significant after adjustment. During the first 6 months of follow-up the incidence rate for AITD was 39.3 (9.2-61.9) cases per 1000 patients/year. These data show that AITD is quite common, and support the need for screening at 6-month intervals, unless clinical follow-up dictates otherwise or further information regarding the prognosis of untreated subclinical AITD is available.

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Leishmania amazonensis causes a wide spectrum of disease in humans. In this study, we evaluated BALB/c mice infected with five strains of L. amazonensis isolated from patients with either cutaneous, mucosal, or visceral leishmaniasis. Mice infected with cutaneous and mucosal isolates developed ulcerating footpad lesions with parasite-loaded macrophages and extensive tissue destruction. Skin metastases, early dissemination of parasites to the spleen, and high anti-Leishmania antibody levels were also noted. Mice infected with L. amazonensis strains isolated from patients with visceral disease had a controlled infection, with small footpad lesions with mononuclear cell infiltration, few infected macrophages, and granuloma formation. They had no skin metastases, delayed dissemination of the parasite to the spleen, lower levels of IgG and higher levels of IgG2a against L. amazonensis. These findings demonstrate an unexpected resistance of BALB/c mice to the infection with L. amazonensis isolated from patients with visceral leishmaniasis. This resistance seems to be due to differences in these parasites that may be related to the altered course of the disease in humans and in isogenic BALB/c mice.

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Cell-mediated immunity to Schistosoma mansoni antigens, unrelated antigens and mitogens was evaluated in 50 subjects with the same degree of exposure to infection living in an endemic area of schistosomiasis. The degree of infection, assessed by the number of eggs/g of stool, was variable in this population (0-5604), suggesting differences in susceptibility to infection. Absence of lymphoproliferative response was observed in 56% of this group, despite having a response to purified protein derivative of tuberculin (PPD) and tetanus toxoid (TT) antigens and to pokeweed mitogen. The 50 subjects were divided into two groups, according to their degree of infection. The lymphoproliferative responses to schistosomula and adult worm antigens in the group with a low degree of infection (< 400 eggs/g of stool) were higher than the ones documented in patients with a high degree of infection (> 400 eggs/g of stool), and these differences were statistically significant (p < 0.001). An inverse correlation between the lymphocyte proliferation in response to S. mansoni antigens and the degree of infection was also observed (p = 0.02), indicating that subjects with a lower degree of infection have a higher lymphoproliferative response to schistosomula and adult worm antigens. No differences in the lymphocyte reactivity to other antigens (PPD and TT) were detected in these groups. An impairment of interferon-gamma in vitro production was observed when the lymphocytes from these subjects were stimulated with S. mansoni adult worm antigen, although they produced gamma interferon in response to phytohemagglutinin.

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In this study, retting was carried out by Aspergillus niger. The pH, galacturonic acid (GA), and total reducing sugar were determined; the end point was identified by the classic empirical processes and by the maximal GA content of the retting water. The process gave clear and resistent fibers, and the retting time was similar to that of current industrial processes with bacterial enzymes. Control of total acidity was not required, since the pH remained close to neutrality throughout the entire process.