TNF-α and IL-10 downregulation and marked oxidative stress in Neuromyelitis Optica

<p>Abstract</p> <p>Background</p> <p>Neuromyelitis optica is a central nervous system demyelinating and inflammatory syndrome. The objective of this study is to identify cytokines related to the cellular immune response as well as blood brain barrier integrity and oxidative stress.</p> <p>Methods</p> <p>We performed a molecular characterization of cellular immune response and oxidative stress in serum from relapsing-NMO (R-NMO) patients and established the correlations between the clinical measurements and molecular parameters using the Bayesian approach.</p> <p>Serum samples from 11 patients with R-NMO diagnosed according to Wingerchuk criteria and matched in terms of age, gender and ethnicity with the healthy controls were analyzed. The levels of TNF-<it>α</it>, IFN-<it>γ</it>, IL-10, MMP-9, TIMP-1 and oxidative stress markers: malondialdehyde, advanced oxidation protein products, peroxidation potential, superoxide dismutase, catalase, and total hydroperoxides were measured.</p> <p>Results</p> <p>We found almost undetectable levels of TNF-<it>α</it>, a decreased production of IL-10 and a significant up-regulation of every oxidative stress biomarker studied. The insufficient production of TNF-<it>α </it>and IL-10 in R-NMO patients, which are two important players of T cell mediated immunoregulation, suggest an effector – regulator imbalance. The overproduction of oxygen reactive species as a consequence of the chronic inflammatory milieu is reflected on the excess of oxidative damage mediators detected. Furthermore, Multidimensional Scaling and a Bayesian linear regression model revealed a significant linear dependence between Expanded Disability Status Scale Kurtzke and TIMP-1; pointing to a possible predictive or prognostic value of this clinical-molecular relationship.</p> <p>Conclusion</p> <p>These results suggest that there is a breakdown in immunoregulatory mechanisms and noteworthy pro-oxidant environment contributing to NMO pathogenesis.</p

Catálogo y distribución geográfica de los Odonatos en la Región de Murcia (SE España).

Se actualiza el catálogo y la distribución del orden Odonata en la Región de Murcia, comparándolo a uno anterior realizado en los años 50 del siglo XX. Los resultados indican que a mitad del siglo pasado se localizaron 40 especies en 17 localidades, mientras que las 2.087 citas recopiladas entre 1991-2017 confirman la presencia de 47 especies en 191 localidades. Se han identificado 11 nuevas especies para la Región de Murcia, que se pueden haber visto favorecidas por la construcción de charcas, embalses y otras infraestructuras para abastecer a las 225.000 ha de regadíos. De ellas, 9 especies se están expandiendo su área de distribución hacia el norte de Europa y/o Asia, efecto que podría estar relacionado con el proceso de cambio climático actual. Por el contrario, en la revisión actual no han sido detectadas 4 especies citadas en el estudio realizado a mediados del siglo XX

Comparison of two recombinant erythropoietin formulations in patients with anemia due to end-stage renal disease on hemodialysis: A parallel, randomized, double blind study

BACKGROUND: Recombinant human erythropoietin (EPO) is used for the treatment of last stage renal anemia. A new EPO preparation was obtained in Cuba in order to make this treatment fully nationally available. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of two recombinant EPO formulations in patients with anemia due to end-stage renal disease on hemodialysis. METHODS: A parallel, randomized, double blind study was performed. A single 100 IU/Kg EPO dose was administered subcutaneously. Heberitro (Heber Biotec, Havana, formulation A), a newly developed product and Eprex (CILAG AG, Switzerland, formulation B), as reference treatment were compared. Thirty-four patients with anemia due to end-stage renal disease on hemodialysis were included. Patients had not received EPO previously. Serum EPO level was measured by enzyme immunoassay (EIA) during 120 hours after administration. Clinical and laboratory variables were determined as pharmacodynamic and safety criteria until 216 hours. RESULTS: Both groups of patients were similar regarding all demographic and baseline characteristics. EPO kinetics profiles were similar for both formulations; the pharmacokinetic parameters were very close (i.e., AUC: 4667 vs. 4918 mIU.h/mL; Cmax: 119.1 vs. 119.7 mIU/mL; Tmax: 13.9 vs. 18.1 h; half-life, 20.0 vs. 22.5 h for formulations A and B, respectively). The 90% confidence intervals for the ratio between both products regarding these metrics were close to the 0.8 – 1.25 range, considered necessary for bioequivalence. Differences did not reach 20% in any case and were not determined by a formulation effect, but probably by a patients' variability effect. Concerning pharmacodynamic features, a high similitude in reticulocyte counts increments until 216 hours and the percentage decrease in serum iron until 120 hours was observed. There were no differences between formulations regarding the adverse events and their intensity. The more frequent events were pain at injection site (35.3%) and hypertension (29%). Additionally, further treatment of the patients with the study product yielded satisfactory increases in hemoglobin and hematocrit values. CONCLUSION: The formulations are comparable. The newly developed product should be acceptable for long-term application

CIGB-300, a synthetic peptide-based drug that targets the CK2 phosphoaceptor domain. Translational and clinical research

CK2 represents an oncology target scientifically validated. However, clinical research with inhibitors of the CK2-mediated phosphorylation event is still insufficient to recognize it as a clinically validated target. CIGB-300, an investigational peptide-based drug that targets the phosphoaceptor site, binds to a CK2 substrate array in vitro but mainly to B23/nucleophosmin in vivo. The CIGB-300 proapoptotic effect is preceded by its nucleolar localization, inhibition of the CK2-mediated phosphorylation on B23/nucleophosmin and nucleolar disassembly. Importantly, CIGB-300 shifted a protein array linked to apoptosis, ribosome biogenesis, cell proliferation, glycolisis, and cell motility in proteomic studies which helped to understand its mechanism of action. In the clinical ground, CIGB-300 has proved to be safe and well tolerated in a First-in-Human trial in women with cervical malignancies who also experienced signs of clinical benefit. In a second Phase 1 clinical trial in women with cervical cancer stage IB2/II, the MTD and DLT have been also identified in the clinical setting. Interestingly, in cervical tumors the B23/nucleophosmin protein levels were significantly reduced after CIGB-300 treatment at the nucleus compartment. In addition, expanded use of CIGB-300 in case studies has evidenced antitumor activity when administered as compassional option. Collectively, our data outline important clues on translational and clinical research from this novel peptide-based drug reinforcing its perspectives to treat cancer and paving the way to validate CK2 as a promising target in oncology.Fil: Perea, Silvio E.. Center for Genetic Engineering and Biotechnology; CubaFil: Baladron, Idania. Center for Genetic Engineering and Biotechnology; CubaFil: Garcia, Yanelda. Center for Genetic Engineering and Biotechnology; CubaFil: Perera, Yasser. Center for Genetic Engineering and Biotechnology; CubaFil: Lopez, Adlin. Center for Genetic Engineering and Biotechnology; CubaFil: Soriano, Jorge L.. Center for Genetic Engineering and Biotechnology; Cuba. General Hospital ‘‘Hermanos Ameijeiras’; CubaFil: Batista, Noyde. Center for Genetic Engineering and Biotechnology; Cuba. General Hospital ‘‘Hermanos Ameijeiras’; CubaFil: Palau, Aley. Center for Genetic Engineering and Biotechnology; Cuba. General Hospital ‘‘Hermanos Ameijeiras’; CubaFil: Hernández, Ignacio. Center for Genetic Engineering and Biotechnology; CubaFil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Idrian. Center for Genetic Engineering and Biotechnology; CubaFil: Gonzalez, Lidia. Center for Genetic Engineering and Biotechnology; CubaFil: Gil, Jeovanis. Center for Genetic Engineering and Biotechnology; CubaFil: Rodriguez, Arielis. Center for Genetic Engineering and Biotechnology; CubaFil: Solares, Margarita. Center for Genetic Engineering and Biotechnology; CubaFil: Santana, Agueda. Center for Genetic Engineering and Biotechnology; CubaFil: Cruz, Marisol. Center for Genetic Engineering and Biotechnology; CubaFil: Lopez, Matilde. Center for Genetic Engineering and Biotechnology; CubaFil: Valenzuela, Carmen. Center for Genetic Engineering and Biotechnology; CubaFil: Reyes, Osvaldo. Center for Genetic Engineering and Biotechnology; CubaFil: López Saura, Pedro A.. Center for Genetic Engineering and Biotechnology; CubaFil: González, Carlos A.. Center for Genetic Engineering and Biotechnology; CubaFil: Diaz, Alina. Center for Genetic Engineering and Biotechnology; CubaFil: Castellanos, Lila. Center for Genetic Engineering and Biotechnology; CubaFil: Sanchez, Aniel. Center for Genetic Engineering and Biotechnology; CubaFil: Betancourt, Lazaro. Center for Genetic Engineering and Biotechnology; CubaFil: Besada, Vladimir. Center for Genetic Engineering and Biotechnology; CubaFil: González, Luis J.. Center for Genetic Engineering and Biotechnology; CubaFil: Garay, Hilda. Center for Genetic Engineering and Biotechnology; CubaFil: Gómez, Roberto. Center for Genetic Engineering and Biotechnology; CubaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes; ArgentinaFil: Alonso, Daniel Fernando. Universidad Nacional de Quilmes; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Perrin, Phillipe. No especifíca;Fil: Renualt, Jean Yves. No especifíca;Fil: Sigman, Hugo. No especifíca;Fil: Herrera, Luis. Center for Genetic Engineering and Biotechnology; CubaFil: Acevedo, Boris. Center for Genetic Engineering and Biotechnology; Cub

Safety and preliminary efficacy data of a novel Casein Kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies

<p>Abstract</p> <p>Background</p> <p>Cervical cancer is now considered the second leading cause of death among women worldwide, and its incidence has reached alarming levels, especially in developing countries. Similarly, high grade squamous intraepithelial lesion (HSIL), the precursor stage for cervical cancer, represents a growing health problem among younger women as the HSIL management regimes that have been developed are not fully effective. From the etiological point of view, the presence of Human Papillomavirus (HPV) has been demonstrated to play a crucial role for developing cervical malignancies, and viral DNA has been detected in 99.7% of cervical tumors at the later stages. CIGB-300 is a novel cyclic synthetic peptide that induces apoptosis in malignant cells and elicits antitumor activity in cancer animal models. CIGB-300 impairs the Casein Kinase (CK2) phosphorylation, by targeting the substrate's phosphoaceptor domain. Based on the perspectives of CIGB-300 to treat cancer, this "first-in-human" study investigated its safety and tolerability in patients with cervical malignancies.</p> <p>Methods</p> <p>Thirty-one women with colposcopically and histologically diagnosed microinvasive or pre-invasive cervical cancer were enrolled in a dose escalating study. CIGB-300 was administered sequentially at 14, 70, 245 and 490 mg by intralesional injections during 5 consecutive days to groups of 7 – 10 patients. Toxicity was monitored daily until fifteen days after the end of treatment, when patients underwent conization. Digital colposcopy, histology, and HPV status were also evaluated.</p> <p>Results</p> <p>No maximum-tolerated dose or dose-limiting toxicity was achieved. The most frequent local events were pain, bleeding, hematoma and erythema at the injection site. The systemic adverse events were rash, facial edema, itching, hot flashes, and localized cramps. 75% of the patients experienced a significant lesion reduction at colposcopy and 19% exhibited full histological regression. HPV DNA was negative in 48% of the previously positive patients. Long term follow-up did not reveal recurrences or adverse events.</p> <p>Conclusion</p> <p>CIGB 300 was safe and well tolerated. This is the first clinical trial where a drug has been used to target the CK2 phosphoaceptor domain providing an early proof-of-principle of a possible clinical benefit.</p

Adjuvant interferon gamma in patients with drug – resistant pulmonary tuberculosis: a pilot study

BACKGROUND: Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments. METHODS: To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 10(6 )IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly. RESULTS: Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed. CONCLUSIONS: These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged

Adjuvant interferon gamma in patients with pulmonary atypical Mycobacteriosis: A randomized, double-blind, placebo-controlled study

<p>Abstract</p> <p>Background</p> <p>High antibiotic resistance is described in atypical Mycobacteriosis, mainly by <it>Mycobacterium avium </it>complex (MAC).</p> <p>Methods</p> <p>A randomized, double-blind, placebo-controlled clinical trial was carried out in two hospitals to evaluate the effect of interferon (IFN) gamma as immunoadjuvant to chemotherapy on patients with atypical mycobacteria lung disease. Patients received placebo or 1 × 10⁶IU recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to daily oral azithromycin, ciprofloxacin, ethambutol and rifampin. Sputum samples collection for direct smear observation and culture as well as clinical and thorax radiography assessments were done during treatment and one year after. Cytokines and oxidative stress determinations were carried out in peripheral blood before and after treatment.</p> <p>Results</p> <p>Eighteen patients were included in the IFN group and 14 received placebo. Groups were homogeneous at entry; average age was 60 years, 75% men, 84% white; MAC infection prevailed (94%). At the end of treatment, 72% of patients treated with IFN gamma were evaluated as complete responders, but only 36% in the placebo group. The difference was maintained during follow-up. A more rapid complete response was obtained in the IFN group (5 months before), with a significantly earlier improvement in respiratory symptoms and pulmonary lesions reduction. Disease-related deaths were 35.7% of the patients in the placebo group and only 11.1% in the IFN group. Three patients in the IFN group normalized their globular sedimentation rate values. Although differences in bacteriology were not significant during the treatment period, some patients in the placebo group converted again to positive during follow-up. Significant increments in serum TGF-beta and advanced oxidation protein products were observed in the placebo group but not among IFN receiving patients. Treatments were well tolerated. Flu-like symptoms predominated in the IFN gamma group. No severe events were recorded.</p> <p>Conclusion</p> <p>These data suggest that IFN gamma is useful and well tolerated as adjuvant therapy in patients with pulmonary atypical Mycobacteriosis, predominantly MAC. Further wider clinical trials are encouraged.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN70900209.</p

Hamstring extensibility differences among elite adolescent and young dancers of different dance styles and non-dancers

Background Hamstrings have been analyzed extensively due to their tendency to shorten and their effect in the lumbo-pelvic dynamics and the sagittal position of the spine in trunk flexion with extended knees positions. It has been demonstrated that practicing a certain sport results in long-term changes in hamstring extensibility. Despite this, adequate extensibility of the hamstring musculature is essential for the dancer’s performance. Several studies have found differences in the extensibility of the hamstrings depending on the dance style, but none have compared ballet, Spanish dance and modern dance. The purpose of the present research was to analyze the differences in hamstring extensibility among professional dance students based on dance style practiced and non-dancers. Methods The sample was comprised of 210 students from the Professional Dance Conservatory (70 for ballet, 70 for Spanish dance and 70 for modern dance) and 70 non-dancers. For the assessment of hamstring extensibility, the angle in the passive and active straight leg raise (PSLR and ASLR, respectively) test, and the scores of the pelvic tilt in sit-and-reach (SR) test and the toe-touch (TT) test were randomly conducted. Results The results showed significant differences for all the tests according to group (p < 0.001). In the PSLR and ASLR test, for both legs, and in the pelvic tilt in the SR test, the ballet dancers showed greater ranges of hamstring extensibility than the modern dancers and Spanish dancers (p ≤ 0.001). In the distance in the SR test and in the pelvic tilt in the TT test, the ballet dancers obtained higher values than the Spanish dancers (p = 0.004 and p = 0.003, respectively). The modern dancers showed higher ranges of hip flexion than the Spanish dancers in the ASLR test for both legs and in the pelvic tilt in the SR test (p from 0.007 to <0.001). Dancers showed significantly higher hamstring extensibility than non-dancers in all the tests (p < 0.001). Conclusions The systematic practice of dance, regardless of the style, seems to lead to high ranges of hamstring extensibility. Ballet dancers have the greatest hamstring extensibility

Tratamiento con eritropoyetina recombinante humana, hipertrofia ventricular izquierda y balance beneficio riesgo en la ERC-3b

Introducción: la anemia renal es frecuente en la enfermedad renal crónica avanzada (ERC 3b-4) y el tratamiento con eritropoyetina recombinante humana la mejora pero aún está a debate cual meta de hemoglobina alcanzar y cuál es su repercusión sobre las funciones cardíacas. Objetivo de este trabajo fue evaluar la mejoría de la anemia tratada con EPOrHu sobre parámetros de la función cardiovascular ventricular izquierda en la ERC 3b-4 y el riesgo beneficio. Material y métodos: ensayo clínico abierto, no controlado, no aleatorizado, multicéntrico, prospectivo, seguimiento durante 56 semanas de seguimiento. Se evalúan los cambios en la Tasa de Filtración Glomerular por la fórmula del MDRD y por ecocardiografía en relación al nivel basal, al final del seguimiento estimada la variación al año de la HVI. Resultados: se observó un incremento significativo del hematócrito en todos los pacientes al final del estudio (n = 33, 0.29 ± 0,02 (V%) versus 0.38 ± 0.03, P (Wilcoxon)= 0.000. Al eco inicial el 90,9% tenían HVI y al final solo el 78.8% con una disminución de 2.2 mm (14 a 11.8 mm), y una correlación inversa lineal entre la HVI y la mejoría de la hemoglobina (r = -0.379; p = 0.030). La progresión del daño renal fue lenta (mL/min). En los pacientes diabéticos de 37.2 ± 8.4 versus 34.7 ± 6.7, (p Wilcoxon=0.119) y en los no diabéticos de 35.1 ± 7.833.6 ± 7.7 (p Wilcoxon= 0.119). El 48.5% de los pacientes presentaron algún tipo de evento adverso, ninguno falleció o comenzó hemodiálisis durante el seguimiento. El Balance Beneficio- Riesgo (EA moderados o graves) estimados por el cálculo del Factor de Bayes fue a favor del Beneficio (FB=1,5). Conclusiones: la corrección de la anemia renal en pacientes con ERC-3b con EPOrHu cubana mejora la HVI sin provocar otros daños Este trabajo apoya el tratamiento de la anemia severa con EPOrHU