Glia-Motoneuron dialogue in ALS onset and progression in SOD1G93A-mice model

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the pro-gressive loss of motoneurons (MN). Increasing evidence points glial cells as key players for ALS onset and progression. Indeed, MN-glia signalling pathways involving either neuroprotection or inflammation are likely to be altered in ALS. We aimed to study the molecules related with glial function and/or reactivity by evaluating glial markers and hemichannels, mainly present in astrocytes. We also studied molecules involved in mi-croglia-MN dialogue (CXCR3/CCL21; CX3CR1/CX3CL1; MFG-E8), as well as proliferation (Ki-67) and inflammatory-related molecules (TLR2/4, NLRP3; IL-18) and alarming/calming signals (HMGB1/autotaxin). We used lumbar spinal cord (SC) homogenates from mice expressing a mutant human-SOD1 protein (mSOD1) at presymptomatic and late-symptomatic ALS stages. SJL (WT) mice at same ages were used as controls. We observed decreased expression of genes associated with astrocytic (GFAP and S100B) and microglial (CD11b) markers in mSOD1 at the presymptomatic phase, as well as diminished levels of gap junction components pannexin1 and connexin43 and expression of Ki-67 and decreased autotax-in. In addition, microglial-MN communication was negatively affected in mSOD1 mice as well as in-flammatory response. Interestingly, we observed astrocytic (S100B) and microglial (CD11b) reactivity, increased proliferation (Ki-67) and increased autotaxin expression in symptomatic mSOD1 mice. In-creased MN-microglial dialogue (CXCR3/CCL21; CX3CR1/CX3CL1; MFG-E8) and hemichannel activ-ity, namely connexin43 and pannexin1, were also observed in mSOD1 at the symptomatic phase, along with an elevated inflammatory response as indicated by increased levels of HMGB1 and NLRP3. Our results suggest that decreased autotaxin expression is a feature of the presymptomatic stage, and precede the network of pro-inflammatory-related symptomatic determinants, including HMGB1, CCL21, CX3CL1, and NLRP3. The identification of the molecules and signaling pathways that are dif-ferentially activated along ALS progression will contribute for a better design of therapeutic strategies for disease onset and progression.

Evaluation of laboratory markers of progression of HIV disease to death

INTRODUCTION: One of the important current problems in HIV/AIDS infection is the establishment of epidemiological and laboratorial prognostic parameters during patient follow-up. This study aimed at analyzing the evolution of laboratory tests: CD4 lymphocyte count, viral load, hemoglobin (Hb), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and the epidemiological variables sex and age as prognostic factors for survival in progression to death among AIDS patients. METHODS: A retrospective study was conducted using analysis of medical records, and prospective 24-month follow-up of patients with HIV/ AIDS attended at the President Vargas Hospital Outpatient Clinic, a reference center in HIV/ AIDS attendance in the State of Maranhão, Brazil. The study analyzed patients aged 10 to 60 years old, who manifested AIDS and who were not using antiretroviral therapy or had used it for less than 5 years. The Chi-square test was used for statistical analysis. RESULTS: The sample included 100 patients - 57 were current outpatients, and 43 had died. The variables viral load (p=0.726), ALT (p=0.314), sex (p=0.687), and age (p=0.742) were analyzed, and no evidence of association between them and worst prognosis was observed. CONCLUSIONS: A significant relation was verified between low Hb levels (p=0.000) and CD4 (p=0.000) and shorter survival.

Liver fibrosis progression in HIV/hepatitis C virus coinfected patients with normal aminotransferases levels

INTRODUCTION: Approximately 30% of hepatitis C virus (HCV) monoinfected patients present persistently normal alanine aminotransferase (ALT) levels. Most of these patients have a slow progression of liver fibrosis. Studies have demonstrated the rate of liver fibrosis progression in hepatitis C virus-human immunodeficiency virus (HCV-HIV) coinfected patients is faster than in patients infected only by HCV. Few studies have evaluated the histological features of chronic hepatitis C in HIV-infected patients with normal ALT levels. METHODS: HCV-HIV coinfected patients (HCV-RNA and anti-HIV positive) with known time of HCV infection (intravenous drugs users) were selected. Patients with hepatitis B surface antigen (HBsAg) positive or hepatitis C treatment before liver biopsy were excluded. Patients were considered to have a normal ALT levels if they had at least 3 normal determinations in the previous 6 months prior to liver biopsy. All patients were submitted to liver biopsy and METAVIR scale was used. RESULTS: Of 50 studied patients 40 (80%) were males. All patients were treated with antiretroviral therapy. The ALT levels were normal in 13 (26%) patients. HCV-HIV co-infected patients with normal ALT levels had presented means of the liver fibrosis stages (0.77±0.44 versus 1.86±1.38; p<0.001) periportal inflammatory activity (0.62±0.77 versus 2.24±1.35; p<0.001) and liver fibrosis progression rate (0.058±0.043 fibrosis unit/year versus 0.118±0.102 fibrosis unit/year) significantly lower as compared to those with elevated ALT. CONCLUSIONS: HCV-HIV coinfected patients with persistently normal ALTs showed slower progression of liver fibrosis. In these patients the development of liver cirrhosis is improbable.

Evaluation of the cytokine mannose-binding lectin as a mediator of periportal fibrosis progression in patients with schistosomiasis

INTRODUCTION : We hypothesized higher mannose-binding lectin level and classic factors (i.e., age, sex, alcohol consumption, exposure, and specific treatment) are associated with the severity of periportal fibrosis in schistosomiasis. METHODS : This cross-sectional study involved 79 patients infected with Schistosoma mansoni with severe or mild/moderate periportal fibrosis. Serum concentrations of mannose-binding lectin were obtained by enzyme-linked immunosorbent assay (ELISA). RESULTS: Higher serum level of mannose-binding lectin was significantly associated with advanced periportal fibrosis. CONCLUSIONS: Mannose-binding lectin may contribute to liver pathology in schistosomiasis and may represent a risk factor for advanced periportal fibrosis in the Brazilian population studied.

The absence of the human platelet antigen polymorphism effect on fibrosis progression in human immunodeficiency virus-1/hepatitis C virus coinfected patients

AbstractINTRODUCTION:Hepatic fibrosis progression in patients with chronic hepatitis C virus infections has been associated with viral and host factors, including genetic polymorphisms. Human platelet antigen polymorphisms are associated with the rapid development of fibrosis in HCV-monoinfected patients. This study aimed to determine whether such an association exists in human immunodeficiency virus-1/hepatitis C virus-coinfected patients.METHODS:Genomic deoxyribonucleic acid from 36 human immunodeficiency virus-1/hepatitis C virus-coinfected patients was genotyped to determine the presence of human platelet antigens-1, -3, or -5 polymorphisms. Fibrosis progression was evaluated using the Metavir scoring system, and the patients were assigned to two groups, namely, G1 that comprised patients with F1, portal fibrosis without septa, or F2, few septa (n = 23) and G2 that comprised patients with F3, numerous septa, or F4, cirrhosis (n = 13). Fisher's exact test was utilized to determine possible associations between the human platelet antigen polymorphisms and fibrosis progression.RESULTS:There were no deviations from the Hardy-Weinberg equilibrium in the human platelet antigen systems evaluated. Statistically significant differences were not observed between G1 and G2 with respect to the distributions of the allelic and genotypic frequencies of the human platelet antigen systems.CONCLUSION:The greater stimulation of hepatic stellate cells by the human immunodeficiency virus and, consequently, the increased expression of transforming growth factor beta can offset the effect of human platelet antigen polymorphism on the progression of fibrosis in patients coinfected with the human immunodeficiency virus-1 and the hepatitis C virus.

Progression of the load of waterborne and intestinal parasitic diseases in the State of Amazonas

In the State of Amazonas, Brazil, urban expansion together with precarious basic sanitation conditions and human settlement on river banks has contributed to the persistence of waterborne and intestinal parasitic diseases. Time series of the recorded cases of cholera, typhoid fever, hepatitis A and leptospirosis are described, using data from different levels of the surveillance systems. The sources for intestinal parasitosis prevalence data (non-compulsory reporting in Brazil) were Medical Literature Analysis and Retrieval System Online (MEDLINE), Literatura Latino-Americana (LILACS) and the annals of major scientific meetings. Relevant papers and abstracts in all languages were accessed by two independent reviewers. The references cited by each relevant paper were scrutinized to locate additional papers. Despite its initial dissemination across the entire State of Amazonas, cholera was controlled in 1998. The magnitude of typhoid fever has decreased; however, a pattern characterized by eventual outbreaks still remains. Leptospirosis is an increasing cause of concern in association with the annual floods. The overall prevalence of intestinal parasites is high regardless of the municipality and the characteristics of areas and populations. The incidence of hepatitis A has decreased over the past decade. A comparison of older and recent surveys shows that the prevalence of intestinal parasitic diseases has remained constant. The load of waterborne and intestinal parasitic diseases ranks high among the health problems present in the State of Amazonas. Interventions aiming at basic sanitation and vaccination for hepatitis A were formulated and implemented, but assessment of their effectiveness in the targeted populations is still needed.

Correlation between osteochondral changes depicted by magnetic resonance imaging and disease progression

PURPOSE: To determine the consequences of the chronic use of systemic corticosteroids in children with juvenile rheumatoid arthritis by means of evaluating osteochondral effects depicted by magnetic resonance imaging. PATIENTS AND METHODS: We reviewed clinical and magnetic resonance imaging findings in 69 children (72 knees) with juvenile rheumatoid arthritis. Two groups were studied. Group I: 34 (49.3%) children had previous or current use of systemic corticotherapy (22 girls; 12 boys; mean age: 11.3 years; mean disease duration: 5.9 years; mean corticotherapy duration: 2.9 years; mean cumulative dose of previous corticosteroids: 5000 mg); Group II: 35 (50.7%) children had no previous use of corticosteroids (27 girls; 8 boys; mean age: 11.7 years; mean disease duration: 5.3 years). The groups were compared statistically. RESULTS: In the group that had received corticotherapy (Group I), osteochondral abnormalities were significantly correlated to long-standing disease (>3.5 years; p<0.001). This correlation was not found in the group that had no previous history of corticotherapy (Group II). No correlations were established between median dose of corticosteroids and magnetic resonance imaging findings. CONCLUSION: It is important to further investigate the long-term intra-articular effects of systemic corticotherapy to ensure that the side effects of the aggressive therapy will not be more harmful for the joints than the symptoms suffered over the natural course of the disease.

The reasons behind the progression in PISA scores: An education production function approach using semi-parametric techniques

Research Masters

Stabilization in early adult-onset myopia with corneal refractive therapy

Purpose: To describe the stabilization of early adult-onset myopia in three university students after initiating orthokeratology treatment with corneal refractive therapy contact lenses. Methods: Three Caucasian early adult-onset progressing myopic subjects (1 male, 2 females) were fitted with corneal refractive therapy lenses to correct myopia between ?1.50 and ?2.50 D of sphere using Paragon CRT (Paragon Vision Sciences, Mesa, AZ)lenses for overnight orthokeratology. The pre-treatment refractive history from 2005 as well as refraction and axial length after treatment onset are reported over a period of 3 years between December 2009 and January 2013 with an additional year of follow-up after treatment discontinuation (January–December 2013). The peripheral refractive patterns and topographic changes are also reported individually. Results: Treatment was successful in all three subjects achieving uncorrected visual acuity of 20/20 or better monocularly. During a period of 3 years of follow-up the subjects did not experience progression in their refractive error, nor in their axial length (measured during the last 2 years of treatment and 1 year after discontinuation). Furthermore, the subjects recovered to their baseline refraction and did not progressed further over the following year after lens wear discontinuation. Conclusions: We cannot attribute a causative effect to the orthokeratology treatment alone as underlying mechanism for myopia stabilization in this 3 patients. However, the present report points to the possibility of stabilization of early adult-onset myopia progression in young adults using corneal refractive therapy treatment.

Urothelial bladder cancer progression: lessons learned from the bench

Urothelial bladder carcinoma (UBC) is an intricate malignancy with a variable natural history and clinical behavior. Despite developments in diagnosis/prognosis refinement and treatment modalities, the recurrence rate is high, and progression from non-muscle to muscle invasive UBC commonly leads to metastasis. Moreover, patients with muscle-invasive or extra-vesical disease often fail the standard chemotherapy treatment, and overall survival rates are poor. Thus, UBC remains a challenge in the oncology field, representing an ideal candidate for research on biomarkers that could identify patients at increased risk of recurrence, progression, and chemo-refractoriness. However, progress toward personalized medicine has been hampered by the unique genetic complexity of UBC. Recent genome-wide expression and sequencing studies have brought new insights into its molecular features, pathogenesis and clinical diversity, revealing a landscape where classical pathology is intersected by the novel and heterogeneous molecular groups. Hence, it seems plausible to postulate that only an integrated signature of prognostic/predictive biomarkers inherent in different cancer hallmarks will reach clinical validation. In this review, we have summarized ours and others' research into novel putative biomarkers of progression and chemoresistance that encompass several hallmarks of cancer: tumor neovascularization, invasion and metastasis, and energy metabolism reprogramming of the tumor microenvironment.

A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for Monocarboxylate Transporters as metabolic targets for therapy.

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia-inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors.

Transmission and progression to disease of Mycobacterium tuberculosis phylogenetic lineages in The Netherlands

The aim of this study was to determine if mycobacterial lineages affect infection risk, clustering, and disease progression among Mycobacterium tuberculosis cases in The Netherlands. Multivariate negative binomial regression models adjusted for patient-related factors and stratified by patient ethnicity were used to determine the association between phylogenetic lineages and infectivity (mean number of positive contacts around each patient) and clustering (as defined by number of secondary cases within 2 years after diagnosis of an index case sharing the same fingerprint) indices. An estimate of progression to disease by each risk factor was calculated as a bootstrapped risk ratio of the clustering index by the infectivity index. Compared to the Euro-American reference, Mycobacterium africanum showed significantly lower infectivity and clustering indices in the foreign-born population, while Mycobacterium bovis showed significantly lower infectivity and clustering indices in the native population. Significantly lower infectivity was also observed for the East African Indian lineage in the foreign-born population. Smear positivity was a significant risk factor for increased infectivity and increased clustering. Estimates of progression to disease were significantly associated with age, sputum-smear status, and behavioral risk factors, such as alcohol and intravenous drug abuse, but not with phylogenetic lineages. In conclusion, we found evidence of a bacteriological factor influencing indicators of a strain's transmissibility, namely, a decreased ability to infect and a lower clustering index in ancient phylogenetic lineages compared to their modern counterparts. Confirmation of these findings via follow-up studies using tuberculin skin test conversion data should have important implications on M. tuberculosis control efforts.

Real-time monitoring of progression towards renal failure in primary care patients

First published online: December 16, 2014.

Rol de la infección bacteriana en el desarrollo y progresión del cáncer prostático. Influence of bacterial infection in the development and progression of prostatitic cancer.

En la patogénesis del cáncer, factores microambientales como la inflamación están estrechamente vinculados al desarrollo y crecimiento tumoral, sustentando la clásica hipótesis de Virchow del origen del cáncer en sitios de inflamación crónica, la cual incitaría a carcinogénesis por múltiples factores. Estudios previos en este laboratorio evidenciaron en un modelo de prostatitis bacteriana agudo con E. coli, profundos cambios estromales semejantes al "estroma reactivo", con predominio de miofibroblasto, que se genera en el cáncer. En correlación, existe abundante evidencia obtenida en modelos experimentales animales confirmando que el microambiente estromal en el cual se desarrollan los tumores epiteliales influencia profundamente la progresión tumoral. El rol protagónico del estroma del huésped en el crecimiento neoplásico, también se ha demostrado inoculando la misma línea tumoral en diferentes tejidos y analizando su comportamiento en comparación con su implantación en el sitio anatómico original del tumor (implante ortotópico); otro factor clave en la repuesta del huésped al tumor está dado por el infiltrado de células inmunes que puede favorecer o limitar el crecimiento tumoral de acuerdo al perfil de citoquinas que secreten. Teniendo en cuenta estos antecedentes, este proyecto tiene como Objetivo General estudiar la influencia de la infección bacteriana crónica en la inducción y evolución del cáncer prostático. Para ello trabajaremos in vivo con dos formas de formas de Tumores Prostáticos, un Tumor Inducido por combinación del carcinógeno N-methyl-N-nitrosourea (MNU) y testosterona; el segundo mediante Transplante Ortotópico de células tumorales prostáticas MAT-LU. En ambos modelos se inducirá previamente una prostatitis bacteriana, a fin de estudiar los efectos de la prostatitis en la inducción del tumor en el primer modelo, y en la implantación de las células tumorales en el segundo. También se inducirá prostatitis después de establecido el tumor por ambos procedimientos, a fin de determinar si la prostatitis bacteriana modula la progresión neoplásica. Finalmente, proponemos un modelo in vitro que permita estudiar la interacción tumor/estroma separado de la influencia del sistema inmune. A tal fin se utilizarán co-cultivos combinando células tumorales con estromales modificadas de diferente modo. La Inducción de Tumores Prostáticos se realizará en ratas de la cepa Wistar adultas, en las cuales se inducirán lesiones displásicas y neoplásicas siguiendo protocolos de carcinogénesis prostática por MNU, para lo cual es necesario el tratamiento previo con acetato de ciprosterona y propionato de testosterona, seguido por administración crónica de testosterona. Los estudios con Transplante Ortotópico de células tumorales se realizarán en ratas Copenhagen. La influencia de la infección bacteriana en el desarrollo tumoral será investigada inyectando E. coli intraprostáticamente: Se realizará Análisis Macroscópico, de Parámetros Morfológicos de las lesiones tumorales, grado de malignidad, extensión e invasión de las lesiones de acuerdo a consensos internacionales, y Bioquímicos mediante análisis de la expresión, por IHQ y WB, de fosfatasa ácida, citoqueratina 8, Prostatic Binding Protein, PTEN (gen supresor tumoral) y el receptor de Andrógenos, todos parámetros de actividad y de transformación celular. También se evaluará apoptosis por TUNEL y proliferación celular. Los cambios del compartimiento estromal en respuesta al implante tumoral y la influencia de la inflamación bacteriana se evaluarán mediante análisis morfológico e inmunocitoquímico, caracterizando el fenotipo de las poblaciones celulares con a-actina, vimentina, calponina y tenascina. Se espera que los resultados aporten evidencias acerca de las interacciones bidireccionales entre células neoplásicas prostáticas y su entorno estromal, que en un futuro puedan servir como base para establecr estrategias para prevenir y/o modificar el crecimiento neoplásico.