Chest Radiograph Screening for Detecting Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru.

The World Health Organization's end TB strategy promotes the use of symptom and chest radiograph screening for tuberculosis (TB) disease. However, asymptomatic early states of TB beyond latent TB infection and active disease can go unrecognized using current screening criteria. We conducted a longitudinal cohort study enrolling household contacts initially free of TB disease and followed them for the occurrence of incident TB over 1 year. Among 1,747 screened contacts, 27 (52%) of the 52 persons in whom TB subsequently developed during follow-up had a baseline abnormal radiograph. Of contacts without TB symptoms, persons with an abnormal radiograph were at higher risk for subsequent TB than persons with an unremarkable radiograph (adjusted hazard ratio 15.62 [95% CI 7.74-31.54]). In young adults, we found a strong linear relationship between radiograph severity and time to TB diagnosis. Our findings suggest chest radiograph screening can extend to detecting early TB states, thereby enabling timely intervention.

First reported double drug-drug interaction in a cancer renal patient under everolimus treatment: therapeutic drug monitoring and review of literature.

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) used in both transplantation and cancer treatment (breast, renal and neuroendocrine). In transplantation, therapeutic drug monitoring (TDM) is recommended due to the potential drug-drug interactions with chronic medications, which can affect everolimus pharmacokinetics. In cancer treatment, everolimus is used at higher doses than in transplantation and without a systematic drug monitoring.We present a case report of a 72-year-old woman with epilepsy history to whom everolimus 10 mg QD was prescribed as third line of treatment for renal cell carcinoma (RCC). The potential drug interactions between everolimus and the patient's chronic medications, carbamazepine and phenytoin, are significant as both are known as strong inducers CYP3A4 metabolism, potentially leading to underexposure to everolimus.TDM of everolimus was recommended by the pharmacist. The literature suggests that a minimum plasma concentration (Cminss) of everolimus over 10 ng/ml is associated with better response to treatment and progression-free survival (PFS). The patient's everolimus dose had to be increased until 10 mg BID, and regular monitoring of everolimus levels showed an increase in Cminss from 3.7 ng/ml to 10.8 ng/ml.This case highlights the importance of checking for potential drug interactions and monitoring everolimus levels in patients on chronic medication, especially those with several inducers or inhibitors of CYP3A4 metabolism. TDM can help to ensure that patients are treated with their optimal dose, which can improve the effectiveness of the treatment or minimize the risk of toxicities.

Locomotion Outcome Improvement in Mice with Glioblastoma Multiforme after Treatment with Anastrozole.

Glioblastoma Multiforme (GBM) is a tumor that infiltrates several brain structures. GBM is associated with abnormal motor activities resulting in impaired mobility, producing a loss of functional motor independence. We used a GBM xenograft implanted in the striatum to analyze the changes in Y (vertical) and X (horizontal) axis displacement of the metatarsus, ankle, and knee. We analyzed the steps dissimilarity factor between control and GBM mice with and without anastrozole. The body weight of the untreated animals decreased compared to treated mice. Anastrozole reduced the malignant cells and decreased GPR30 and ERα receptor expression. In addition, we observed a partial recovery in metatarsus and knee joint displacement (dissimilarity factor). The vertical axis displacement of the GBM+anastrozole group showed a difference in the right metatarsus, right knee, and left ankle compared to the GBM group. In the horizontal axis displacement of the right metatarsus, ankle, and knee, the GBM+anastrozole group exhibited a difference at the last third of the step cycle compared to the GBM group. Thus, anastrozole partially modified joint displacement. The dissimilarity factor and the vertical and horizontal displacements study will be of interest in GBM patients with locomotion alterations. Hindlimb displacement and gait locomotion analysis could be a valuable methodological tool in experimental and clinical studies to help diagnose locomotive deficits related to GBM.

Asociación entre sobrepeso/obesidad y tuberculosis multidrogoresistente / Association between overweight/obesity and multidrug-resistant tuberculosis

Objetivo. Evaluar la asociación entre el sobrepeso/obesidad y la multidrogoresistencia en pacientes con y sin antecedentes de tratamiento para tuberculosis. Materiales y métodos. Estudio transversal realizado a través de un análisis secundario de la base de datos de una cohorte de tuberculosis, que incluyó datos de pruebas antropométricas y pruebas de sensibilidad a drogas en la visita basal de pacientes con y sin tratamiento previo para tuberculosis. Resultados. Se evaluaron 3,734 casos nuevos y 766 con antecedente de haber recibido tratamiento para tuberculosis. El sobrepeso/obesidad no se asoció a la multidrogoresistencia en pacientes con antecedente de tratamiento para tuberculosis, mostrando una razón de prevalencia de 0,97 con un intervalo de confianza al 95% de 0,68-1,38. Conclusiones. El sobrepeso/obesidad no está asociado a la multidrogoresistencia en tuberculosis; siendo el sobrepeso/obesidad un proceso dinámico que puede influir en las relaciones entre el sistema inmune y el sistema metabólico.

Objective. To evaluate the association between overweight/obesity and multidrug resistance in patients with and without a history of tuberculosis treatment. Materials and methods. Cross-sectional study of secondary data from a tuberculosis cohort, which included anthropometric and drug-sensitivity testing data at the baseline visit of patients with and without previous tuberculosis treatment. Results. We evaluated 3,734 new cases and 766 with a history of having received treatment for tuberculosis. Overweight/obesity was not associated with multidrug resistance in patients with a history of tuberculosis treatment, with a prevalence ratio of 0.97 and a 95% confidence interval of 0.68-1.38. Conclusions. Overweight/obesity is not associated with multidrug resistance in tuberculosis. Overweight/obesity is a dynamic process that may influence the relationship between the immune system and the metabolic system.

Sensitivity of Various Case Detection Algorithms for Community-based Tuberculosis Screening.

Using data from 388 people diagnosed with tuberculosis through a community-based screening program in Lima, Peru, we estimated that cough screening followed by sputum smear microscopy would have detected only 23% of cases found using an algorithm of radiographic screening followed by rapid nucleic acid amplification testing and clinical evaluation.

Geospatial analysis of reported activity locations to identify sites for tuberculosis screening.

Mobile screening units can help close tuberculosis case detection gaps. Placing screening units where people at high risk for undiagnosed tuberculosis preferentially spend time could make screening more resource-effective. We conducted a case-control study in Lima, Peru to identify locations where people with tuberculosis were more likely to spend time than community controls. We surveyed participants about activity locations over the past 6 months. We used density-based clustering to assess how patient and control activity locations differed, and logistic regression to compare location-based exposures. We included 109 tuberculosis patients and 79 controls. In density-based clustering analysis, the two groups had similar patterns of living locations, but their work locations clustered in distinct areas. Both groups were similarly likely to use public transit, but patients predominantly used buses and were less likely to use rapid transit (adjusted odds ratio [aOR] 0.31, 95% confidence interval [CI] 0.10-0.96) or taxis (aOR 0.42, 95% CI 0.21-0.85). Patients were more likely to have spent time in prison (aOR 11.55, 95% CI 1.48-90.13). Placing mobile screening units at bus terminals serving locations where tuberculosis patients have worked and within and around prisons could help reach people with undiagnosed tuberculosis.

Proliferation and apoptosis regulation by G protein-coupled estrogen receptor in glioblastoma C6 cells.

Glioblastoma is the most frequent primary tumor in the human brain. Glioblastoma cells express aromatase and the classic estrogen receptors ERα and ERß and can produce estrogens that promote tumor growth. The membrane G protein-coupled estrogen receptor (GPER) also plays a significant role in numerous types of cancer; its participation in glioblastoma tumor development is not entirely known. The present study investigated the effect of the agonists [17ß-estradiol (E2) and G1] and antagonist (G15) of GPER on proliferation and apoptosis of C6 glioblastoma cells. GPER expression was evaluated by immunofluorescence, western blotting and reverse transcription-quantitative PCR. Cell proliferation was determined using Ki67 immunopositivity. Cell viability was examined using the MTT assay and apoptosis using caspase-3 immunostaining and ELISA. C6 cells express GPER, and the immunopositivity increased after exposure to E2, G1, or their combination. GPER protein expression increased after treatment with E2 combined with G1. However, GPER mRNA expression decreased in treated cells compared with control. The percentage of Ki67 immunopositive C6 cells increased under the effect of E2 in combination with G1 or G1 alone. G15 significantly reduced Ki67 immunopositivity. Pearson's correlation analysis revealed a positive relationship between GPER and Ki67 immunopositivity across the study conditions. Additionally, the MTT assay showed a significant reduction in C6 cell viability after G15 treatment, alone or in combination with G1. The exposure to G15 increased the percentage of caspase-3 immunopositivity cells and caspase-3 levels. Pearson's correlation analysis demonstrated a negative correlation between GPER and caspase-3 immunopositivity across the study conditions. Glioblastoma C6 cells express GPER, and this receptor modulates cell proliferation and apoptosis. The GPER agonists E2 and G1 favored cell proliferation; meanwhile, the antagonist G15 reduced cell proliferation, viability and favored apoptosis. Therefore, GPER may be used as a biomarker of glioblastoma and as a target to develop new therapeutic strategies for glioblastoma treatment.

First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Geographic accessibility to health facilities predicts uptake of community-based tuberculosis screening in an urban setting.

OBJECTIVES: Annually, more than 30% of individuals with tuberculosis (TB) remain undiagnosed. We aimed to assess whether geographic accessibility measures can identify neighborhoods that would benefit from TB screening services targeted toward closing the diagnosis gap. METHODS: We used data from a community-based mobile TB screening program in Carabayllo district, Lima, Peru. We constructed four accessibility measures from the geographic center of neighborhoods to health facilities. We used logistic regression to assess the association between these measures and screening uptake in one's residential neighborhood versus elsewhere, with quasi-information criterion values to assess the association. RESULTS: We analyzed the screening locations for 25,000 Carabayllo residents from 49 neighborhoods. Pedestrian walk time was preferable to Euclidean distance or vehicular time in our models. For each additional 12 minutes walking time between the neighborhood and the health facility, the odds of residents using TB screening units located in their neighborhoods increased by 50% (95% CI: 26%-78%). Females had 9% (95% CI: 3%-16%) increased odds versus males of using a screening unit in their own neighborhood. CONCLUSION: Placing mobile TB screening units in neighborhoods with longer pedestrian time to access health facilities could benefit individuals who face more acute access barriers to health care.

A role for community-level socioeconomic indicators in targeting tuberculosis screening interventions.

Tuberculosis screening programs commonly target areas with high case notification rates. However, this may exacerbate disparities by excluding areas that already face barriers to accessing diagnostic services. We compared historic case notification rates, demographic, and socioeconomic indicators as predictors of neighborhood-level tuberculosis screening yield during a mobile screening program in 74 neighborhoods in Lima, Peru. We used logistic regression and Classification and Regression Tree (CART) analysis to identify predictors of screening yield. During February 7, 2019-February 6, 2020, the program screened 29,619 people and diagnosed 147 tuberculosis cases. Historic case notification rate was not associated with screening yield in any analysis. In regression analysis, screening yield decreased as the percent of vehicle ownership increased (odds ratio [OR]: 0.76 per 10% increase in vehicle ownership; 95% confidence interval [CI]: 0.58-0.99). CART analysis identified the percent of blender ownership (≤ 83.1% vs > 83.1%; OR: 1.7; 95% CI: 1.2-2.6) and the percent of TB patients with a prior tuberculosis episode (> 10.6% vs ≤ 10.6%; OR: 3.6; 95% CI: 1.0-12.7) as optimal predictors of screening yield. Overall, socioeconomic indicators were better predictors of tuberculosis screening yield than historic case notification rates. Considering community-level socioeconomic characteristics could help identify high-yield locations for screening interventions.

Effect of 17ß-Estradiol, Progesterone, and Tamoxifen on Neurons Infected with Toxoplasma gondii In Vitro.

Toxoplasma gondii (T. gondii) is the causal agent of toxoplasmosis, which produces damage in the central nervous system (CNS). Toxoplasma-CNS interaction is critical for the development of disease symptoms. T. gondii can form cysts in the CNS; however, neurons are more resistant to this infection than astrocytes. The probable mechanism for neuron resistance is a permanent state of neurons in the interface, avoiding the replication of intracellular parasites. Steroids regulate the formation of Toxoplasma cysts in mice brains. 17ß-estradiol and progesterone also participate in the control of Toxoplasma infection in glial cells in vitro. The aim of this study was to evaluate the effects of 17ß-estradiol, progesterone, and their specific agonists-antagonists on Toxoplasma infection in neurons in vitro. Neurons cultured were pretreated for 48 h with 17ß-estradiol or progesterone at 10, 20, 40, 80, or 160 nM/mL or tamoxifen 1 µM/mL plus 17ß-estradiol at 10, 20, 40, 80, and 160 nM/mL. In other conditions, the neurons were pretreated during 48 h with 4,4',4″-(4-propyl-[1H] pyrozole-1,3,5-triyl) trisphenol or 23-bis(4-hydroxyphenyl) propionitrile at 1 nM/mL, and mifepristone 1 µM/mL plus progesterone at 10, 20, 40, 80, and 160 nM/mL. Neurons were infected with 5000 tachyzoites of the T. gondii strain RH. The effect of 17ß estradiol, progesterone, their agonists, or antagonists on Toxoplasma infection in neurons was evaluated at 24 and 48 h by immunocytochemistry. T. gondii replication was measured with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. 17ß-Estradiol alone or plus tamoxifen reduced infected neurons (50%) compared to the control at 48 h. Progesterone plus estradiol decreased the number of intracellular parasites at 48 h of treatment compared to the control (p < 0.001). 4,4',4″-(4-propyl-[1H] pyrozole-1,3,5-triyl) trisphenol and 23-bis(4-hydroxyphenyl) propionitrile reduced infected neurons at 48 h of treatment significantly compared to the control (p < 0.05 and p < 0.001, respectively). The Toxoplasma infection process was decreased by the effect of 17ß-estradiol alone or combined with tamoxifen or progesterone in neurons in vitro. These results suggest the essential participation of progesterone and estradiol and their classical receptors in the regulation of T. gondii neuron infection.

Toxoplasmosis Is More Frequent in Schizophrenia Patients Than in the General Population in Mexico and Is Not Associated with More Severe Course of Schizophrenia Measured with the Brief Psychiatric Rating Scale.

Toxoplasmosis is a disease, which was discovered in 1908, caused by the intracellular parasite Toxoplasma gondii. T. gondii infects neuronal, glial, and muscle cells, and chronic infections are characterized by the presence of cysts, in the brain and muscle cells, formed by bradyzoites. T. gondii is capable of synthesizing L-DOPA, a precursor of dopamine. Dopamine is a neurotransmitter that is key in the etiology of neuropsychological disorders such as schizophrenia. Previous studies have shown high levels of IgG Toxoplasma antibodies in schizophrenia patients. Many published studies show that the prevalence of toxoplasmosis is higher in schizophrenia patients. In this study, we aimed to identify the prevalence of Toxoplasma infection in patients with schizophrenia and the relationships between, sociodemographic factors and the Brief Psychiatric Rating Scale. A total of 27 schizophrenic patients were included and IgG anti-T. gondii was determined in serum samples by ELISA. The Brief Psychiatric Rating Scale, sociodemographic factors were associated with seropositivity. We found that the prevalence of Toxoplasma antibodies was 51.7%. In the Brief Psychiatric Rating Scale, statistical significant association (p = 0.024) was found in Item 13 which is related to motor retardation, however, the association turned non-significant after of correction for multiple tests or after of analyzed with a logistic regression p = 0.059, odds ratio (OR) = 2.316 with a 95% confidence interval [0.970 to 5.532]. Other association was not found between toxoplasmosis and others factors. The prevalence of toxoplasmosis on our population under study was significantly higher than that reported by general population or other group of Mexican schizophrenia patients.

Unsupervised and scalable low train pathology detection system based on neural networks.

Currently, there exist different technologies applied in the world of medicine dedicated to the detection of health problems such as cancer, heart diseases, etc. However, these technologies are not applied to the detection of lower body pathologies. In this article, a Neural Network (NN)-based system capable of classifying pathologies of the lower train by the way of walking in a non-controlled scenario, with the ability to add new users without retraining the system is presented. All the signals are filtered and processed in order to extract the Gait Cycles (GCs), and those cycles are used as input for the NN. To optimize the network a random search optimization process has been performed. To test the system a database with 51 users and 3 visits per user has been collected. After some improvements, the algorithm can correctly classify the 92% of the cases with 60% of training data. This algorithm is a first approach of creating a system to make a first stage pathology detection without the requirement to move to a specific place.

Closing delivery gaps in the treatment of tuberculosis infection: Lessons from implementation research in Peru.

BACKGROUND: Targeted testing and treatment of TB infection to prevent disease is a pillar of TB elimination. Despite recent global commitments to greatly expand access to preventive treatment for TB infection, there remains a lack of research on how best to expand preventive treatment programs in settings with high TB burdens. METHODS: We conducted implementation research in Lima, Peru, around a multifaceted intervention to deliver TB preventive treatment to close contacts of all ages, health care workers, and people in congregate settings. Key interventions included use of the interferon gamma release assay (IGRA), specialist support for generalist physicians at primary-level health facilities, and treatment support by community health workers. We applied a convergent mixed methods approach to evaluate feasibility and acceptability based on a care cascade framework. FINDINGS: During April 2019-January 2020, we enrolled 1,002 household contacts, 148 non-household contacts, 107 residents and staff of congregate settings, and 357 health care workers. Cumulative completion of the TB preventive care cascade was 34% for contacts <5 years old, 28% for contacts 5-19 years old, 18% for contacts ≥20 years old, 0% for people in congregate settings, and 4% of health care workers. IGRA testing was acceptable to adults exposed to TB. Preventive treatment was acceptable to contacts, but less acceptable to physicians, who frequently had doubts about prescribing preventive treatment for adults. Community-based treatment support was both acceptable and feasible, and periodic home-visits or calls were identified as facilitators of adherence. CONCLUSIONS: We attempted to close the gap in TB preventive treatment in Peru by expanding preventive services to adult contacts and other risk groups. While suboptimal, care cascade completion for adult contacts was consistent with what has been observed in high-income settings. The major losses in the care cascade occurred in completing evaluations and having doctors prescribe preventive treatment.

Early progression to active tuberculosis is a highly heritable trait driven by 3q23 in Peruvians.

Of the 1.8 billion people worldwide infected with Mycobacterium tuberculosis, 5-15% will develop active tuberculosis (TB). Approximately half will progress to active TB within the first 18 months after infection, presumably because they fail to mount an effective initial immune response. Here, in a genome-wide genetic study of early TB progression, we genotype 4002 active TB cases and their household contacts in Peru. We quantify genetic heritability ([Formula: see text]) of early TB progression to be 21.2% (standard error 0.08). This suggests TB progression has a strong genetic basis, and is comparable to traits with well-established genetic bases. We identify a novel association between early TB progression and variants located in a putative enhancer region on chromosome 3q23 (rs73226617, OR = 1.18; P = 3.93 × 10-8). With in silico and in vitro analyses we identify rs73226617 or rs148722713 as the likely functional variant and ATP1B3 as a potential causal target gene with monocyte specific function.

Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.

IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions. HAP binds specifically to IL-17A and inhibits the interaction of the cytokine with its receptor, IL-17RA. Tested in primary human cells, HAP blocked the production of multiple inflammatory cytokines. Crystal structure studies revealed that two HAP molecules bind to one IL-17A dimer symmetrically. The N-terminal portions of HAP form a ß-strand that inserts between two IL-17A monomers while the C-terminal section forms an α helix that directly blocks IL-17RA from binding to the same region of IL-17A. This mode of inhibition suggests opportunities for developing peptide antagonists against this challenging target.

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve.

OBJECT: Transection of peripheral nerves produces loss of sensory and/or motor function. After complete nerve cutting, the distal and proximal segment ends retract, but if both ends are bridged with unaltered chitosan, progesterone-impregnated chitosan, or silicone tubes, an axonal repair process begins. Progesterone promotes nerve repair and has neuroprotective effects thwarting regulation of neuron survival, inflammation, and edema. It also modulates aberrant axonal sprouting and demyelination. The authors compared the efficacy of nerve recovery after implantation of progesterone-loaded chitosan, unaltered chitosan, or silicone tubes after sciatic nerve transection in rats. METHODS: After surgical removal of a 5-mm segment of the proximal sciatic nerve, rats were implanted with progesterone-loaded chitosan, unaltered chitosan, or silicone tubes in the transected nerve for evaluating progesterone and chitosan effects on sciatic nerve repair and ipsilateral hindlimb kinematic function, as well as on gastrocnemius electro-myographic responses. In some experiments, tube implantation was performed 90 minutes after nerve transection. RESULTS: At 90 days after sciatic nerve transection and tube implantation, rats with progesterone-loaded chitosan tubes showed knee angular displacement recovery and better outcomes for step length, velocity of locomotion, and normal hindlimb raising above the ground. In contrast, rats with chitosan-only tubes showed reduced normal raising and pendulum-like hindlimb movements. Aberrant fibers coming from the tibial nerve innervated the gastrocnemius muscle, producing electromyographic responses. Electrical responses in the gastrocnemius muscle produced by sciatic nerve stimulation occurred only when the distal nerve segment was stimulated; they were absent when the proximal or intratubular segment was stimulated. A clear sciatic nerve morphology with some myelinated fiber fascicles appeared in the tube section in rats with progesterone-impregnated chitosan tubes. Some gastrocnemius efferent fibers were partially repaired 90 days after nerve resection. The better outcome in knee angle displacement may be partially attributable to the aberrant neuromuscular synaptic effects, since nerve conduction in the gastrocnemius muscle could be blocked in the progesterone-impregnated chitosan tubes. In addition, in the region of the gap produced by the nerve resection, the number of axons and amount of myelination were reduced in the sciatic nerve implanted with chitosan, progesterone-loaded chitosan, and silicone tubes. At 180 days after sciatic nerve sectioning, the knee kinematic function recovered to a level observed in control rats of a similar age. In rats with progesterone-loaded chitosan tubes, stimulation of the proximal and intratubular sciatic nerve segments produced an electromyographic response. The axon morphology of the proximal and intratubular segments of the sciatic nerve resembled that of the contralateral nontransected nerve. CONCLUSIONS: Progesterone-impregnated chitosan tubes produced aberrant innervation of the gastrocnemius muscle, which allowed partial recovery of gait locomotion and could be adequate for reinnervating synergistic denervated muscles while a parent innervation is reestablished. Hindlimb kinematic parameters differed between younger (those at 90 days) and older (those at 180 days) rats.

Transient transfection of human CDNF gene reduces the 6-hydroxydopamine-induced neuroinflammation in the rat substantia nigra.

BACKGROUND: The anti-inflammatory effect of the cerebral dopamine neurotrophic factor (CDNF) was shown recently in primary glial cell cultures, yet such effect remains unknown both in vivo and in 6-hydroxydopamine (6-OHDA) models of Parkinson's disease (PD). We addressed this issue by performing an intranigral transfection of the human CDNF (hCDNF) gene in the critical period of inflammation after a single intrastriatal 6-OHDA injection in the rat. METHODS: At day 15 after lesion, the plasmids p3xNBRE-hCDNF or p3xNBRE-EGFP, coding for enhanced green florescent protein (EGFP), were transfected into the rat substantia nigra (SN) using neurotensin (NTS)-polyplex. At day 15 post-transfection, we measured nitrite and lipoperoxide levels in the SN. We used ELISA to quantify the levels of TNF-α, IL-1ß, IL-6, endogenous rat CDNF (rCDNF) and hCDNF. We also used qRT-PCR to measure rCDNF and hCDNF transcripts, and immunofluorescence assays to evaluate iNOS, CDNF and glial cells (microglia, astrocytes and Neuron/Glial type 2 (NG2) cells). Intact SNs were additional controls. RESULTS: In the SN, 6-OHDA triggered nitrosative stress, increased inflammatory cytokines levels, and activated the multipotent progenitor NG2 cells, which convert into astrocytes to produce rCDNF. In comparison with the hemiparkinsonian rats that were transfected with the EGFP gene or without transfection, 6-OHDA treatment and p3xNBRE-hCDNF transfection increased the conversion of NG2 cells into astrocytes resulting in 4-fold increase in the rCDNF protein levels. The overexpressed CDNF reduced nitrosative stress, glial markers and IL-6 levels in the SN, but not TNF-α and IL-1ß levels. CONCLUSION: Our results show the anti-inflammatory effect of CDNF in a 6-OHDA rat of Parkinson's disease. Our results also suggest the possible participation of TNF-α, IL-1ß and IL-6 in rCDNF production by astrocytes, supporting their anti-inflammatory role.

A novel Bcr-Abl-mTOR-eIF4A axis regulates IRES-mediated translation of LEF-1.

Internal ribosome entry sites (IRESs) in cellular mRNAs direct expression of growth-promoting factors through an alternative translation mechanism that has yet to be fully defined. Lymphoid enhancer factor-1 (LEF-1), a Wnt-mediating transcription factor important for cell survival and metastasis in cancer, is produced via IRES-directed translation, and its mRNA is frequently upregulated in malignancies, including chronic myeloid leukaemia (CML). In this study, we determined that LEF1 expression is regulated by Bcr-Abl, the oncogenic protein that drives haematopoietic cell transformation to CML. We have previously shown that the LEF1 5' untranslated region recruits a complex of proteins to its IRES, including the translation initiation factor eIF4A. In this report, we use two small molecule inhibitors, PP242 (dual mTOR (mammalian target of rapamycin) kinase inhibitor) and hippuristanol (eIF4A inhibitor), to define IRES regulation via a Bcr-Abl-mTOR-eIF4A axis in CML cell lines and primary patient leukaemias. We found that LEF1 and other IRESs are uniquely sensitive to the activities of Bcr-Abl/mTOR. Most notably, we discovered that eIF4A, an RNA helicase, elicits potent non-canonical effects on the LEF1 IRES. Hippuristanol inhibition of eIF4A stalls translation of IRES mRNA and triggers dissociation from polyribosomes. We propose that a combination drug strategy which targets mTOR and IRES-driven translation disrupts key factors that contribute to growth and proliferation in CML.

The role of hormones on Toxoplasma gondii infection: a systematic review.

BACKGROUND: Toxoplasma gondii is the causal agent of toxoplasmosis in which one third of the world's population has been infected. In pregnant women, it may cause abortion and severe damage to the fetal central nervous system. During pregnancy, the prevalence of toxoplasmosis increases throughout the second and third quarter of gestation, simultaneously progesterone and 17ß-estradiol also increase. Thus, it has been suggested that these hormones can aggravate or reduce parasite reproduction. The aim of this study was reviewing the relationship between hormones and infection caused by T. gondii in several experimental animal models and humans, focused mainly on: (a) congenital transmission, (b) parasite reproduction, (c) strain virulence, (d) levels of hormone in host induced by T. gondii infection, and (e) participation of hormone receptors in T. gondii infection. Are the hormones specific modulators of T. gondii infection? A systematic review methodology was used to consult several databases (Pub Med, Lilacs, Medline, Science direct, Scielo, Ebsco, Sprinker, Wiley, and Google Scholar) dated from September, 2013 to March, 2014. RESULTS: Thirty studies were included; eight studies in humans and 22 in animals and cell cultures. In the human studies, the most studied hormones were testosterone, progesterone, prolactin, and 17ß-estradiol. Type I (RH and BK) and Type II (Prugniaud, SC, ME49, T45, P78, and T38) were the most frequent experimental strains. CONCLUSIONS: Thirty-five years have passed since the first studies regarding T. gondii infection and its relationship with hormones. This systematic review suggests that hormones modulate T. gondii infection in different animal models. However, given that data were not comparable, further studies are required to determine the mechanism of hormone action in the T. gondii infectious process.