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Trypanosoma cruzi is a flagellate protozoan pathogen that causes Chagas disease. Currently there is no preventive treatment and the efficiency of the two drugs available is limited to the acute phase. Therefore, there is an unmet need for innovative tools to block transmission in endemic areas. In this study, we engineered a novel recombinant molecule able to adhere to the T. cruzi surface, termed scFv-10D8, that consists of a single-chain variable fragment (scFv) derived from mAb-10D8 that targets gp35/50. The synthetic gene encoding scFv-10D8 was cloned and fused to a 6×His tag and expressed in a prokaryotic expression system. Total periplasmic or 6xHis tag affinity-purified fractions of scFv-10D8 retained the capacity to bind to gp35/50, as shown by Western blot analyses. Pre-incubation of metacyclic trypomastigotes with scFv-10D8 showed a remarkable reduction in cell invasion capacity. Our results suggest that scFv-10D8 can be used in a paratransgenic approach to target parasites in insect vectors, avoiding dissemination of infective forms. Such advances in the development of this functional molecule will surely prompt the improvement of alternative strategies to control Chagas disease by targeting mammalian host stages., Competing Interests: The authors have declared that no competing interests exist.

The goal of this study was to document current clinical practice and report patient outcomes in presurgical language functional MRI (fMRI) for epilepsy surgery. Epilepsy surgical programs worldwide were surveyed as to the utility, implementation, and efficacy of language fMRI in the clinic; 82 programs responded. Respondents were predominantly US (61%) academic programs (85%), and evaluated adults (44%), adults and children (40%), or children only (16%). Nearly all (96%) reported using language fMRI. Surprisingly, fMRI is used to guide surgical margins (44% of programs) as well as lateralize language (100%). Sites using fMRI for localization most often use a distance margin around activation of 10mm. While considered useful, 56% of programs reported at least one instance of disagreement with other measures. Direct brain stimulation typically confirmed fMRI findings (74%) when guiding margins, but instances of unpredicted decline were reported by 17% of programs and 54% reported unexpected preservation of function. Programs reporting unexpected decline did not clearly differ from those which did not. Clinicians using fMRI to guide surgical margins do not typically map known language-critical areas beyond Broca's and Wernicke's. This initial data shows many clinical teams are confident using fMRI not only for language lateralization but also to guide surgical margins. Reported cases of unexpected language preservation when fMRI activation is resected, and cases of language decline when it is not, emphasize a critical need for further validation. Comprehensive studies comparing commonly-used fMRI paradigms to predict stimulation mapping and post-surgical language decline remain of high importance., (© 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

With the number of deaths due to stroke decreasing, more individuals are forced to live with crippling disability resulting from the stroke. To date, no therapeutics exist after the first 4.5 h after the stroke onset, aside from rest and physical therapy. Following stroke, a large influx of astrocytes and microglia releasing proinflammatory cytokines leads to dramatic inflammation and glial scar formation, affecting brain tissue's ability to repair itself. Pathological conditions, such as a stroke, trigger neural progenitor cells (NPCs) proliferation and migration toward the damaged site. However, these progenitors are often found far from the cavity or the peri-infarct tissue. Poststroke tissue remodeling results in a compartmentalized cavity that can directly accept a therapeutic material injection. Here, this paper shows that the injection of a porous hyaluronic acid hydrogel into the stroke cavity significantly reduces the inflammatory response following stroke while increasing peri-infarct vascularization compared to nonporous hydrogel controls and stroke only controls. In addition, it is shown that the injection of this material impacts NPCs proliferation and migration at the subventricular zone niche and results, for the first time, in NPC migration into the stroke site., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The healthcare financing reforms initiated by the Government of Georgia in 2007 have positively affected inpatient service utilisation and enhanced financial protection, especially for the poor, but they have failed to facilitate outpatient service use among chronic patients. Non-communicable diseases significantly affect Georgia's ageing population. Consequently, in this paper, we look at the evidence emerging from determinants analysis of outpatient service utilisation and if the finding can help identify possible policy choices in Georgia, especially regarding benefit package design for individuals with chronic conditions., Methods: We used Andersen's behavioural model of health service utilisation to identify the critical determinants that affect outpatient service use. A multinomial logistic regression was carried out with complex survey design using the data from two nationally representative cross-sectional population-based health utilisation and expenditure surveys conducted in Georgia in 2007 and 2010, which allowed us to assess the relationship between the determinants and outpatient service use., Results: The study revealed the determinants that significantly impede outpatient service use. Low income, 45- to 64-year-old Georgian males with low educational attainment and suffering from a chronic health problem have the lowest odds for service use compared to the rest of the population., Conclusions: Using Andersen's behavioural model and assessing the determinants of outpatient service use has the potential to inform possible policy responses, especially those driving services use among chronic patients. The possible policy responses include reducing financial access barriers with the help of public subsidies for sub-groups of the population with the lowest access to care; focusing/expanding state-funded benefits for the most prevalent chronic conditions, which are responsible for the greatest disease burden; or supporting chronic disease management programs for the most prevalent chronic diseases and for special age groups aimed at the timely detection, education and management of chronic patients.

Stem cell therapies have shown promise in promoting recovery in stroke but have been limited by poor cell survival and differentiation. We have developed a hyaluronic acid (HA)-based self-polymerizing hydrogel that serves as a platform for adhesion of structural motifs and a depot release for growth factors to promote transplant stem cell survival and differentiation. We took an iterative approach in optimizing the complex combination of mechanical, biochemical and biological properties of an HA cell scaffold. First, we optimized stiffness for a minimal reaction of adjacent brain to the transplant. Next hydrogel crosslinkers sensitive to matrix metalloproteinases (MMP) were incorporated as they promoted vascularization. Finally, candidate adhesion motifs and growth factors were systemically changed in vitro using a design of experiment approach to optimize stem cell survival or proliferation. The optimized HA hydrogel, tested in vivo, promoted survival of encapsulated human neural progenitor cells (iPS-NPCs) after transplantation into the stroke core and differentially tuned transplanted cell fate through the promotion of glial, neuronal or immature/progenitor states. This HA hydrogel can be tracked in vivo with MRI. A hydrogel can serve as a therapeutic adjunct in a stem cell therapy through selective control of stem cell survival and differentiation in vivo., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Stroke disability is the only major disease without an effective treatment. The substantial clinical burden of stroke in disabled survivors and the lack of a medical therapy that promotes recovery provide an opportunity to explore the use of biomaterials to promote brain repair after stroke. Hydrogels can be injected as a liquid and solidify in situ to form a gelatinous solid with similar mechanical properties to the brain. These biomaterials have been recently explored to generate pro-repair environments within the damaged organ. This review highlights the clinical problem of stroke treatment and discusses recent advances in using in situ forming hydrogels for brain repair., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: This study documented the performance of providers of visual inspection with acetic acid (VIA) at primary health centers, assessing their compliance with the VIA skills checklist and determinants of non-compliance, and exploring their perceptions of VIA training sessions., Materials and Methods: A cross- sectional study was conducted among VIA providers in the Meknes-Tafilalet region of Morocco. Structured observation of their performance was conducted through supervisory visits and multiple focus group discussions (FGDs)., Results: Performance of all the recommended steps for effective communication was observed in a low proportion of procedures (36.4%). Midwives/nurses had higher compliance than general practitioners (GPs) (p<0.001). All recommended steps for VIA examination were performed for a high proportion of procedures (82.5%). Compliance was higher among midwives/nurses than among GPs (p<0.001) and among providers in rural areas than those in urban areas (p<0.001). For pre-VIA counselling, all recommended steps were performed for only 36.8% of procedures. For post-VIA counseling, all recommended steps were performed in a high proportion (85.5% for VIA-negative and 85.1% for VIA-positive women). Midwives/nurses had higher compliance than GPs when advising VIA-positive women (p=0.009). All infection prevention practices were followed for only 14.2% of procedures, and compliance was higher among providers in rural areas than those in urban areas (p<0.001). Most FGD participants were satisfied with the content of VIA training sessions. However, they suggested periodic refresher training and supportive supervision., Conclusions: Quality assurance of a cervical cancer screening program is a key element to ensure that the providers perform VIA correctly and confidently.

The long circulation persistence of human serum albumin (HSA) is enabled by its domain III (DIII) interaction with the neonatal Fc receptor (FcRn). A protein scaffold based on HSA DIII was designed. To modify the serum half life of the scaffold, residues H535, H510, and H464 were individually mutated to alanine. HSA DIII wild type (WT) and variants were fused to the anti-carcinoembryonic antigen (CEA) T84.66 diabody (Db), radiolabeled with (124)I and injected into xenografted athymic mice for serial PET/CT imaging. All proteins targeted the CEA-positive tumor. The mean residence times (MRT) of the proteins, calculated by quantifying blood activity from the PET images, were: Db-DIII WT (56.7 h), H535A (25 h), H510A (20 h), H464A (17 h), compared with Db (2.9 h). Biodistribution confirmed the order of blood clearance from slow to fast: Db-DIII WT > H535A > H510A > H464A > Db with 4.0, 2.0, 1.8, 1.6 and 0.08 %ID/g of remaining blood activity at 51 h, respectively. This study demonstrates that attenuating the DIII-FcRn interaction provides a way of controlling the pharmacokinetics of the entire Db-DIII fusion protein without compromising tumor targeting. H464 appears to be most crucial for FcRn binding (greatest reduction in MRT), followed by H510 and H535. By mutating the DIII scaffold, we can dial serum kinetics for imaging or therapy applications.

Background: Gross albuminuria is associated with increased stroke risk, but it is unclear whether stroke incidence varies by level of albuminuria. We meta-analyzed prospective cohort studies to investigate the impact of various albuminuria levels and continuous urinary albumin excretion (UAE) change on stroke risk., Methods: Systematic search for studies reporting quantitative estimates of the multivariate-adjusted relative risk (RR) and 95% CI for stroke risk associated with microalbuminuria (UAE 30-300 mg/day or nearest equivalent interval) and macroalbuminuria (UAE >300 mg/day) and studies that analyzed the relation of stroke with UAE continuously. Estimates were combined using a random-effect model., Results: We identified seven studies comprising 46,638 participants with 1,479 stroke events. Incident stroke risk was greater for macroalbuminuria (RR 2.65, 95% CI 2.25-3.14) than microalbuminuria (RR 1.58, 95% CI 1.39-1.80), a difference that was significant (p for heterogeneity < 0.001, I(2) = 96%). In addition, risk of stroke increased proportionally with rising UAE (p < 0.001), even for UAE within normal range (beginning from levels as low as 2-4 mg/g)., Conclusions: Higher albuminuria level confers greater stroke risk. These findings provide additional weight to evidence that albuminuria is strongly linked to stroke risk, and suggest that persons with elevated UAE levels may especially benefit from more intensive vascular risk reduction., (Copyright © 2010 S. Karger AG, Basel.)

Apathy is the most commonly observed behavioral disturbance in Alzheimer's disease (AD) and has been suggested to be frontally mediated. Neuritic plaque (NP) and neurofibrillary tangle (NFT) counts were performed for 8 brain regions in 29 subjects with definite AD. Neuropsychiatric Inventory (NPI) for autopsied subjects was obtained from questioning of caregivers of subjects included in the study. Chronic apathy and total NPI composite scores correlated with anterior cingulate NFT counts (r = 0.518, p = 0.01, and r = 0.438, p = 0.032). This analysis suggests that chronic apathy in AD correlates with a greater anterior cingulate NFT burden and that chronic behavioral changes are more reflective than acute changes of disease pathology.

Study Design: Patients with adolescent idiopathic scoliosis that underwent spine fusion using the principle of segmental correction and a specific instrumentation., Objectives: Evaluation of the methodology used., Summary of Background Data: The results of surgical correction of scoliosis today are mainly related to the popular use of the CD and other similar instrumentations. Most of its users report that the corrective mechanisms allow coronal and sagittal correction of the deformed spine but not derotation in the horizontal plane. The results of a corrective methodology using segmental correction are reviewed here to evaluate triplanar correction of the deformity., Materials and Methods: Two hundred seventy-three adolescents with idiopathic scoliosis underwent corrective arthrodesis with the Lea Plaza Frame at the average age of 15.2 years. Coronal and sagittal values were measured with the Cobb method, rotation with the Pedrialle ruler. Trunk, shoulder imbalance and the rib prominence was documented by plain pictures. Follow-up average is 7.8 years., Results: Preoperative: Coronal curves averaged 54 degrees. Associated preoperative thoracic hypokyphosis = 8 degrees. Lordosis = -3 degrees. Hyperkyphosis = 56 degrees. Apical rotation was 23 degrees. Postoperative: Long-term values: corrected coronal curves measured 20 degrees, hypokyphosis decreased to 23 degrees, and lordosis reversed to 18 degrees, whereas hyperkyphosis decreased to 41 degrees. Apical derotation is 31%. Of the patients with preoperative trunk imbalance over the pelvis, 95% were completely corrected and the 98% with shoulder unleveled had also full correction of these phenomena., Conclusions: This review shows that tridimensional correction in flexible curves can be obtained by following the principle of segmental correction.

Irregularities of the cervical margin of restorations facilitate the retention of bacterial plaque, hindering plaque control through the habitual procedures of oral hygiene and favoring the development of periodontal disease. The aim of this study was to evaluate the periodontal condition and treatment needs (applying CPITN) in relation to the cervical margin of dental restorations. Three hundred and sixty-seven teeth with class II and V cavities restored with amalgam, class III cavities restored with composite resin, cast metal restorations and unitary prostheses were examined. With a WHO periodontal probe, the position of the cervical margins of restorations was verified (supragingival, subgingival or at the gingival margin level); the presence of defects (lack or excess of restoring material) and the presence of score 2 of CPITN were also assessed. After the analysis of the data, it was possible to conclude that: 1) supragingival margins offered the best marginal adaptation and the lowest frequency of score 2; 2) both the lack and the excess of restoring material favor the development of score 2, despite the utilized material and 3) in subgingival margins, incorrect marginal adaptation was the most frequent event, mainly due to excess of restoring material, and in these cases there was higher frequency of score 2 of CPITN.

Background: Gabapentin, a new anti-epileptic agent, has been anecdotally reported to be effective in the treatment of mania. We systematically assessed the response rate in bipolar patients being treated adjunctively with gabapentin for manic symptoms, depressive symptoms, or rapid cycling not responsive to standard treatments., Method: Twenty-eight bipolar patients experiencing manic (n = 18), depressive (n = 5), or rapid-cycling (n = 5) symptoms inadequately responsive to at least one mood stabilizer were treated in an open fashion with adjunctive gabapentin. Illness response was assessed using the Clinical Global Impression Scale modified for bipolar disorder (CGI-BP). A 'positive response' was operationalized as a CGI response of much or very much improved., Results: Fourteen of the 18 (78%) treated for hypomania or mania had a positive response to a dosage range of 600-3,600 mg/day. Patients with hypomania responded fastest, with a positive response achieved in 12.7 +/- 7.2 days. Patients with classic mania had a mean time to positive response of 25 +/- 12 days, and in patients with mixed mania it was 31.8 +/- 20.9 days. All of the five patients treated for depression had a positive response within 21 +/- 13.9 days. Only one of five patients with rapid cycling had a positive response. Gabapentin was well tolerated by all patients, with the most common side-effect being sedation., Conclusions: Gabapentin appears to have acute anti-manic and anti-depressant properties as an adjunctive agent for refractory bipolar illness. Prospective double-blind studies are needed to further delineate its acute efficacy when used as monotherapy and its prophylactic efficacy as monotherapy or in conjuction with other mood stabilizers.

Excellent correction of the scoliotic deformity in the three space planes is planes is obtained with the use of the Lea-Plaza frame. This article discusses the indications and contraindications, surgical technique, results, and complications of this technique.

Rats injected with colchicine (0.5 mg/100 g of body weight) 1 h before ingestion of a margarine emulsion (1 g in 2 ml of saline) do not show the rise in plasma triacylglycerol concentration found in controls during the subsequent hours. The effect of colchicine is more dramatic when the experiment is performed after prior administration of Triton WR-1339, a substance known to inhibit the catabolism of lipoproteins. Colchicine-treated rats also showed a five-fold increase in the content of triacylglycerol in proximal jejunum, when compared to controls. These results are consistent with the idea that colchicine interferes with the intracellular phase of fat absorption, suggesting that the microtubular-microfilamentous system could be involved in the release of chylomicrons from the intestinal cell into the circulation.