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1.  Sheets of Vertically Aligned BaTiO3 Nanotubes Reduce Cell Proliferation but Not Viability of NIH-3T3 Cells 
PLoS ONE  2014;9(12):e115183.
All biomaterials initiate a tissue response when implanted in living tissues. Ultimately this reaction causes fibrous encapsulation and hence isolation of the material, leading to failure of the intended therapeutic effect of the implant. There has been extensive bioengineering research aimed at overcoming or delaying the onset of encapsulation. Nanotechnology has the potential to address this problem by virtue of the ability of some nanomaterials to modulate interactions with cells, thereby inducing specific biological responses to implanted foreign materials. To this effect in the present study, we have characterised the growth of fibroblasts on nano-structured sheets constituted by BaTiO3, a material extensively used in biomedical applications. We found that sheets of vertically aligned BaTiO3 nanotubes inhibit cell cycle progression - without impairing cell viability - of NIH-3T3 fibroblast cells. We postulate that the 3D organization of the material surface acts by increasing the availability of adhesion sites, promoting cell attachment and inhibition of cell proliferation. This finding could be of relevance for biomedical applications designed to prevent or minimize fibrous encasement by uncontrolled proliferation of fibroblastic cells with loss of material-tissue interface underpinning long-term function of implants.
doi:10.1371/journal.pone.0115183
PMCID: PMC4266647  PMID: 25506693
2.  The study of cardiovascular risk in adolescents – ERICA: rationale, design and sample characteristics of a national survey examining cardiovascular risk factor profile in Brazilian adolescents 
BMC Public Health  2015;15:94.
Background
The Study of Cardiovascular Risk in Adolescents (Portuguese acronym, “ERICA”) is a multicenter, school-based country-wide cross-sectional study funded by the Brazilian Ministry of Health, which aims at estimating the prevalence of cardiovascular risk factors, including those included in the definition of the metabolic syndrome, in a random sample of adolescents aged 12 to 17 years in Brazilian cities with more than 100,000 inhabitants. Approximately 85,000 students were assessed in public and private schools. Brazil is a continental country with a heterogeneous population of 190 million living in its five main geographic regions (North, Northeast, Midwest, South and Southeast). ERICA is a pioneering study that will assess the prevalence rates of cardiovascular risk factors in Brazilian adolescents using a sample with national and regional representativeness. This paper describes the rationale, design and procedures of ERICA.
Methods/Design
Participants answered a self-administered questionnaire using an electronic device, in order to obtain information on demographic and lifestyle characteristics, including physical activity, smoking, alcohol intake, sleeping hours, common mental disorders and reproductive and oral health. Dietary intake was assessed using a 24-hour dietary recall. Anthropometric measures (weight, height and waist circumference) and blood pressure were also be measured. Blood was collected from a subsample of approximately 44,000 adolescents for measurements of fasting glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, glycated hemoglobin and fasting insulin.
Discussion
The study findings will be instrumental to the development of public policies aiming at the prevention of obesity, atherosclerotic diseases and diabetes in an adolescent population.
doi:10.1186/s12889-015-1442-x
PMCID: PMC4334602
Cardiovascular diseases; Metabolic syndrome X; Adolescent
3.  Oxidized Fatty Acids: A Potential Pathogenic Link Between Fatty Liver and Type 2 Diabetes in Obese Adolescents? 
Antioxidants & Redox Signaling  2014;20(2):383-389.
Abstract
In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3±3.31 years; body mass index 33.0±6.79 kg/m2), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D. Antioxid. Redox Signal. 20, 383–389.
doi:10.1089/ars.2013.5466
PMCID: PMC3887421  PMID: 23815500
4.  Giant colonic diverticulum: Clinical presentation, diagnosis and treatment: Systematic review of 166 cases 
AIM: To investigate the clinical presentation, diagnosis, and treatment of giant colonic diverticulum (GCD, by means of a complete and updated literature review). GCD is a rare manifestation of diverticular disease of the colon. Less than 200 studies on GCD were published in the literature, predominantly case reports or small patient series.
METHODS: A systematic review of the literature was performed using the Embase and PubMed databases to identify all the GCD studies. The following MESH search headings were used: “giant colonic diverticulum”; “giant sigmoid diverticulum”. The “related articles” function was used to broaden the search, and all of the abstracts, studies, and citations were reviewed by two authors. The following outcomes were of interest: the disease and patient characteristics, study design, indications for surgery, type of operation, and post-operative outcomes. Additionally, a subgroup analysis of cases treated in the last 5 years was performed to show the current trends in the treatment of GCD. A GCD case in an elderly patient treated in our department by a sigmoidectomy with primary anastomosis and a diverting ileostomy is presented as a typical example of the disease.
RESULTS: In total, 166 GCD cases in 138 studies were identified in the literature. The most common clinical presentation was abdominal pain, which occurred in 69% of the cases. Among the physical signs, an abdominal mass was detected in 48% of the cases, whereas 20% of the patients presented with fever and 14% with abdominal tenderness. Diagnosis is based predominantly on abdominal computed tomography. The most frequent treatment was colic resection with en-bloc resection of the diverticulum, performed in 57.2% of cases, whereas Hartmann’s procedure was followed in 11.4% of the cases and a diverticulectomy in 10.2%. An analysis of sixteen cases reported in the last 5 years showed that the majority of patients were treated with sigmoidectomy and en-bloc resection of the diverticulum; the postoperative mortality was null, morbidity was very low (1 patient was hospitalized in the intensive care unit for postoperative hypotension), and the patients were discharged 4-14 d after surgery.
CONCLUSION: Giant colonic diverticulum is a rare manifestation of diverticular diseases. Surgical treatment, consisting predominantly of colonic resection with en bloc resection of the diverticulum, is the preferred option for GCD and guarantees excellent results.
doi:10.3748/wjg.v21.i1.360
PMCID: PMC4284356  PMID: 25574112
Giant; Colonic; Diverticulum; Sigmoid; Surgery
5.  The multifaceted roles of metabolic enzymes in the Paracoccidioides species complex 
Paracoccidioides species are dimorphic fungi and are the etiologic agents of paracoccidioidomycosis, which is a serious disease that involves multiple organs. The many tissues colonized by this fungus suggest a variety of surface molecules involved in adhesion. A surprising finding is that most enzymes in the glycolytic pathway, tricarboxylic acid (TCA) cycle and glyoxylate cycle in Paracoccidioides spp. have adhesive properties that aid in interacting with the host extracellular matrix and thus act as ‘moonlighting’ proteins. Moonlighting proteins have multiple functions, which adds a dimension to cellular complexity and benefit cells in several ways. This phenomenon occurs in both eukaryotes and prokaryotes. For example, moonlighting proteins from the glycolytic pathway or TCA cycle can play a role in bacterial pathogenesis by either acting as proteins secreted in a conventional pathway and/or as cell surface components that facilitate adhesion or adherence. This review outlines the multifunctionality exhibited by many Paracoccidioides spp. enzymes, including aconitase, aldolase, glyceraldehyde-3-phosphate dehydrogenase, isocitrate lyase, malate synthase, triose phosphate isomerase, fumarase, and enolase. We discuss the roles that moonlighting activities play in the virulence characteristics of this fungus and several other human pathogens during their interactions with the host.
doi:10.3389/fmicb.2014.00719
PMCID: PMC4271699  PMID: 25566229
Paracoccidioides spp.; moonlighting proteins; virulence; glycolytic pathway and tricarboxylic acid cycle; glyoxylate cycle; adhesins
6.  How Do Metal Ion Levels Change over Time in Hip Resurfacing Patients? A Cohort Study 
The Scientific World Journal  2014;2014:291925.
Metal-on-metal hip resurfacing (MOM-HR) is offered as an alternative to traditional hip arthroplasty for young, active adults with advanced osteoarthritis. Nevertheless, concerns remain regarding wear and corrosion of the bearing surfaces and the resulting increase in metal ion levels. We evaluated three cohorts of patients with Birmingham hip resurfacing (BHR) at an average follow-up of 2, 5, and 9 years. We asked whether there would be differences in ion levels between the cohorts and inside the gender. Nineteen patients were prospectively analyzed. The correlation with clinical-radiographic data was also performed. Chromium, cobalt, nickel, and molybdenum concentrations were measured by atomic absorption spectrophotometry. Chromium and cobalt levels demonstrated a tendency to decrease over time. Such tendency was present only in females. An inverse correlation between chromium, implant size, and Harris hip score was present at short term; it disappeared over time together with the decreased ion levels. The prospective analysis showed that, although metal ion levels remained fairly constant within each patient, there was a relatively large variation between subjects, so mean data in this scenario must be interpreted with caution. The chronic high exposure should be carefully considered during implant selection, particularly in young subjects, and a stricter monitoring is mandatory.
doi:10.1155/2014/291925
PMCID: PMC4279264  PMID: 25580456
7.  Alterations of protein expression in conditions of copper-deprivation for Paracoccidioides lutzii in the presence of extracellular matrix components 
BMC Microbiology  2014;14(1):302.
Background
Paracoccidioides spp is a fungi genus and the agent of paracoccidioidomycosis. The strategies of infection used by these pathogens involve the expression of proteins related to adaptation to the host, particularly regarding the uptake of micronutrients. This study analyzed the adhesion of Paracoccidioides lutzii during conditions of copper (Cu) and iron (Fe) deprivation, while also evaluating the proteins expressed in conditions of Cu depletion in the presence of four extracellular matrix (ECM) components (laminin, fibronectin and types I and IV collagen).
Results
We cultured the P. lutzii in a chemically defined media without Cu and Fe. The fungus was then placed in contact with different ECM components and adhesion was evaluated. A significant increase in binding to all ECM components was observed when the fungus was cultured without Cu; which might be related to some adhesins expression. A proteomic assay was developed and revealed 39 proteins expressed that are involved in processes such as virulence, protein synthesis, metabolism, energy, transcription, transport, stress response and the cell cycle when the fungus was interacting with the ECM components. The up-regulated expression of two important adhesins, enolase and 14-3-3, was observed at the fungal cell wall during the interaction with the ECM components, indicating the role of these proteins in the Paracoccidioides–host interaction.
Conclusions
This study is important for determining prospective proteins that may be involved in the interaction of Paracoccidioides with a host. Understanding the adaptive response to different growth conditions, elucidating the processes of adhesion and cell invasion, and identifying the proteins that are differentially expressed during the fungus-host interaction may help elucidate mechanisms used for survival and growth of Paracoccidioides in various human tissues.
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0302-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12866-014-0302-7
PMCID: PMC4302596  PMID: 25495274
Paracoccidioides spp; Copper; Adhesion; Protein expression; Paracoccidioidomycosis
8.  PCAF ubiquitin ligase activity inhibits Hedgehog/Gli1 signaling in p53-dependent response to genotoxic stress 
Cell Death and Differentiation  2013;20(12):1688-1697.
The Hedgehog (Hh) signaling regulates tissue development, and its aberrant activation is a leading cause of malignancies, including medulloblastoma (Mb). Hh-dependent tumorigenesis often occurs in synergy with other mechanisms, such as loss of p53, the master regulator of the DNA damage response. To date, little is known about mechanisms connecting DNA-damaging events to morphogen-dependent processes. Here, we show that genotoxic stress triggers a cascade of signals, culminating with inhibition of the activity of Gli1, the final transcriptional effector of Hh signaling. This inhibition is dependent on the p53-mediated elevation of the acetyltransferase p300/CBP-associated factor (PCAF). Notably, we identify PCAF as a novel E3 ubiquitin ligase of Gli1. Indeed PCAF, but not a mutant with a deletion of its ubiquitination domain, represses Hh signaling in response to DNA damage by promoting Gli1 ubiquitination and its proteasome-dependent degradation. Restoring Gli1 levels rescues the growth arrest and apoptosis effect triggered by genotoxic drugs. Consistently, DNA-damaging agents fail to inhibit Gli1 activity in the absence of either p53 or PCAF. Finally, Mb samples from p53-null mice display low levels of PCAF and upregulation of Gli1 in vivo, suggesting PCAF as potential therapeutic target in Hh-dependent tumors. Together, our data define a mechanism of inactivation of a morphogenic signaling in response to genotoxic stress and unveil a p53/PCAF/Gli1 circuitry centered on PCAF that limits Gli1-enhanced mitogenic and prosurvival response.
doi:10.1038/cdd.2013.120
PMCID: PMC3824589  PMID: 24013724
Hedgehog signaling; ubiquitylation; PCAF; p53; medulloblastoma
9.  Molecular Diagnostics of Fine Needle Aspiration for the Presurgical Screening of Thyroid Nodules 
Current Genomics  2014;15(3):171-177.
“The incidence of thyroid cancer, the most common endocrine malignancy, is rising. The two most common types of thyroid cancer are papillary and follicular” thyroid carcinomas. “Fine-needle aspiration (FNA) of thyroid nodules” can permit to detect many genetic mutations and other molecular alterations, including RAS and BRAF point mutations, PAX8/peroxisome proliferator-activated receptor (PPAR)γ and “RET/PTC rearrangements, occurring in thyroid papillary and follicular carcinomas” (more than 70% of cases), which can be used successfully to improve the diagnosis “and the management of patients with thyroid nodules”. The most extensive experience has been accumulated with “the diagnostic use of BRAF mutation”, which is highly specific for malignancy. “Testing FNA samples for a panel of mutations” that typically includes RAS, BRAF, PAX8/PPARγ and RET/PTC could permit to achieve the biggest diagnostic impact. “The accuracy of cancer diagnosis in thyroid nodules could be improved significantly using these and other emerging molecular markers”.
doi:10.2174/1389202915999140404100347
PMCID: PMC4064556  PMID: 24955024
Thyroid nodules; Thyroid cancer; Cytology; RET; BRAF; RAS; PAX8/PPARγ.
10.  Antifungal Activity of Decyl Gallate against Several Species of Pathogenic Fungi 
This work aims to demonstrate that the gallic acid structure modification to the decyl gallate (G14) compound contributed to increase the antifungal activity against several species of pathogenic fungi, mainly, Candida spp., Cryptococcus spp., Paracoccidioides spp., and Histoplasma capsulatum, according to standardized microdilution method described by Clinical Laboratory Standard Institute (CLSI) documents. Moreover this compound has a particularly good selectivity index value, which makes it an excellent candidate for broad-spectrum antifungal prototype and encourages the continuation of subsequent studies for the discovery of its mechanism of action.
doi:10.1155/2014/506273
PMCID: PMC4258339  PMID: 25505923
11.  An Optimized Table-Top Small-Angle X-ray Scattering Set-up for the Nanoscale Structural Analysis of Soft Matter 
Scientific Reports  2014;4:6985.
The paper shows how a table top superbright microfocus laboratory X-ray source and an innovative restoring-data algorithm, used in combination, allow to analyze the super molecular structure of soft matter by means of Small Angle X-ray Scattering ex-situ experiments. The proposed theoretical approach is aimed to restore diffraction features from SAXS profiles collected from low scattering biomaterials or soft tissues, and therefore to deal with extremely noisy diffraction SAXS profiles/maps. As biological test cases we inspected: i) residues of exosomes' drops from healthy epithelial colon cell line and colorectal cancer cells; ii) collagen/human elastin artificial scaffolds developed for vascular tissue engineering applications; iii) apoferritin protein in solution. Our results show how this combination can provide morphological/structural nanoscale information to characterize new artificial biomaterials and/or to get insight into the transition between healthy and pathological tissues during the progression of a disease, or to morphologically characterize nanoscale proteins, based on SAXS data collected in a room-sized laboratory.
doi:10.1038/srep06985
PMCID: PMC4225548  PMID: 25382272
12.  Quality of life of people living with HIV, preliminary results from IANUA (Investigation on Antiretroviral Therapy) study 
Journal of the International AIDS Society  2014;17(4Suppl 3):19581.
Introduction
The introduction of combined antiretroviral treatment (cART) has reduced HIV-associated morbidity and mortality, and changed the patients’ perspective of life. As a result, Health Related Quality of Life (HRQOL) has become a crucial clinical issue.
Objective
Assessment of HRQOL in a sample of Italian patients from IANUA study. Investigate correlation between CD4 cell counts, viral load and changes in HRQOL.
Materials and Methods
EQ-5D-3L self-reported questionnaire has been used in the evaluation of HRQOL. It assesses five dimensions: “mobility,” “self care,” “usual activities,” “pain/discomfort” and “anxiety/depression.” Each dimension has three levels: no problems, some problems and extreme problems. In addition, it includes a Visual Analogue Scale (VAS) where one's own health “today” is rated from 0 “worst imaginable health” to 100 “best imaginable health.” The respondents provide information on marital status, education, employment/unemployment, other treatments used in addition to HAART (1,2,3,4,5 or more) and number of hospitalizations due to HIV/AIDS.
Results
684 patients completed the questionnaire: 231 females and 453 males. The mean age of the sample was 51 years (range 21–78). The mean VAS score was 69.9. 558 patients (81.5%) reported no problems in mobility. 642 patients (93.5%) had no problems in self care. 423 patients (61.8%) had no pain/discomfort while 219 had some problems. 326 patients (46.1%) had some problems in anxiety/depression.
Conclusions
The analysis of self-reported questionnaires indicates that HRQOL in our sample group is not deeply affected by HIV/AIDS. The dimensions that are affected in the least are “mobility” and “self care” while the major problem is “anxiety/depression” with half of the sample reporting moderate or high level.
doi:10.7448/IAS.17.4.19581
PMCID: PMC4224913  PMID: 25394088
13.  Aβ-related angiitis 
Neurology  2013;81(18):1596-1603.
Objective:
To analyze the clinical findings, response to therapy, and outcomes of patients with cerebral vascular amyloid-β (Aβ) deposition with and without inflammatory vascular infiltration.
Methods:
We report 78 consecutive patients with cerebral vascular Aβ deposition examined at Mayo Clinic Rochester over 25 years (1987 through 2011). Specimens reviewed by a neuropathologist showed 40 with vascular Aβ peptide without inflammation (cerebral amyloid angiopathy [CAA]), 28 with granulomatous vasculitis (Aβ-related angiitis or ABRA), and 10 with perivascular CAA-related inflammation. We also matched findings in 118 consecutive patients with primary CNS vasculitis (PCNSV) without Aβ seen over 25 years (1983 through 2007).
Results:
Compared to the 40 with CAA, the 28 with ABRA were younger at diagnosis (p = 0.05), had less altered cognition (p = 0.02), fewer neurologic deficits (p = 0.02), and fewer intracranial hemorrhages (<0.001), but increased gadolinium leptomeningeal enhancement (p = 0.01) at presentation, and less mortality and disability at last follow-up (p < 0.001). Compared with PCNSV, the 28 patients with ABRA were older at diagnosis (p < 0.001), had a higher frequency of altered cognition (p = 0.05), seizures/spells (p = 0.006), gadolinium leptomeningeal enhancement (p < 0.001), and intracerebral hemorrhage (p = 0.02), lower frequency of hemiparesis (p = 0.01), visual symptoms (p = 0.04), and MRI evidence of cerebral infarction (p = 0.003), but higher CSF protein levels (p = 0.03). Results of treatment and outcomes in ABRA and PCNSV were similar.
Conclusions:
ABRA appears to represent a distinct subset of PCNSV.
doi:10.1212/WNL.0b013e3182a9f545
PMCID: PMC3806912  PMID: 24078731
14.  Interictal Scalp Electroencephalography and Intraoperative Electrocorticography in Magnetic Resonance Imaging–Negative Temporal Lobe Epilepsy Surgery 
JAMA neurology  2014;71(6):702-709.
IMPORTANCE
Scalp electroencephalography (EEG) and intraoperative electrocorticography (ECoG) are routinely used in the evaluation of magnetic resonance imaging–negative temporal lobe epilepsy (TLE) undergoing standard anterior temporal lobectomy with amygdalohippocampectomy (ATL), but the utility of interictal epileptiform discharge (IED) identification and its role in outcome are poorly defined.
OBJECTIVES
To determine whether the following are associated with surgical outcomes in patients with magnetic resonance imaging–negative TLE who underwent standard ATL: (1) unilateral-only IEDs on preoperative scalp EEG; (2) complete resection of tissue generating IEDs on ECoG; (3) complete resection of opioid-induced IEDs recorded on ECoG; and (4) location of IEDs recorded on ECoG.
DESIGN, SETTING, AND PARTICIPANTS
Data were gathered through retrospective medical record review at a tertiary referral center. Adult and pediatric patients with TLE who underwent standard ATL between January 1, 1990, and October 15, 2010, were considered for inclusion. Inclusion criteria were magnetic resonance imaging–negative TLE, standard ECoG performed at the time of surgery, and a minimum follow-up of 12 months. Univariate analysis was performed using log-rank time-to-event analysis. Variables reaching significance with log-rank testing were further analyzed using Cox proportional hazards.
MAIN OUTCOMES AND MEASURES
Excellent or nonexcellent outcome at time of last follow-up. An excellent outcome was defined as Engel class I and a nonexcellent outcome as Engel classes II through IV.
RESULTS
Eighty-seven patients met inclusion criteria, with 48 (55%) achieving an excellent outcome following ATL. Unilateral IEDs on scalp EEG (P = .001) and complete resection of brain regions generating IEDs on baseline intraoperative ECoG (P = .02) were associated with excellent outcomes in univariate analysis. Both were associated with excellent outcomes when analyzed with Cox proportional hazards (unilateral-only IEDs, relative risk = 0.31 [95% CI, 0.16-0.64]; complete resection of IEDs on baseline ECoG, relative risk = 0.39 [95% CI, 0.20-0.76]). Overall, 25 of 35 patients (71%) with both unilateral-only IEDs and complete resection of baseline ECoG IEDs had an excellent outcome.
CONCLUSIONS AND RELEVANCE
Unilateral-only IEDs on preoperative scalp EEG and complete resection of IEDs on baseline ECoG are associated with better outcomes following standard ATL in magnetic resonance imaging–negative TLE. Prospective evaluation is needed to clarify the use of ECoG in tailoring temporal lobectomy.
doi:10.1001/jamaneurol.2014.585
PMCID: PMC4183227  PMID: 24781216
16.  Electroencephalogram and Magnetic Resonance Imaging Comparison as a Predicting Factor for Neurodevelopmental Outcome in Hypoxic Ischemic Encephalopathy Infant Treated with Hypothermia 
Pediatric Reports  2014;6(3):5532.
Hypoxic-ischemic encephalopathy (HIE) is an important cause of acute neurological damage in newborns at (or near) term. Several trials in recent years have shown that moderate hypothermia by total body cooling or selective head is an effective intervention to reduce mortality and major disability in infants survived a perinatal hypoxic-ischemic attack. Follow-up in these patients is very important to establish neurodevelopmental outcome, and specific markers can lead us to detect predicting sign for good or poor outcome. We reported a few cases of newborn with HIE treated with hypothermia, in whom the comparison between electroencephalogram (EEG) and magnetic resonance imaging (MRI) represents the first marker for neurodevelopment outcome prediction. The continuous EEG monitoring showed a depressed EEG activity with diffuse burst depression in 7 patients. No epileptic abnormalities were registered. In 10 out of 20 patients no abnormalities of the background activity and no epileptic abnormalities were observed. We found that a depressed EEG activity during the first 72 h of life and a diffused alteration of basal ganglia at MRI were correlated with a poor neurodevelopmental outcome at 18 months of follow-up.
doi:10.4081/pr.2014.5532
PMCID: PMC4292060  PMID: 25635216
hypothermia; neonates; magnetic resonance imaging; long term; electroencephalogram monitoring
18.  Serological Diagnosis of Paracoccidioidomycosis: High Rate of Inter-laboratorial Variability among Medical Mycology Reference Centers 
Background
Serological tests have long been established as rapid, simple and inexpensive tools for the diagnosis and follow-up of PCM. However, different protocols and antigen preparations are used and the few attempts to standardize the routine serological methods have not succeeded.
Methodology/Principal findings
We compared the performance of six Brazilian reference centers for serological diagnosis of PCM. Each center provided 30 sera of PCM patients, with positive high, intermediate and low titers, which were defined as the “reference” titers. Each center then applied its own antigen preparation and serological routine test, either semiquantitative double immunodifusion or counterimmmunoelectrophoresis, in the 150 sera from the other five centers blindly as regard to the “reference” titers. Titers were transformed into scores: 0 (negative), 1 (healing titers), 2 (active disease, low titers) and 3 (active disease, high titers) according to each center's criteria. Major discordances were considered between scores indicating active disease and scores indicating negative or healing titers; such discordance when associated with proper clinical and other laboratorial data, may correspond to different approaches to the patient's treatment. Surprisingly, all centers exhibited a high rate of “major” discordances with a mean of 31 (20%) discordant scores. Alternatively, when the scores given by one center to their own sera were compared with the scores given to their sera by the remaining five other centers, a high rate of major discordances was also found, with a mean number of 14.8 sera in 30 presenting a discordance with at least one other center. The data also suggest that centers that used CIE and pool of isolates for antigen preparation performed better.
Conclusion
There are inconsistencies among the laboratories that are strong enough to result in conflicting information regarding the patients' treatment. Renewed efforts should be promoted to improve standardization of the serological diagnosis of PCM.
Author Summary
Paracoccidioidomycosis (PCM) is a neglected systemic fungal infection prevalent mostly in South America. Serological tests have long been established as rapid, simple and inexpensive tools for the diagnosis and follow-up of PCM. However, different protocols and reagents are used. We compared here the performance of six Brazilian reference centers for serological diagnosis of PCM. Each center provided 30 sera of PCM patients, with positive high, intermediate and low titers, which were defined as the “reference” titers. Each center then applied its serological routine test to the 150 sera from the other five centers blindly as regards to the “reference” titers. Surprisingly, all centers exhibited a high rate of discordances (mean of 31 discordant scores in 150 sera tested). When the scores given by one center to their own sera were compared with the scores given to their sera by the other centers, a high rate of major discordances was found (a mean of 14.8 sera in 30 presented a discordance with at least one other center). We concluded that there are inconsistencies among the laboratories that can potentially result in conflicting information regarding the patient's treatment. Renewed efforts should be promoted to improve standardization of the serological diagnosis of PCM.
doi:10.1371/journal.pntd.0003174
PMCID: PMC4161321  PMID: 25211336
19.  Validation of the angular measurements of a new inertial-measurement-unit based rehabilitation system: comparison with state-of-the-art gait analysis 
Background
Several rehabilitation systems based on inertial measurement units (IMU) are entering the market for the control of exercises and to measure performance progression, particularly for recovery after lower limb orthopaedic treatments. IMU are easy to wear also by the patient alone, but the extent to which IMU’s malpositioning in routine use can affect the accuracy of the measurements is not known. A new such system (Riablo™, CoRehab, Trento, Italy), using audio-visual biofeedback based on videogames, was assessed against state-of-the-art gait analysis as the gold standard.
Methods
The sensitivity of the system to errors in the IMU’s position and orientation was measured in 5 healthy subjects performing two hip joint motion exercises. Root mean square deviation was used to assess differences in the system’s kinematic output between the erroneous and correct IMU position and orientation.
In order to estimate the system’s accuracy, thorax and knee joint motion of 17 healthy subjects were tracked during the execution of standard rehabilitation tasks and compared with the corresponding measurements obtained with an established gait protocol using stereophotogrammetry.
Results
A maximum mean error of 3.1 ± 1.8 deg and 1.9 ± 0.8 deg from the angle trajectory with correct IMU position was recorded respectively in the medio-lateral malposition and frontal-plane misalignment tests. Across the standard rehabilitation tasks, the mean distance between the IMU and gait analysis systems was on average smaller than 5°.
Conclusions
These findings showed that the tested IMU based system has the necessary accuracy to be safely utilized in rehabilitation programs after orthopaedic treatments of the lower limb.
doi:10.1186/1743-0003-11-136
PMCID: PMC4169865  PMID: 25212257
Inertial measurement unit; Gait analysis; Rehabilitation; Knee; Hip; Thorax; Joint flexion; Audio-visual bio-feedback; Video-games
20.  A minimally invasive technique for surgical treatment of hallux valgus: simple, effective, rapid, inexpensive (SERI) 
International Orthopaedics  2013;37(9):1805-1813.
Purpose
Several bony and soft tissue procedures have been described for the treatment of hallux valgus, and currently mini-invasive surgical techniques are preferred in order to reduce surgical trauma, complications, time of surgery and to allow an earlier recovery. The aim of this study is to analyse a series of 1,000 consecutive cases of hallux valgus, surgically treated by the minimally invasive SERI technique, reporting results at mid-term follow-up.
Methods
We prospectively studied 641 patients (1,000 feet) with symptomatic hallux valgus surgically treated by SERI osteotomy. Inclusion criteria were: age between 20 and 65 years, reducible mild or moderate hallux valgus, HVA ≤ 40°, IMA ≤ 20°, and arthritis of the first metatarsophalangeal joint up to grade 2 according to the Regnauld classification.
Results
The American Orthopaedic Foot and Ankle Society (AOFAS) score rose from 46.8 ± 16.7 preoperatively to 89 ± 10.3 at last follow-up. Radiographic control at follow-up showed a complete healing of the osteotomy and remodelling of the metatarsal bone. Low rate of complication has been reported.
Conclusions
This study demonstrated that the SERI technique is effective in treating mild to moderate hallux valgus in terms of relief from symptoms and functional improvement. This technique allowed correction of the main parameters of the deformity, with durable clinical and radiographic results at a mid-term follow-up.
Electronic supplementary material
The online version of this article (doi:10.1007/s00264-013-1980-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00264-013-1980-8
PMCID: PMC3764292  PMID: 23820757
Hallux valgus; SERI; Osteotomy; Early metatarsophalangeal arthritis
21.  Do Ion Levels in Metal-on-metal Hip Resurfacing Differ From Those in Metal-on-metal THA at Long-term Followup? 
Background
Metal-on-metal hip resurfacing arthroplasty (MOM HR) has become an established alternative to traditional metal-on-metal total hip arthroplasty (MOM THA) for younger, more active patients. Nevertheless, concerns remain regarding wear and corrosion of the bearing surfaces and the resulting systemic metal ion distribution.
Questions/purposes
We therefore asked whether (1) serum ion concentrations in patients with MOM HR at the time of long-term followup were higher than concentrations in a control population with no hip implants; (2) the ion concentrations in patients with MOM HR were different from those in patients with MOM THA; and (3) sex would influence ion levels with regard to implant type.
Methods
The MOM HR and MOM THA groups consisted of 25 patients (evaluated at a minimum of 96 months) and 16 patients (evaluated at a minimum of 106 months), respectively. Forty-eight healthy donors were recruited for reference values. Cobalt, chromium, nickel, and molybdenum were measured by furnace graphite atomic absorption spectrophotometry.
Results
Ion concentrations of cobalt, chromium, and molybdenum in MOM HR were higher than in controls. Chromium and cobalt release were higher in MOM HR than in MOM THA. The sex-based analysis showed the difference was because women had higher concentrations in the MOM HR group than in the MOM THA group, whereas there was no difference between the men in the two groups.
Conclusions
In MOM HR, high metal ion release persists for the long term. Consequently, it is important to implement strict biomonitoring for patients who have received these implants. The sustained high levels of chromium in females within the MOM HR group are concerning and merits strong consideration when choosing implants in this patient group.
Level of Evidence
Level III, therapeutic study. See the Instructions for Authors online for a complete description of level of evidence.
doi:10.1007/s11999-013-2981-z
PMCID: PMC3734417  PMID: 23572350
22.  Phase II Study of Bevacizumab in Combination with Sorafenib in Recurrent Glioblastoma (N0776): A North Central Cancer Treatment Group Trial1 
Purpose
We hypothesized that vertical blockade of VEGF signaling by combining bevacizumab with sorafenib in recurrent glioblastoma (rGBM) patients would result in a synergistic therapeutic effect. We also investigated whether VEGF, VEGFR2, and HIF-1α single nucleotide polymorphisms (SNPs), circulating biomarkers of angiogenesis and Magnetic Resonance (MR) imaging markers, such as apparent diffusion coefficient (ADC), correlated with treatment efficacy and/or toxicity.
Patients/Methods
Patients received bevacizumab (5 mg/kg every 2 weeks) with sorafenib (200 mg bid, weekly, days 1-5) (Group A), but due to toxicity the starting sorafenib dose was subsequently modified to 200 mg qd (Group B).
Results
54 patients were enrolled: 19 patients in Group A and 35 in Group B. Objective response rate was 18.5% with median duration of 6.7 mo (range 0.5-24.1 mo). Six-month progression free survival (PFS6) was 20.4% (11/54), and median OS was 5.6 months (95% CI 4.7 – 8.2); outcome was similar between the two dose groups. We identified single nucleotide polymorphisms in the VEGF and VEGFR2 promoter regions which were associated with PFS6 (p<0.022). Among molecular markers of angiogenesis, a higher log2 baseline level of stromal cell derived factor-1 was associated with PFS6 success (p=0.04). The circulating endothelial cell log2-fold decreased during treatment with subsequent increase at disease progression (p=0.022). Imaging analysis demonstrated a trend associating ADC-L with poor outcome.
Conclusions
The bevacizumab/sorafenib combination did not improve outcome of recurrent GBM patients versus historic bevacizumab treated controls. Biologic markers of response and resistance to bevacizumab in gliomas were identified which merit prospective validation.
doi:10.1158/1078-0432.CCR-13-0708
PMCID: PMC3869574  PMID: 23833308
bevacizumab; sorafenib; recurrent glioblastoma
23.  Hepatic osteodystrophy 
Summary
Metabolic disturbances of bone are frequent in patients with chronic liver disease. The prevalence of osteoporosis among patients with advanced chronic liver disease is reported between 12% and 55%; it is higher in primary biliary cirrhosis. All patients with advanced liver disease should be screened for osteoporosis with a densitometry, especially if the etiology is cholestatic and in the presence of other risk factors. Clinical relevance of hepatic osteodystrophy increases after liver transplantation. After liver transplant, a rapid loss of bone mineral density can be detected in the first 6 months, followed by stabilization and slight improvement of the values. At the time of transplantation, bone density values are very important prognostic factors.
Therapy of hepatic osteodystrophy is based primarily on the control of risk factors: cessation of tobacco and alcohol assumption, reduction of caffeine ingestion, exercise, supplementation of calcium and vitamin D, limitation of drugs such as loop diuretics, corticosteroids, cholestyramine.
Bisphosphonates have been proposed for the therapy of osteoporosis in patients with liver disease, particularly after liver transplantation. The possible side effects of oral administration of bisphosphonates, such as the occurrence of esophageal ulcerations, are of particular concern in patients with liver cirrhosis and portal hypertension, due to the risk of gastrointestinal hemorrhage from ruptured esophageal varices, although this risk is probably overestimated.
PMCID: PMC4269141  PMID: 25568651
hepatic osteodystrophy; liver cirrhosis; liver transplantation; vitamin D
24.  Evaluation of Systemic and Mucosal Anti-HPV16 and 18 Antibody Responses from Vaccinated Women 
Vaccine  2008;26(0):3608-3616.
Ideal methods to monitor HPV neutralizing antibodies induced by vaccination have not been established yet. Here, we evaluated systemic and cervical antibody levels induced by HPV16/18 AS04-adjuvanted vaccine (GlaxoSmithKline Biologicals) using a secreted alkaline phosphatase neutralization assay (SEAP) and ELISA. Serum and cervical secretions from 50 vaccinated women were used to assess 1) overall assay reproducibility, 2) inter-assay and inter-specimen correlation; 3) correlations between month 1 and month 12 titers. Strong correlations between SEAP-NA and ELISA were observed (serum anti-HPV16/18, ρ=0.91/0.85; cervix anti-HPV16/18, ρ=0.84/0.89). Systemic and cervical antibody measures also correlated well (ρ range: 0.64 – 0.75); except at mid-cycle (ρ range: 0.28 – 0.65). Correlations between antibody levels at one and twelve months following the start of vaccination were poor (ρ range: 0.16 – 0.38). In conclusion, HPV16/18 VLP-based ELISA is a reliable and valid method to monitor anti-HPV16/18 neutralizing potential for the first year following vaccination; however, additional studies will be required to better define the effects of the time on cycle and patterns of antibody response over time following vaccination.
doi:10.1016/j.vaccine.2008.04.074
PMCID: PMC4131294  PMID: 18541349
Human papillomavirus; Neutralization Assay; cervical secretions
25.  Genotype-phenotype correlation in Pompe disease, a step forward 
Background
Pompe’s disease is a progressive myopathy caused by mutations in the lysosomal enzyme acid alphaglucosidase gene (GAA). A wide clinical variability occurs also in patients sharing the same GAA mutations, even within the same family.
Methods
For a large series of GSDII patients we collected some clinical data as age of onset of the disease, presence or absence of muscular pain, Walton score, 6-Minute Walking Test, Vital Capacity, and Creatine Kinase. DNA was extracted and tested for GAA mutations and some genetic polymorphisms able to influence muscle properties (ACE, ACTN3, AGT and PPARα genes).
We compared the polymorphisms analyzed in groups of patients with Pompe disease clustered for their homogeneous genotype.
Results
We have been able to identify four subgroups of patients completely homogeneous for their genotype, and two groups homogeneous as far as the second mutation is defined “very severe” or “potentially less severe”. When disease free life was studied we observed a high significant difference between groups. The DD genotype in the ACE gene and the XX genotype in the ACTN3 gene were significantly associated to an earlier age of onset of the disease. The ACE DD genotype was also associated to the presence of muscle pain.
Conclusions
We demonstrate that ACE and ACTN3 polymorphisms are genetic factors able to modulate the clinical phenotype of patients affected with Pompe disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0102-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0102-z
PMCID: PMC4249737  PMID: 25103075
Glycogen storage disease type II; Genetic polymorphisms; Modifier genes; GAA; ACE; ACTN3

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