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1.  Parakinesia brachialis oscitans during thrombolytic therapy 
BMJ Case Reports  2013;2013:bcr2012007079.
The authors describe a case report of a patient with parakinesia brachialis oscitans, which occurred during thrombolytic therapy, in a patient with left-middle cerebral artery occlusion.
doi:10.1136/bcr-2012-007079
PMCID: PMC3604546  PMID: 23420718
2.  Vertical Movement Patterns and Ontogenetic Niche Expansion in the Tiger Shark, Galeocerdo cuvier 
PLoS ONE  2015;10(1):e0116720.
Sharks are top predators in many marine ecosystems and can impact community dynamics, yet many shark populations are undergoing severe declines primarily due to overfishing. Obtaining species-specific knowledge on shark spatial ecology is important to implement adequate management strategies for the effective conservation of these taxa. This is particularly relevant concerning highly-mobile species that use wide home ranges comprising coastal and oceanic habitats, such as tiger sharks, Galeocerdo cuvier. We deployed satellite tags in 20 juvenile tiger sharks off northeastern Brazil to assess the effect of intrinsic and extrinsic factors on depth and temperature usage. Sharks were tracked for a total of 1184 d and used waters up to 1112 m in depth. The minimum temperature recorded equaled 4°C. All sharks had a clear preference for surface (< 5 m) waters but variability in depth usage was observed as some sharks used mostly shallow (< 60 m) waters whereas others made frequent incursions into greater depths. A diel behavioral shift was detected, with sharks spending considerably more time in surface (< 10 m) waters during the night. Moreover, a clear ontogenetic expansion in the vertical range of tiger shark habitat was observed, with generalized linear models estimating a ~4-fold increase in maximum diving depth from 150- to 300-cm size-classes. The time spent in the upper 5 m of the water column did not vary ontogenetically but shark size was the most important factor explaining the utilization of deeper water layers. Young-of-the-year tiger sharks seem to associate with shallow, neritic habitats but they progressively move into deeper oceanic habitats as they grow larger. Such an early plasticity in habitat use could endow tiger sharks with access to previously unavailable prey, thus contributing to a wider ecological niche.
doi:10.1371/journal.pone.0116720
PMCID: PMC4309595  PMID: 25629732
3.  Tailored antihypertensive drug therapy prescribed to older women attenuates circulating levels of interleukin-6 and tumor necrosis factor-α 
Objective
To test the hypothesis that antihypertensive drug therapy produces anti-inflammatory effects in clinical practice, this study investigated circulating levels of selected proinflammatory mediators (interleukin-6 [IL-6], tumor necrosis factor-alpha [TNF-α], and interferon-γ [INF-γ]) in response to multivariate drug directions for blood pressure (BP) control.
Methods
Prospective study involving 110 hypertensive, community-dwelling older women with different metabolic disorders. A short-term BP-lowering drug therapy was conducted according to current Brazilian guidelines on hypertension, and basal cytokine levels were measured before and after intervention.
Results
Interventions were found to represent current hypertension-management practices in Brazil and corresponded to a significant reduction in systolic and diastolic BP levels in a whole-group analysis, as well as when users and nonusers of the most common therapeutic classes were considered separately. Considering all patients, mean IL-6 and TNF-α levels showed a significant decrease in circulating concentrations (P<0.01) at the endpoint compared with baseline, whereas the mean INF-γ level was not significantly different from baseline values. In separate analyses, only users of antagonists of the renin–angiotensin system and users of diuretics exhibited the same significant treatment-induced reduction in serum IL-6 and TNF-α observed in the whole group.
Conclusion
Our data demonstrates that a clinically guided antihypertensive treatment is effective in reversing the low-grade proinflammatory state of serum cytokines found in postmenopausal women and support extracardiac benefits from diuretics and renin–angiotensin system antagonists.
doi:10.2147/CIA.S74790
PMCID: PMC4296909  PMID: 25624753
renin–angiotensin system; cytokine; hypertension; drug therapy; guidelines; inflammation
4.  Remote Patient Monitoring Based on ZigBee: Lessons from a Real-World Deployment 
Abstract
Aim: This work presents detailed experimental performance results from tests executed in the hospital environment for Health Monitoring for All (HM4All), a remote vital signs monitoring system based on a ZigBee® (ZigBee Alliance, San Ramon, CA) body sensor network (BSN). Materials and Methods: Tests involved the use of six electrocardiogram (ECG) sensors operating in two different modes: the ECG mode involved the transmission of ECG waveform data and heart rate (HR) values to the ZigBee coordinator, whereas the HR mode included only the transmission of HR values. In the absence of hidden nodes, a non–beacon-enabled star network composed of sensing devices working on ECG mode kept the delivery ratio (DR) at 100%. Results: When the network topology was changed to a 2-hop tree, the performance degraded slightly, resulting in an average DR of 98.56%. Although these performance outcomes may seem satisfactory, further investigation demonstrated that individual sensing devices went through transitory periods with low DR. Other tests have shown that ZigBee BSNs are highly susceptible to collisions owing to hidden nodes. Nevertheless, these tests have also shown that these networks can achieve high reliability if the amount of traffic is kept low. Contrary to what is typically shown in scientific articles and in manufacturers' documentation, the test outcomes presented in this article include temporal graphs of the DR achieved by each wireless sensor device. Conclusions: The test procedure and the approach used to represent its outcomes, which allow the identification of undesirable transitory periods of low reliability due to contention between devices, constitute the main contribution of this work.
doi:10.1089/tmj.2013.0059
PMCID: PMC3880127  PMID: 24229401
e-health; remote patient monitoring; body sensor network; ZigBee; telemedicine
5.  Denervation impairs regeneration of amputated zebrafish fins 
Background
Zebrafish are able to regenerate many of its tissues and organs after damage. In amphibians this process is regulated by nerve fibres present at the site of injury, which have been proposed to release factors into the amputated limbs/fins, promoting and sustaining the proliferation of blastemal cells. Although some candidate factors have been proposed to mediate the nerve dependency of regeneration, the molecular mechanisms involved in this process remain unclear.
Results
We have used zebrafish as a model system to address the role of nerve fibres in fin regeneration. We have developed a protocol for pectoral fin denervation followed by amputation and analysed the regenerative process under this experimental conditions. Upon denervation fins were able to close the wound and form a wound epidermis, but could not establish a functional apical epithelial cap, with a posterior failure of blastema formation and outgrowth, and the accumulation of several defects. The expression patterns of genes known to be key players during fin regeneration were altered upon denervation, suggesting that nerves can contribute to the regulation of the Fgf, Wnt and Shh pathways during zebrafish fin regeneration.
Conclusions
Our results demonstrate that proper innervation of the zebrafish pectoral fin is essential for a successful regenerative process, and establish this organism as a useful model to understand the molecular and cellular mechanisms of nerve dependence, during vertebrate regeneration.
Electronic supplementary material
The online version of this article (doi:10.1186/s12861-014-0049-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12861-014-0049-2
PMCID: PMC4333893  PMID: 25551555
6.  Prognostic Factors and Scoring System for Death from Visceral Leishmaniasis: An Historical Cohort Study in Brazil 
Background
In Brazil, case-fatality rates attributable to visceral leishmaniasis (VL) are high and knowledge of the risk factors associated with death may help reduce mortality. The aim of this study was to construct and validate a scoring system for prognosis of death from VL by using all cases reported in Brazil from 2007 to 2011.
Methodology
In this historical cohort study, 18,501 VL cases were analyzed; of these, 17,345 cases were cured and 1,156 cases caused death. The database was divided into two series: primary (two-thirds of cases), to develop the model score, and secondary (one-third of cases), to validate the scoring system. Multivariate logistic regression models were performed to identify factors associated with death from VL, and these were included in the scoring system.
Principal Findings
The factors associated with death from VL were: bleeding (score 3); splenomegaly (score 1); edema (score 1); weakness (score 1); jaundice (score 1); Leishmania–HIV co-infection (score 1); bacterial infection (score 1); and age (≤0.5 years [score 5]; >0.5 and ≤1 [score 2]; >19 and ≤50 [score 2]; >50 and <65 [score 3]; ≥65 [score 5]). It was observed that patients with a score of 4 had a probability of death of approximately 4.5% and had a worse prognosis. The sensitivity, specificity, and accuracy of this score were 89.4, 51.2, and 53.5, respectively.
Conclusions/Significance
The scoring system based on risk factors for death showed good performance in identifying patients with signs of severity at the time of clinical suspicion of VL and can contribute to improving the surveillance system for reducing case fatalities. The classification of patients according to their prognosis for death may assist decision-making regarding the transfer of the patients to hospitals more capable of handling their condition, admission to the intensive care unit, and adequate support and specific treatment.
Author Summary
Visceral leishmaniasis (VL) is a fatal disease if not diagnosed and treated appropriately. In the present study, we investigated the risk factors associated with death caused by VL identifiable at the time of clinical suspicion. This study was conducted using all VL cases registered in Brazil during 2007 to 2011. The prognostic factors associated with death caused by VL were bleeding, age (1 year or younger and older than 19 years), Leishmania–human immunodeficiency virus (HIV) co-infection, bacterial infection, splenomegaly, edema, weakness, and jaundice. A prognostic scoring system for death caused by VL ranging from 0 to 14 was developed and validated using these risk factors. Patients with scores of 4 or more presented with a worsening prognosis. The scoring system showed good performance in identifying the severe cases. Classification of patients according to their prognosis for death can contribute to improving the clinical management of severe cases and reducing case-fatality rates associated with VL.
doi:10.1371/journal.pntd.0003374
PMCID: PMC4263605  PMID: 25503575
7.  S-Nitrosoglutathione Accelerates Recovery from 5-Fluorouracil-Induced Oral Mucositis 
PLoS ONE  2014;9(12):e113378.
Introduction
Mucositis induced by anti-neoplastic drugs is an important, dose-limiting and costly side-effect of cancer therapy.
Aim
To evaluate the effect of the topical application of S-nitrosoglutathione (GSNO), a nitric oxide donor, on 5-fluorouracil (5-FU)-induced oral mucositis in hamsters.
Materials and Methods
Oral mucositis was induced in male hamsters by two intraperitoneal administrations of 5-FU on the first and second days of the experiment (60 and 40 mg/kg, respectively) followed by mechanical trauma on the fourth day. Animals received saline, HPMC or HPMC/GSNO (0.1, 0.5 or 2.0 mM) 1 h prior to the 5-FU injection and twice a day for 10 or 14 days. Samples of cheek pouches were harvested for: histopathological analysis, TNF-α and IL-1β levels, immunohistochemical staining for iNOS, TNF-α, IL-1β, Ki67 and TGF-β RII and a TUNEL assay. The presence and levels of 39 bacterial taxa were analyzed using the Checkerboard DNA-DNA hybridization method. The profiles of NO released from the HPMC/GSNO formulations were characterized using chemiluminescence.
Results
The HPMC/GSNO formulations were found to provide sustained release of NO for more than 4 h at concentration-dependent rates of 14 to 80 nmol/mL/h. Treatment with HPMC/GSNO (0.5 mM) significantly reduced mucosal damage, inflammatory alterations and cell death associated with 5-FU-induced oral mucositis on day 14 but not on day 10. HPMC/GSNO administration also reversed the inhibitory effect of 5-FU on cell proliferation on day 14. In addition, we observed that the chemotherapy significantly increased the levels and/or prevalence of several bacterial species.
Conclusion
Topical HPMC/GSNO accelerates mucosal recovery, reduces inflammatory parameters, speeds up re-epithelization and decreases levels of periodontopathic species in mucosal ulcers.
doi:10.1371/journal.pone.0113378
PMCID: PMC4257535  PMID: 25478918
8.  Further characterization of Tsol-p27 as a diagnostic antigen in sub-Saharan Africa 
Experimental parasitology  2013;135(3):573-579.
Commercial antigens used to diagnose human neurocysticercosis are obtained from either a soluble parasite extract or a parasite-derived glycoprotein fraction. The aim of the present study was to identify antigenic proteins as potential diagnostic candidates in Mozambique. Soluble proteins from Taenia solium cysticerci were separated by two-dimensional electrophoresis and blotted onto nitrocellulose membranes. Subtracted hybridization was performed with serum samples obtained from patients with neurocysticercosis (NCC) and from a NCC-negative control group. Six antigenic proteins were identified and sequenced by liquid chromatography–mass spectrometry. Among these we found Tsol-p27, which was previously identified as a diagnostic candidate in a study conducted in Nicaragua, Central America. Here, we evaluated Tsol-p27 and the antigen cC1 as potential recombinant diagnostic reagents, and also investigated the localization and partial function of Tsol-p27. Immunoblotting demonstrated that Tsol-p27 was recognized by all 10 serum samples from NCC-positive individuals, whereas cC1 was identified by only five of the 10 positive sera. None of the antigens were recognized by negative control sera. Despite the limited number of serum samples evaluated in this study, the results suggest that Tsol-p27 can be a suitable candidate for diagnosis of human NCC, not only in Central America but also in sub-Saharan Africa.
doi:10.1016/j.exppara.2013.09.006
PMCID: PMC4257600  PMID: 24042013
Cysticercosis; Diagnosis; Immunoreactive proteins; Serology; Taenia solium
10.  Age estimation using the radiographic visibility of the periodontal ligament in lower third molars in a Portuguese population 
Objectives: The mineralization of third molars has been used repeatedly as a method of forensic age estimation. However, this procedure is of little use beyond age 18, especially to determinate if an individual is older than 21 years of age; thus, the development of new approaches is essential. The visibility of the periodontal ligament has been suggested for this purpose. The aim of this work was to determine the usefulness of this methodology in a Portuguese population. Study Design: Periodontal ligament visibility was assessed in the lower third molars, using a sample of 487 orthopantomograms, 228 of which belonging to females and 259 to males, from a Portuguese population aged 17 to 31 years. A classification of four stages based on the visual phenomenon of disappearance of the periodontal ligament of fully mineralized third molars was used. For each stage, median, variance, minimal and maximal age were assessed. Results: The relationship between age and stage of periodontal ligament had a statistical significance for both sexes. In this population, stage 3 can be used to state that a male person is over 21 years-old; for females, another marker should be used. Conclusions: This technique can be useful for determining age over 21, particularly in males. Differences between studies are evident, suggesting that specific population standards should be used when applying this technique.
Key words:Forensic sciences, forensic odontology, age estimation, third molar, periodontal ligament.
doi:10.4317/jced.51813
PMCID: PMC4312684
11.  Death by dengue fever in a Brazilian child: a case report 
BMC Research Notes  2014;7(1):855.
Background
Dengue is an important worldwide public health problem, and continues to spread in Brazil. This article presents the first Brazilian case report of the death of an indigenous child by dengue fever.
Case presentation
In August 2013, a child aged 2 years and from the Tremembé ethnic group, who was previously healthy with no complaints, suddenly presented intense crying, precordial pain, and general malaise. A few minutes after these non-specific symptoms, the patient started tonic–clonic convulsions and had cyanosis, a substantial increase in body temperature to the touch, cold sudoresis, sphincter relaxation, and unconsciousness. This situation remained for 15 minutes, progressing to respiratory insufficiency, with consequent absence of peripheral pulses. Death was confirmed approximately 40 minutes after the first symptoms. An autopsy was performed using the usual techniques. Immunohistochemistry was positive for dengue, and microscopic examination indicated micro perivascular edema and cerebral hemorrhage.
Conclusion
Considering that the death occurred during the major endemic seasonal period for dengue fever, primary clinical evidence suggestive of viral infection presenting with sudden and quick death, and positive immunohistochemistry results, the case was closed as severe dengue fever. Clinicians must consider dengue as a diagnostic hypothesis among the indigenous population in Brazil.
doi:10.1186/1756-0500-7-855
PMCID: PMC4255653  PMID: 25428248
Autopsy; Death; Dengue; Indigenous
12.  Hepatitis A virus subgenotyping based on RT-qPCR assays 
BMC Microbiology  2014;14(1):296.
Background
The hepatitis A virus (HAV) is the most frequent cause of viral hepatitis worldwide and is recognized as one of the most widespread foodborne pathogens. HAV genotypes and subtypes differ in their geographic distribution and the incidence of HAV infection varies considerably among countries, and is particularly high in areas with poor sanitation and hygiene. Phylogenetic analyses are traditionally used in clinical microbiology for tracing the geographic origin of HAV strains. In food microbiology, this approach is complicated by the low contamination levels of food samples. To date, real-time reverse-transcription PCR has been one of the most promising detection methods due to its sensitivity, specificity and ability to deliver quantitative data in food samples, but it does not provide HAV subtyping information.
Results
Six subtype-specific RT-qPCR assays were developed for human HAV. The limit of detection of HAV was 50 genome copies/assay for subtype IIB, 500 genome copies assay for IA, IB, IIA and IIIB and 5000 genome copies/assay for IIIA. The specificity of the assays was evaluated by testing reference isolates and in vitro HAV RNA transcripts. No significant cross reactivity was observed. Subtyping results concordant with sequencing analysis were obtained from 34/35 clinical samples. Co-infection with a minor strain of a different subtype was suggested in 5 cases and a recombinant event in one case.
Conclusions
These RT-qPCR assays may be particularly useful for accurately tracing HAV in low-level contaminated samples such as food matrices but also to allow co-infection identification in human samples.
doi:10.1186/s12866-014-0296-1
PMCID: PMC4258257  PMID: 25420941
Hepatitis A virus; RT-qPCR assays; Genotyping
13.  Leishmania infantum Ecto-Nucleoside Triphosphate Diphosphohydrolase-2 is an Apyrase Involved in Macrophage Infection and Expressed in Infected Dogs 
Background
Visceral leishmaniasis is an important tropical disease, and Leishmania infantum chagasi (synonym of Leishmania infantum) is the main pathogenic agent of visceral leishmaniasis in the New World. Recently, ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) were identified as enablers of infection and virulence factors in many pathogens. Two putative E-NTPDases (∼70 kDa and ∼45 kDa) have been found in the L. infantum genome. Here, we studied the ∼45 kDa E-NTPDase from L. infantum chagasi to describe its natural occurrence, biochemical characteristics and influence on macrophage infection.
Methodology/Principal Findings
We used live L. infantum chagasi to demonstrate its natural ecto-nucleotidase activity. We then isolated, cloned and expressed recombinant rLicNTPDase-2 in bacterial system. The recombinant rLicNTPDase-2 hydrolyzed a wide variety of triphosphate and diphosphate nucleotides (GTP> GDP  =  UDP> ADP> UTP  =  ATP) in the presence of calcium or magnesium. In addition, rLicNTPDase-2 showed stable activity over a pH range of 6.0 to 9.0 and was partially inhibited by ARL67156 and suramin. Microscopic analyses revealed the presence of this protein on cell surfaces, vesicles, flagellae, flagellar pockets, kinetoplasts, mitochondria and nuclei. The blockade of E-NTPDases using antibodies and competition led to lower levels of parasite adhesion and infection of macrophages. Furthermore, immunohistochemistry showed the expression of E-NTPDases in amastigotes in the lymph nodes of naturally infected dogs from an area of endemic visceral leishmaniasis.
Conclusions/Significance
In this work, we cloned, expressed and characterized the NTPDase-2 from L. infantum chagasi and demonstrated that it functions as a genuine enzyme from the E-NTPDase/CD39 family. We showed that E-NTPDases are present on the surface of promastigotes and in other intracellular locations. We showed, for the first time, the broad expression of LicNTPDases in naturally infected dogs. Additionally, the blockade of NTPDases led to lower levels of in vitro adhesion and infection, suggesting that these proteins are possible targets for rational drug design.
Author Summary
Visceral leishmaniasis is a dangerous and important, but neglected, tropical disease that affects millions of people, mainly in underdeveloped and developing countries. Presently, there are no vaccines against Leishmaniasis, and the few drugs with which the disease is treated have low efficacy and high side effects. The pathogenic agent of this disease in the New World is Leishmania infantum chagasi. In this work, we studied a protein from this parasite named ENTPDase-2. We expressed it in a bacterial system, purified it and characterized it as a genuine nucleotidase of the ENTPDase family. This protein seems to be localized at the surface of the parasite and in other intracellular locations. ENTPDase seems to facilitate in vitro infection because its blockade leads to lower levels of infection of macrophages. In addition, the protein is found in naturally infected dogs. A previous study demonstrated that ENTPDase-2 from L. infantum chagasi is a good antigen for immunodiagnosis of canine visceral leishmaniasis. We have now studied this protein in greater depth and suggest that it may be a good target for drug development.
doi:10.1371/journal.pntd.0003309
PMCID: PMC4230930  PMID: 25393008
14.  Evaluation of tests to predict metallo-β-lactamase in cystic fibrosis (CF) and non-(CF) Pseudomonas 
Brazilian Journal of Microbiology  2014;45(3):835-839.
Double disks synergy test (DDST) and combined disks test (CD) were evaluated to predict the presence of metallo-β-lactamase in 70 Pseudomonas aeruginosa isolates recovered from cystic fibrosis and non-cystic fibrosis patients. DDSTCAZ-EDTA 1 cm and CDIMP-EDTA tests showed the best accuracy (94.3%). Furthermore, for other combinations, accuracy unsatisfactory was obtained.
PMCID: PMC4204966  PMID: 25477915
Pseudomonas aeruginosa; metallo-β-lactamase; phenotypic tests
15.  Hypovitaminosis D in HIV-infected patients in Lisbon: a link with antiretroviral treatment 
Journal of the International AIDS Society  2014;17(4Suppl 3):19826.
Introduction
Recent data indicates that low vitamin D (25(OH)D) levels can lead to a worst prognosis in HIV-infected individuals, even in those on successful antiretroviral therapy (ART) [1]. Portugal is the European country that has the largest average sun exposure time but prevalence of hypovitaminosis D is mostly unknown. Our aim was to determine the prevalence of hypovitaminosis D in HIV patients in Lisbon and the possible association with ART.
Methods
From 2012 to January 2014, plasma samples from 518 HIV-infected patients were collected to 25(OH)D levels determination. Data on demographic features (age, ethnicity, country of origin) and clinical/laboratory parameters were collected from clinical files (HIV subtype, CD4+ cell count, CD4+ nadir, viral load (VL), HBV/HCV co-infection and ART). 25(OH)D status was defined as: deficiency <20 ng/mL, insufficiency 20–30 ng/mL, optimal >30 ng/mL.
Results
Median age was 46 years old (±11); 62.0% (321/518) were male; 81.3% (421/518) were Caucasian and 78.6% (407/518) were Portuguese. Most patients (96.1%; 498/518), were HIV-1 infected, 22.9% (114/498) and 4.0% (20/498) of them were HCV and/or HBV co-infected, respectively. Mean CD4+ cell count was 648 cells/µL (±333) and nadir was 219 cells/µL (±179). On treated patients VL was <40 HIV RNA/mL in 86.7% (417/481). The median levels of 25(OH)D was 20.0 ng/mL (range 4.1–99.7) and we found differences between values observed during Winter (median 16.7 ng/mL) and Summer (median 24.9 ng/mL) (p<0.0001). Low 25(OH)D levels were not correlated to ethnicity (p=0.066). 25(OH)D level was <30 ng/mL in 80.1% (415/518) of the patients, from which 30.9% (160/518) and 49.2% (255/518) had insufficiency and deficiency levels, respectively. Most (92.9%; 481/518) were on ART: regimens containing PI (47.5%), NNRTI (40.3%; 41.3% on NVP and 58.7% on EFV), II (1.2%), PI+NNRTI (3.9%). Comparing the 25(OH)D level along the different ART regimens (PI vs NVP; PI vs EFV; PI vs no ART) there were differences between PI and EFV (p=0.044).
Conclusions
In this study, 80.1% of the HIV-infected patients had hypovitaminosis D and ART regimens with EFV were more often associated with low 25(OH)D levels. Understanding the impact of the different antiretroviral drugs on 25(OH)D status could help to decide in clinical practice whether 25(OH)D supplementation or drug switch are the best options for each patient.
doi:10.7448/IAS.17.4.19826
PMCID: PMC4225260  PMID: 25397570
16.  Molecular Epidemiology of Merkel Cell Polyomavirus: Evidence for Geographically Related Variant Genotypes 
Journal of Clinical Microbiology  2014;52(5):1687-1690.
Merkel cell polyomavirus (MCPyV) is linked to a cutaneous cancer mainly occurring in Caucasians. DNA from skin swabs of 255 adults, originating from the 5 continents, were subjected to MCPyV PCRs. Phylogenetic analyses demonstrate the existence of 5 major geographically related MCPyV genotypes (Europe/North America, Africa [sub-Saharan], Oceania, South America, and Asia/Japan).
doi:10.1128/JCM.02348-13
PMCID: PMC3993677  PMID: 24523477
17.  Quantification of BOLD fMRI Parameters to Infer Cerebrovascular Reactivity of the Middle Cerebral Artery 
Journal of magnetic resonance imaging : JMRI  2012;38(5):10.1002/jmri.23943.
Purpose
To quantify the amplitude and temporal aspects of the BOLD response to an auditory stimulus during normocapnia and hypercapnia in healthy subjects in order to establish which BOLD parameters are best suited to infer the cerebrovascular reactivity (CVR) in the middle cerebral artery (MCA) territory.
Materials and Methods
Twenty healthy volunteers (mean age: 23.6 ± 3.7 years, 11 women) were subjected to a functional paradigm composed of five epochs of auditory stimulus (3 seconds) intercalated by six intervals of rest (21 seconds). Two levels of hypercapnia were achieved by a combination of air and CO2 while the End-Tidal CO2 (ETCO2) was continually measured. An autoregressive method was applied to analyze four parameters of the BOLD signal: onset-time, time-to-peak, full-width-at-half-maximum (FWHM) and amplitude.
Results
BOLD onset time (p < 0.001) and FWHM (P < 0.05) increased linearly, while BOLD amplitude decreased (p < 0.001) linearly with increasing levels of hypercapnia. Test-retest for reproducibility in five subjects revealed excellent concordance for onset time and amplitude.
Conclusion
The robust linear dependence of BOLD onset time, FWHM and amplitude to hypercapnia envisages future application of this protocol in clinical studies aimed at evaluating CVR of the MCA territory.
doi:10.1002/jmri.23943
PMCID: PMC3586985  PMID: 23188762
BOLD; fMRI; Hypercapnia; Cerebrovascular Reactivity; Auditory Stimulus; Middle Cerebral Artery
18.  Separate Evolution of Virulent Newcastle Disease Viruses from Mexico and Central America 
Journal of Clinical Microbiology  2014;52(5):1382-1390.
An outbreak of Newcastle disease (ND) in poultry was reported in Belize in 2008. The characteristics of three virulent Newcastle disease virus (NDV) isolates from this outbreak (NDV-Belize-3/08, NDV-Belize-4/08, and NDV-Belize-12/08) were assessed by genomic analysis and by clinicopathological characterization in specific-pathogen-free (SPF) chickens. The results showed that all three strains belong to NDV genotype V and are virulent, as assessed by the intracerebral pathogenicity index and the polybasic amino acid sequence at the fusion protein cleavage site. In 4-week-old SPF chickens, NDV-Belize-3/08 behaved as a typical velogenic viscerotropic NDV strain, causing severe necrohemorrhagic lesions in the lymphoid organs, with systemic virus distribution. Phylogenetic analysis of multiple NDV genotype V representatives revealed that genotype V can be divided into three subgenotypes, namely, Va, Vb, and Vc, and that all tested Belizean isolates belong to subgenotype Vb. Furthermore, these isolates are nearly identical to a 2007 isolate from Honduras and appear to have evolved separately from other contemporary viruses circulating in Mexico, clustering into a new clade within NDV subgenotype Vb.
doi:10.1128/JCM.00066-14
PMCID: PMC3993629  PMID: 24523463
19.  An Embedded 4-Channel Receive-Only RF Coil Array for fMRI Experiments of the Somatosensory Pathway in Conscious Awake Marmosets at 7T 
NMR in biomedicine  2013;26(11):1395-1402.
Functional Magnetic Resonance Imaging (fMRI) has established itself as the main research tool in neuroscience and brain cognitive research. The common marmoset (Callithrix jacchus) is a non-human primate model of increasing interest in biomedical research. However, commercial MRI coils for marmosets are not generally available. The present work describes the design and construction of a 4-channel receive-only surface RF coil array with excellent signal-to-noise ratio (SNR) specifically optimized for fMRI experiments in awake marmosets in response to somatosensory stimulation. The array was designed as part of a helmet-based head restraint system used to prevent motion during the scans. High SNR was obtained by building the coil array using a thin and flexible substrate glued to the inner surface of the restraint helmet, so as to minimize the distance between the array elements and the somatosensory cortex. Decoupling between coil elements was achieved by partial geometrical overlapping and by connecting them to home-built low input impedance preamplifiers. In vivo images show excellent coverage of the brain cortical surface with high sensitivity near the somatosensory cortex. Embedding the coil elements within the restraint helmet allowed fMRI data in response to somatosensory stimulation to be collected with high sensitivity and reproducibility in conscious, awake marmosets.
doi:10.1002/nbm.2965
PMCID: PMC4200535  PMID: 23696219
animal models; marmosets; magnetic resonance imaging; phased arrays; receive-only RF coils
20.  Foodborne Transmission of Hepatitis E Virus from Raw Pork Liver Sausage, France 
Emerging Infectious Diseases  2014;20(11):1945-1947.
doi:10.3201/eid2011.140791
PMCID: PMC4214313  PMID: 25340356
HEV; transmission; foodborne; viruses; France; pork; zoonoses
21.  Comparison of condylar displacement between three biotypological facial groups by using mounted models and a mandibular position indicator 
Korean Journal of Orthodontics  2014;44(6):312-319.
Objective
Facial-type-associated variations in diagnostic features have several implications in orthodontics. For example, in hyperdivergent craniofacial types, growth imbalances are compensated by displacement of the condyle. When diagnosis and treatment planning involves centric relation (CR), detailed knowledge of the condylar position is desirable. The present study aimed to measure condylar displacement (CD) between CR and maximum intercuspation in three facial types of an asymptomatic orthodontic population.
Methods
The study was conducted in 108 patients classified into three groups of 36 individuals each (27 women and 9 men; mean age, 20.5 years), based on the following facial patterns: hyperdivergent, hypodivergent, and intermediate. To quantify CD along the horizontal and vertical axes, the condylar position was analyzed using mounted casts on a semi-adjustable articulator and a mandibular position indicator. The Student t-test was used to compare CD between the groups.
Results
Vertical displacement was found to be significantly different between the hyperdivergent and hypodivergent groups (p < 0.0002) and between the hyperdivergent and intermediate groups (p < 0.0006). The differences in horizontal displacement were not significant between the groups. In each group, vertical CD was more evident than horizontal displacement was.
Conclusions
All facial types, especially the hyperdivergent type, carried a significantly high risk of CD. Therefore, the possibility of CD should be carefully evaluated and considered in the assessment of all orthodontic cases in order to accurately assess jaw relationships and avoid possible misdiagnosis.
doi:10.4041/kjod.2014.44.6.312
PMCID: PMC4250665  PMID: 25473647
Cephalometrics; Centric relation; Condylar displacement; Growth evaluation; Maximum intercuspation
22.  The effect of mouthwashes containing biguanides on the progression of erosion in dentin 
BMC Oral Health  2014;14(1):131.
Background
Dental erosion is caused by frequent exposure to acids without the involvement of microorganism. This study analyzed the effect of biguanides (polyhexamethylene biguanide – PHMB and chlorhexidine – CHX) on dentin erosion due to their possible influence on the enzymatic degradation of the demineralized organic matrix.
Method
Sixty bovine dentin specimens were prepared. On both sides of their surface, nail varnish was applied to maintain the reference surfaces for the determination of dentin loss. Samples were cyclically de- and remineralized for 6 days. Demineralization was performed with a 0.87 M citric acid solution (6×5 min daily). Thereafter, samples were treated with distilled water (negative control), 0.12% CHX (positive control), 0.07% PHMB, Sanifill Perio Premium™ (0.07% PHMB plus 0.05% NaF), or F solution (0.05% NaF) for 1 min and then subjected to enzymatic challenge for 10 min using a bacterial collagenase (Clostridium hystoliticum, 100 μg/ml). Dentin loss was assessed using profilometry (μm) daily. Data were analyzed using 2-way repeated measures-ANOVA and Bonferroni’s test (p < 0.05).
Results
Dentin loss progressed significantly for all groups during the 6 days. After the 3rd day, Sanifill Premium™, CHX, and PHMB significantly reduced dentin erosion compared to control. On the 6th day, the lowest mean (±SD) dentin loss was observed for Sanifill Perio Premium™ (94.4 ± 3.9 μm). PHMB and CHX led to intermediate dentin loss (129.9 ± 41.2 and 135.3 ± 33.5 μm, respectively) that was significantly lower than those found for negative control (168.2 ± 6.2 μm). F (157.4 ± 6.1 μm) did not significantly differ from negative control.
Conclusions
Sanifill Perio Premium™ mouthwash has a good potential to reduce dentin loss, which might be associated with the presence of PHMB.
doi:10.1186/1472-6831-14-131
PMCID: PMC4228096  PMID: 25358631
Biguanide; Demineralization; Dentin; Erosion
23.  Magnetic resonance imaging-guided occult breast lesion localization and simultaneous sentinel lymph node mapping 
Background
Radio-guided occult lesion localization is a valid technique for the diagnosis of suspicious non-palpable lesions. Here we determine the feasibility of pre-operative localization of occult suspect non-palpable breast lesions using radio-guided occult lesion localization, as well as for identifying the sentinel lymph node.
Methods
This is a descriptive study of data collected retrospectively. Pre-operative mapping of 34 breast lesions in 25 patients suspected of being malignant was performed using conventional imaging methods with a magnetic resonance imaging-guided radiopharmaceutical injection.
Results
The mean time required to perform the localization was 25 minutes. After resection of the lesions using a gamma probe, malignancy was confirmed in fifteen patients (60.0%), with nine invasive ductal carcinomas, two invasive lobular carcinomas, and four in situ ductal carcinomas The resection was confirmed by the complete removal of the radioactive material. The pathologic results and images were concordant in all but two cases, which were submitted for new magnetic resonance imaging examinations and surgery that confirmed the malignancies. Of the 15 patients with confirmed malignancies, 10 had sentinel lymph node resection. Of these, eight were negative for metastases, one had micro-metastases and one had confirmed metastases. Three patients had full axillary node dissection, with metastases found in only one. No side effects were observed with magnetic resonance-guided radiopharmaceutical injection.
Conclusions
The sentinel node occult lesion localization technique is a simple, reproducible and effective alternative approach to occult lesions compared to other methods, such as mammotomy and the hook-wire localization technique, for mapping suspect breast lesions and identifying lymph node metastasis.
doi:10.1186/1477-7819-12-320
PMCID: PMC4219021  PMID: 25341393
24.  The Long-HER Study: Clinical and Molecular Analysis of Patients with HER2+ Advanced Breast Cancer Who Become Long-Term Survivors with Trastuzumab-Based Therapy 
PLoS ONE  2014;9(10):e109611.
Background
Trastuzumab improves survival outcomes in patients with HER2+ metastatic breast cancer. The Long-Her study was designed to identify clinical and molecular markers that could differentiate long-term survivors from patients having early progression after trastuzumab treatment.
Methods
Data were collected from women with HER2-positive metastatic breast cancer treated with trastuzumab that experienced a response or stable disease during at least 3 years. Patients having a progression in the first year of therapy with trastuzumab were used as a control. Genes related with trastuzumab resistance were identified and investigated for network and gene functional interrelation. Models predicting poor response to trastuzumab were constructed and evaluated. Finally, a mutational status analysis of selected genes was performed in HER2 positive breast cancer samples.
Results
103 patients were registered in the Long-HER study, of whom 71 had obtained a durable complete response. Median age was 58 years. Metastatic disease was diagnosed after a median of 24.7 months since primary diagnosis. Metastases were present in the liver (25%), lungs (25%), bones (23%) and soft tissues (23%), with 20% of patients having multiple locations of metastases. Median duration of response was 55 months. The molecular analysis included 35 patients from the group with complete response and 18 patients in a control poor-response group. Absence of trastuzumab as part of adjuvant therapy was the only clinical factor associated with long-term survival. Gene ontology analysis demonstrated that PI3K pathway was associated with poor response to trastuzumab-based therapy: tumours in the control group usually had four or five alterations in this pathway, whereas tumours in the Long-HER group had two alterations at most.
Conclusions
Trastuzumab may provide a substantial long-term survival benefit in a selected group of patients. Whole genome expression analysis comparing long-term survivors vs. a control group predicted early progression after trastuzumab-based therapy. Multiple alterations in genes related to the PI3K-mTOR pathway seem to be required to confer resistance to this therapy.
doi:10.1371/journal.pone.0109611
PMCID: PMC4203741  PMID: 25330188
25.  Functional Characterization of a Full Length Pregnane X Receptor, Expression in vivo, and Identification of PXR Alleles in Zebrafish (Danio rerio) 
Aquatic toxicology (Amsterdam, Netherlands)  2013;0:10.1016/j.aquatox.2013.09.014.
The pregnane X receptor (PXR) (nuclear receptor NR1I2) is a ligand activated transcription factor, mediating responses to diverse xenobiotic and endogenous chemicals. The properties of PXR in fish are not fully understood. Here we report on cloning and characterization of full-length PXR of zebrafish, Danio rerio, and pxr expression in vivo. Initial efforts gave a cDNA encoding a 430 amino acid protein identified as zebrafish pxr by phylogenetic and synteny analysis. The sequence of the cloned Pxr DNA binding domain was highly conserved, with 74% identity to human PXR, while the ligand-binding domain (LBD) of the cloned sequence was only 44% identical to human PXR-LBD. Sequence variation among clones in the initial effort prompted sequencing of multiple clones from a single fish. There were two prominent variants, one sequence with S183, Y218 and H383 and the other with I183, C218 and N383, which we designate as alleles pxr*1 (nr1i2*1) and pxr*2 (nr1i2*2), respectively. In COS-7 cells co-transfected with a PXR-responsive reporter gene, the full-length Pxr*1 (the more common variant) was activated by known PXR agonists clotrimazole and pregnenolone 16α-carbonitrile but to a lesser extent than the full-length human PXR. Activation of full-length Pxr*1 was only 10% of that with the Pxr*1 LBD. Quantitative real time PCR analysis showed prominent expression of pxr in liver and eye, as well as brain and intestine of adult zebrafish. The pxr was expressed in heart and kidney at levels similar to that in intestine. The expression of pxr in liver was weakly induced by ligands for mammalian PXR or CAR (NR1I3). The results establish a foundation for PXR studies in this vertebrate model. PXR allelic variation and the differences between the full-length PXR and the LBD in reporter assays have implications for assessing the action of PXR ligands in zebrafish.
doi:10.1016/j.aquatox.2013.09.014
PMCID: PMC3873750  PMID: 24121122

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