The aim of the present study was to investigate the correlation between initialalveolar bone density of upper central incisors (ABD-UI) and external apical rootresorption (EARR) after 12 months of orthodontic movement in cases withoutextraction. 1) andafter 12 months of treatment (T2). ABD-UI and EARR were measured bymeans of densitometry.  A total of 47 orthodontic patients 11 years old or older were submitted toperiapical radiography of upper incisors prior to treatment .  No statistically significant correlation was found between initial ABD-UI andEARR at T Based on the present findings, alveolar density assessed through periapicalradiography is not predictive of root resorption after 12 months of orthodontictreatment in cases without extraction. Radiographs were taken using the RX Timex 70 C  and Pro 70-Intra  x-rayequipment operating with 70 kVp, 7 mA and a 0.25-second exposure time.oC). Intermediate washing was standardized at 30 seconds and fixing timewas standardized at 10 minutes.All procedures were approved by the State University of Maringá Institutional ReviewBoard, Brazil (190 ⁄ 2008). Each volunteer was submitted to periapical radiography ofthe upper incisor region either immediately prior to or immediately after bracketbonding , a trapezoidal region of interest was outlined in the alveolar boneprocess of the apical region of upper central incisors to estimate optical densityexpressed in grey level values ranging from 0 (black) to 255 (white).1 and TLT2; CLT1 andCLT2) were measured at a precision of 0.1 mm with the aid of CorelDRAWX4 software.,,,,,2 wascalculated using the following equation:,,Tooth length (TL) and crown length (CL) of upper incisors #11 and #21) at bothevaluation times  was also employed.Although no statistically significant differences were found between the first andsecond measures, the mean of each variable was used in the subsequent statisticaltests to minimize random error.2. Significance level was set at 5% (P< 0.05) for all statistical tests.Neither EARR nor ABD-UI had normal distribution (Lilliefors test). Thus,nonparametric Spearman correlation test was used to determine potential correlationsbetween initial ABD-UI and EARR at TNo significant differences were found between teeth #11 and #21 regarding EARR andABD-UI. After 12 months of treatment, mean EARR was 3.5%  . Three p,,,,Apical root resorption can occur in the early stages of orthodontic treatment,especially in upper incisors which generally undergo greater movement in comparison toother teeth.,Periapical radiography is the method of choice to assess apical root resorption stemmingfrom orthodontic treatment, mainly due to the cost-benefit ratio of this method.Periapical radiographs are known to have greater reliability in comparison to lateraland panoramic radiographs.,-In previous studies employing dual-energy x-ray absorptiometry (DXA), systemic BMD(lumbar spine and femur) was not correlated with maxillomandibular alveolar BMD.,,,A study investigating alveolar density of anterior and posterior regions of the maxillaand mandible found that only the densities of the anterior maxilla and posteriormandible were correlated.The dentoalveolar complex of each patient is unique in terms of size, orientation anddensity, and associations between EARR and alveolar density and morphology have not yetbeen established.,,,As cortical bone is denser than trabecular bone, a number of studies have investigatedassociations between bone density and root resorption in an indirect manner by analyzingthe proximity of roots and cortical bone during orthodontic movement.Kaley and PhilipsHoriuchi et al,,It makes sense to measure the total displacement of a tooth by the root apex which iswhere pathological resorption occurs.Based on the present findings, alveolar density in the apical region of upper incisorsassessed by means of periapical radiographs is not predictive of root resorption 12months after orthodontic treatment in cases without extraction.


Hypertrophic cardiomyopathy is the most common monogenic disorder in cardiology. Despite important advances in understanding disease pathogenesis, it is not clear how flaws in individual sarcomere components are responsible for the observed phenotype. The aim of this article is to provide a brief interpretative analysis of some currently proposed pathophysiological mechanisms of hypertrophic cardiomyopathy, with a special emphasis on alterations in the cardiac mechanical properties. Hypertrophic cardiomyopathy (HCM) is a relatively rare inherited cardiovascular disease that affects approximately 1 in 500 young individuals and that accounts for 35% of sudden cardiac death cases in young athletes  and myosin binding protein C (MYBPC3) are the most commonly involved genes, followed by troponin I (TNNI3), troponin T (TNNT2), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), alpha tropomyosin (TPM1), and cardiac actin (ACTC)  . Myocardial deformation analysis in the form of magnetic resonance imaging (MRI) has revealed strain dissimilarities between the endocardial and epicardial layers of the left ventricle (LV) wall and among different LV segments  or slow (MYH7). There are certain developmental, environmental, epigenetic and hormonal factors  that regulate the expression of MYH6 and MYH7, which are encoded by a gene cluster on chromosome 14 Gupta, . MYH7 isSeveral studies have examined the mechanical properties of the epicardial and endocardial layers . In general terms, patients with unexplained syncope, documented ventricular tachycardia or aborted SCD, positive family history for SCD, maximal LV wall thickness >30 mm and abnormal drop in blood pressure during exercise, treated with an implantable defibrillator . The mechanisms analyzed in this paper shed some light on the relation of mutations to disease phenotype, although they may not necessarily apply to all patients. A better understanding of the pathophysiological mechanisms leading to hypertrophy will contribute to the further improvement of treatment and to risk stratification for sudden cardiac death.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


AbstractReduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies.Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; β-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer–Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient Considered by the American College of Obstetricians and Gynecologists “the most common and complex problem in modern obstetrics", fetal growth restriction still needs clear criteria because intrauterine fetal growth is not defined by clear parameters but mainly estimated on the basis of multiple factors. Research in this field is trying to find predictive parameters, with the goal of reaching an early diagnosis, which would lead to a better management of the condition [2]. Intrauterine growth restriction is defined as the pathologic inhibition of intrauterine fetal growth and the failure of the fetus to achieve its growth potential [3]. While the majority of such pregnancies will have a physiologically normal fetus that is simply small for gestational age (SGA), pathological fetal growth-restriction is a different category and the ability to differentiate such a condition from SGA is limited. A healthy fetus with estimated weight or birth weight below the 10th percentile according to population standards is commonly defined as SGA [5]. Pathological SGA is known as intrauterine growth restriction (IUGR) or fetal growth restriction (FGR). Fetal development is evaluated through comparison between estimated fetal weight or birth weight and references or standards for different gestational ages [6].Impaired fetal growth is seen in about 10% of pregnancies [ Why detecting intrauterine growth restriction?9]. IUGR is associated with increased fetal and neonatal mortality and morbidity, being linked to immediate perinatal adverse events  and also to adult pathologic conditions  [14]. Former studies showed that cerebral palsy was found to be 4-6 times more frequent in newborns below the 10th percentile compared to those between the 25th and the 75th percentile [15]. A strong association between FGR and stillbirth was also confirmed [16]. From the moment FGR was recognized as a cause of perinatal death, almost 50% of stillbirth were identified as FGR [17], resulting in a decrease of unexplained stillbirth from 67-70% to 15% [18]. Therefore, fetal growth impairment identification triggers a 4-time reduction in neonatal complications and death [14].  Fetal growth is known to be an important predictor of pregnancy outcome and reflects the interaction between physiological and pathological factors influencing the fetus [19]. In addition, the investigation of possible IUGR/FGR has the objective of an early detection and appropriate management that could lower the percentage of stillbirths and other perinatal complications, hoping that the identification of low risk fetuses would decrease the number of unnecessary surveillance [11].  In about 75% of the cases, IUGR remains unrecognized until birth and the diagnosis comes retrospectively, whereas in low-risk pregnancy the detection rate is about 15% [ IUGR: risk factors21]. The main factors assessed in clinical practice include: maternal factors , fetal factors , adnexal factors  [22]. The risk factors for IUGR comprise a wide range of conditions and their assessment should be seriously taken into account, as they are easy to perform and are routinely used during pregnancy [23]. Further diagnostic tests could have a better relevance in a selected high-risk population [24]. However, these clinical factors have shown a different impact for each individual case and their relevance, as effective screening tools have not been proved yet [25].  A positive history for risk factors of IUGR can raise the problem of an increased surveillance with the specific goal of an early detection of growth insufficiency [26]. For this purpose, biochemical serum markers, Doppler study of uterine arteries, placental volume and vascularization as well as first trimester growth pattern, were the object of study for IUGR/FGR assessment. As presented above, IUGR/FGR is linked to serious pregnancy complications and early assessment of the condition is a main topic of research today. Furthermore, preventive measures like administration of low dose aspirin showed efficacy in IUGR treatment if administered before the 16th week of gestation [ Serum markers linked to IUGR27]. The impaired spiral artery transformation is leading to weak development of the utero-placental circulation and is implied in the pathology of preeclampsia and IUGR [21]. The placentation process starts with the migration of trophoblastic cells that invade the walls of spiral arteries and transform them from small caliber high resistant vessels into wide caliber low resistant vessels that deliver blood at low pressure to the intervillous space. Then, the utero-placental circulation develops in two stages: the first stage (until the 10th week of gestation) consists in endovascular plugging of the spiral arteries by trophoblastic cells, subsequently followed by invasion and destruction of the intradecidual spiral arteries; the second stage (between 14-16 weeks of gestation) consists in the invasion of the inner miometrial part of the spiral arteries [21]. Several serum analytes have been studied in hope of finding a relevant marker linked to IUGR, but none of them proved to be sufficiently accurate to be used in routine clinical practice as single predictive marker. The combined approach using clinical data, serum markers, biophysical parameters  showed increased predictive relevance [28]. Maternal serum analytes were first studied with the aim of screening for aneuploidies during the first or second trimester of pregnancy and their use was then further extended in many studies to evaluate their utility as markers for impaired placentation. The trophoblastic invasion failure is thought to be responsible of the changes in the concentration of serum placental products [29]. Furthermore, in the group of 4390 women with singleton pregnancy evaluated by Spencer et al. in 2005 the maternal low levels of serum PAPP-A at 11-13 weeks of gestation resulted significantly associated to adverse pregnancy outcomes [30]. Low levels of PAPP-A were mentioned as predictors of IUGR also by Goetzinger et al. in 2009 and Poon et al. in 2009 . The sensitivity of detecting IUGR for a first trimester PAPP-A level below the 5th percentile ranges only between 8% and 33% and PAPP-A as single marker is an insufficient screening tool for IUGR [33].  Pregnancy associated plasma protein A (PAPP-A), an Insulin–like Growth Factor Binding Protein Protease whose levels depend on placental volume and function, was assessed in several studies with congruent results. In 2000, Ong et al. evaluated 5584 singleton pregnancies at 10-14 weeks of gestation and measured maternal serum free beta human chorionic gonadotropin (β-hCG) and PAPP-A, concluding that low levels of maternal serum PAPP-A or β-hCG were associated with subsequent development of pregnancy complications [34]. Later, Gotzinger et al. showed that high levels of β-hCG were linked to SGA fetuses [31]. Overall, the predictivness of free β-hCG is unsatisfactory today [25]. Dugoff et al. evaluated 34271 pregnancies at 11-14 weeks of gestation and proved that maternal serum free β-hCG was mildly reduced in pregnancies that subsequently developed IUGR [36]. In 2008, in the name of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada, Gagnon et al. reviewed the obstetrical outcomes associated with abnormal levels of single or multiple maternal serum markers used in the screening for aneuploidy. PAPP-A, alphafetoprotein, β-hCG, estriol, unconjugated estriol, inhibin-A were the analytes assessed and among the conclusions an unexplained low PAPP-A (< 0.4 MoM) and/or a low hCG (< 0.5 MoM) in first trimester were associated with an increased frequency of adverse obstetrical outcomes [37]. As in the first trimester biochemical screening starts as early as 8wa, the detection of a low level of hyperglycosylated human chorionic gonadotrophin correlated with a low PAPP-A and resulted a marker of impaired placentation, showing 90% specificity and 69% sensitivity when adjusted for mean arterial pressure and parity .41]. In 2007, Chaftez et al. showed that low levels of first trimester PP-13 were associated with preterm birth in women with IUGR [42]. In 2008, Spencer et al. found poor association between PP-13 and pregnancy outcome like IUGR [43]. In 2008, using the integrated assessment of PP-13, PAPP-A and uterine artery Doppler at 11-13 weeks of gestation, Poon et al. determined a 20% detection rate of FGR at a false positive rate of 5% [44]. Placental Protein 13 (PP-13) is a peptide involved in placental implantation and vascular invasion and remodeling [45]. Soluble fms–like tyrosine kinase-1(sFlt-1) on the other hand, inhibits the effects of VEGF and PlGF by blocking their interaction with the specific receptors. The imbalance between the anti-angiogenic and angiogenic factors seems to be linked of preeclampsia and IUGR [45]. The recent meta-analysis performed by Conde-Agudela et al. in 2013 including 53 studies and 39974 women evaluated 37 new biomarkers among which: Angiogenesis-related biomarkers , Endothelial function/oxidative stress-related biomarkers ; Placental proteins/hormone-related biomarkers  and other markers like metabolomics and genetic biomarkers. Overall, none of the 37 novel biomarkers evaluated showed a significant accuracy for predicting IUGR [45]. Angiogenic factors implied in placentation like Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) were also evaluated in many studies [ Ultrasound markers21]. The Doppler ultrasound sampling of uterine arteries (UAD) is a useful non-invasive method for the assessment of the interaction between fetal and maternal hemodynamic compartment. Starting from the early studies of Campbell et al. and Trudinger et al. in the 1980s, this procedure has been reported in numerous following surveys and showed to be a promising technique for the prediction of the IUGR risk [46-48]. In case of an incomplete trophoblastic invasion of the spiral arteries, the maternal compartment failsed to transform from a high resistance to a low resistance flow district and this impairment is associated with the development of preeclampsia and IUGR. In these cases, a Resistence Index (RI) or a Pulsatility Index (PI) above the 90th-95th percentile and/or the presence of unilateral or bilateral notching is associated with a value of the RI >0,58 or a value of the PI >1,45 [49]. Therefore, in 1994 North et al. and in 1998 Irion et al. stated that UAD was not a reliable screening test for nulliparous women [51]. Further studies performed in the 2000s have evaluated UAD between 10-14 weeks of gestation finding low positive predictive values for IUGR and a slightly better prediction value for preeclampsia with IUGR or IUGR alone with delivery in less than 32 weeks [55]. Most of the studies published to date, disregarding if performed during the first or second trimester, agree that UAD modifications are linked to IUGR but are not a reliable single predictive marker for defining a low risk category [56]. An interesting approach proposed by Gomez et al. in 2006 showed that the sequence of changes in the uterine flow between the first and second trimester correlates with subsequent appearance of IUGR and the highest risk is held by women with persistent low vascular indices [54].  The early studies that assessed UAD were performed during the second trimester of gestation, between weeks 18-23 [49-54]. Although an increased resistance in the uterine arteries is associated with poor obstetric outcome like preeclampsia, IUGR or prematurity, the positive predictive value was found to be only 15% for IUGR [57]. Hung et al. evaluated color and spectral Doppler of the spiral arteries between 13-19 weeks and 20-25 weeks concluding that spiral artery Doppler assessment was not a sensitive tool for detection of IUGR in a low risk population [58]. Furthermore, in studies comparing normal outcome pregnancies versus complicated pregnancies, spiral arteries sampling failed to show any statistically significant predictive value, making spiral arteries Doppler study an insufficient method for screening of IUGR [59].Spiral arteries have been subjected to assessment during the first trimester. Mäkikallio et al. found that spiral arteries impedance decreased starting with the 5th week of gestation and uterine and arcuate artery lost their tonus starting with the 8th week .62]. In a region of interest, three indices are mostly calculated and used: Vascularization Index (VI): the ratio between color vessels and total vessels , representing the percentage of blood vessels in a region of interest; the Flow Index (FI): the sum of a color vessel’s signal intensity divided by the number of color vessels, representing the amount of blood corpuscles in the vessels in a region of interest; the Vascularization Flow Index (VFI): the ratio between the sum of the color vessel’s signal intensity and the total tissue vessels, representing the total number of blood corpuscles in the total tissue volume. In 2004, Merce et al. showed that the 3D-Power Doppler study of the placental vascularization in normal pregnancies is reproducible and seems to be a useful tool in performing “a placental biopsy" [63]. In 2008, Guiot et al. used this technique in the assessment of the 3rd trimester pregnancies complicated with IUGR and compared them to normal pregnancies, correlating VI, VFI and FI values to Umbilical Artery Doppler abnormalities (elevated Systolic/Diastolic ratios and absent End Diastolic Velocity), and the results showed that modifications in vascularization indices could be detected earlier than Umbilical Artery Doppler abnormalities [64]. In 2009, Noguchi et al. performed “placental vascular sonobiopsies" starting with the second trimester, comparing normal and growth restricted pregnancies and proving the differences in vasculature [65]. Against these evidences, in vitro phantom studies performed by Raine-Fenning et al. and Schulten-Wijman et al. in 2008 questioned the technical and methodological aspects of this procedure, doubting the reproducibility¬¬¬¬ [67]. On the other side, the sheep model study conducted by Olivier Morel et al. in 2010 demonstrated a good correlation between true uterine blood flow and flow parameters, as well as a good reproducibility of the technique [68]. The introduction of Virtual Organ Computer–Aided Analysis software (VOCAL) proved useful in the quantification of blood vessel volume and of the flow in an acquired volume [69]. Another way of determining early fetal growth was proposed by Hafner et al. who compared Placental Quotient (PQ) [Placental Volume / Crown Rump Length] assessed during the first trimester with Uterine Artery Doppler at 22 weeks and concluded that PQ has low sensitivity in diagnosis of IUGR in low-risk population, comparable with that of Uterine Artery Doppler, but has the advantage of possible first trimester assessment [70]. In 2013, these authors refined their research showing that Placental Bed Vascularization Index assessed by 3D Power Doppler could be used for a quick and reliable first trimester assessment of severe pregnancy risks because it shows a 66,2% detection rate for severe pregnancy complications, higher than the 50% sensitivity of second trimester Uterine Artery Doppler [71].  In regard to placental volume assessment Rizzo et al. showed in 2009 that first trimester evaluation of placentas in a high risk group with low PAPP-A proved a good correlation between reduced placental volume and low fetus weight (<10th percentile) with Umbilical Artery Doppler modifications [ The multiparameter approach21]. The combined approach reflects various pathological pathways: Doppler ultrasound of the uterine arteries shows inadequate invasion of the spiral arteries and impaired secretory placental function is reflected by the disturbances of biomarker levels [72]. Preeclampsia is associated with IUGR and models of prediction by combining ultrasound assessment of uterine arteries, biochemical markers and maternal history were published concerning the assessment of both conditions, but the need for the development of a model for prediction of SGA without preeclampsia emerged [74]. With the purpose of identifying SGA fetuses not related to preeclampsia, Karagiannis et al. used a model of prediction containing Uterine Artery Doppler Pulsatility Index at 11-13 weeks of gestation, Mean Arterial Pressure, maternal serum PAPP-A, free β-hCG, Placental Growth Factor, PP-13, ADAM-12 and Fetal Nuchal Translucency. Although the study did not distinguish between the constitutional and pathological SGA, it raised the problem of increased surveillance for the whole population at risk for SGA, improving perinatal outcome by individualized management in late-second trimester and third trimester. The study also proved a good detection rate for SGA of 73% for those requiring delivery before 37 weeks and of 46% for those requiring delivery after 37 weeks [28]. Investigators tried to improve the prediction of IUGR by combining Doppler indices with biochemical and clinical parameters due to the insufficient predictive value of each marker alone [26]. A thorough history should be taken to all pregnant women at the first antenatal visit because risk factors determination results are easy and inexpensive. Different single approaches in the screening of this condition have been proposed but did not show sufficient sensitivity, therefore, combined models are proposed with the goal of a better predictive value. Large-scale prospective studies are required to prove the power of such integrated approaches in clinical practice.Although it is a public health problem with around 10% incidence in the pregnancy population, FGR is still a matter of debate starting from the definition, the multifactorial origin, the low levels of prediction, the questionable references like customized or uncustomized growth charts, and the methods of diagnosis and management. The main trajectory of research is towards the first trimester diagnosis, as the optimal interval in which a prophylactic treatment would influence placentation ends in the 16th week [


However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial  Amyotrophic lateral sclerosis (ALS) is a fatal paralyzing disease characterized by the selective degeneration of motor neurons in the spinal cord, brain stem and motor cortex. The majority (∼90%) of ALS cases are sporadic whereas some 10% of patients have dominantly inherited familial ALS (FALS). However, the forms share clinical features. The suggested causative factors for the motor neuron degeneration include oxidative stress, neuroimmune reactions, protein aggregation  are products of normal oxygen metabolism in cells  as superoxide and hydrogen peroxide  which is a highly reactive oxidant  mitochondria. Further in vivo studies revealed that mutSOD1 in spinal cords of G93A SOD1 rodents is destabilized and bound to the inner mitochondrial membrane  which oxidizes it to Ot Figure . Cells lA substantial proportion of SOD1 is found in the mitochondria  which all have a role in mitochondrial import and accumulation (Kawamata and Manfredi, A mitochondrial import mechanism for SOD1 independent of CCS has been described in yeast (Varabyova et al., For maturing into an active enzyme, SOD1 requires three post-translational modifications: the insertions of zinc and copper, intramolecular disulfide bond formation, and dimerization. Zinc is deposited close to the active site stabilizing the structure (Potter et al., Full activation of human SOD1 requires CCS (Wong et al., in vitro (Tiwari and Hayward, in vivo studies did not assess the localization of reduced mutSOD1, one could expect that it would be accessible to mitochondria where a part of that pool could be oxidized. In cell culture, oxidation of Cys111 residues led to accumulation of several SOD1 mutants in mitochondria (Ferri et al., In ALS, mutSOD1 is recruited to mitochondria especially in the spinal cord (Higgins et al., Furukawa and O’Halloran  suggestein vitro (Rodriguez et al., Most forms of mutSOD1 show instability 2O2 (He et al., The IMS-located SOD1 has been suggested to be inactive in the intact mitochondria and activated through oxidative modification of its critical thiol groups by yet poorly known mechanisms (Iñarrea et al., Insertion of copper is required for the activity of SOD1 and altered copper homeostasis is a common feature in mutSOD1 mice (Tokuda et al., in vivo, suggesting that formation of heterodimers may be physiologically relevant in FALS patients as well. It has been proposed that the heterodimers comprise a pool of more soluble and more toxic SOD1 whereas homodimers form less toxic aggregates (Weichert et al., 2O2 production is not known and warrants further elucidation. In the model proposed (Figure 2O2 leads to cytC catalyzed peroxidation and mitochondrial damage.In addition to proper folding and metal acquisition, dimerization is critical for dismutase activity. Mutant and wtSOD1 are able to form either homo- or heterodimers both in animal and cell culture models (Furukawa et al., Under physiological conditions SOD activity in IMS is suppressed by redox state control. However, upon mitochondrial stress SOD1 may undergo oxidative activation and compete with cytochrome C for superoxide released in the IMS, leading to increased ROS production. In ALS, mutSOD1 accumulates in IMS, thus contributing to the misregulation of dismutase activity. The presence of endogenous wt enzyme may provide dismutase activity to inactive mutant by heterodimerization. Here we propose that aberrant regulation of dismutase activity in IMS as a major mechanism for the toxicity should be further evaluated in future studies. Furthermore, the possible involvement of mitochondrial IMS dismutase activity misregulation in sporadic ALS warrants careful assessment.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Neisseria meningitidis serogroup X isolates from sub-Saharan Africa and Europe showed that serogroup X emergence in sub-Saharan Africa resulted from expansion of particular variants within clonal complex 181. Virulence of these isolates in experimental mouse models was high.The epidemiology of meningococcal disease varies by geography and time. Whole-genome sequencing of  Neisseria meningitidis, varies substantially by geography and time. The disease can occur as sporadic cases, outbreaks, and large epidemics. Most cases occur in what has been termed the “meningitis belt” in sub-Saharan Africa, where the World Health Organization estimated that 12,464 suspected cases occurred during the 2013 meningitis season and that 1,131 were fatal  . Molecular typing of meningococci has used multilocus sequence typing (MLST) to determine CCs on the basis of the polymorphism of 7 housekeeping genes  , which runs on the Bacterial Isolate Genome Sequence Database (BIGSdb) platform  from culture grown overnight on gonococcal medium base agar plates with Kellogg supplements . Among genes involved in iron acquisition, the isolates from Africa, unlike those from France, lacked the carriage , panel BluxCDABE operon expressed by the PporB meningococcal promoter  but differed in LNP13407 (obtained in the 1990s), and we detected 23 genes for which alleles were identical in all isolates obtained since 2006 and in LNP13407 but differed in LNP14354 . fHbp (encodes factor H binding protein), lpt3 (encodes the phosphoethanolamine transferase), and lot3 . All serogroup X isolates obtained since the outbreak of 2006 (including those from the BIGSdb platform) harbored the lpt3 allele 45, which differs from allele 136 by the deletion of 2 codons (encoding Glu-211 and Ser-222 residues). These isolates do not react with the monoclonal antibody that recognizes immunotype L3,7,9 on the lipooligosaccharide (Most of these 41 genes encode hypothetical proteins; several encode proteins that are involved in meningococcal survival in the blood , panel CN. meningitidis serogroup X isolates in the meningitis belt of Africa supports the emergence of virulent serogroup X isolates and the belief that CC181 may be considered a hyperinvasive genetic lineage of meningococci. The occurrence of the periodic epidemic waves may be caused by the emergence and spread of successive new clones of meningococci with enhanced virulence and an ability to escape population immunity. Our data underline the need for whole-genome sequencing for reliable tracking of meningococcal isolates and emphasizes the need for an effective vaccine against serogroup X (The extensive characterization of


In There are errors in Notes: GDPpc: Gross Domestic Product per capita; QALYs: Quality Adjusted Life Years. Notes: These five countries were selected to reflect the range of results obtained in the incremental cost-effectiveness ratios (ICERs) in the 30 Latin American and Caribbean countries analysed . Each point represents 1 of the 1000 simulated ICERs in the probabilistic sensitivity analysis for each country. Probabilities of being Cost-Saving, or Cost-Effective at 1 and 3 GDPpc for all countries can be seen in


It is imperative for staff involved in clinical trials to receive appropriate education and training relating to their particular roles to be able to fulfil GCP requirements and ensure successful trial conduct . However, little is known about the ways training is being provided to trial staff.To investigate and summarize training methods currently used in RCTs of health-care interventions.A systematic review was undertaken to identify articles reporting methods and practices of staff training within RCTs. A set of codes was used for the systematic organisation of extracted data.7471 records were screened and 89 studies were identified; 78 (88%) focused on training in an individual RCT and 11 (12%) were network-based. Studies were mainly conducted in USA (55%) and internationally (27%). Most were multi-centre (94%) and funded by non-commercial funders (70%). Different combinations of live (face-to-face and remote) and recorded (text-based and multimedia) training methods were used. Training was mainly provided at a group-level (51%), by trainers from the research team (65%). Intervention delivery/fidelity (49%), protocol and trial-related procedures (39%), trial data (36%), patient recruitment (31%) and outcome assessment (18%) were the top five training objectives. Evaluation information was present in 88% of studies, however, a detailed evaluation was only given in 12% of them. Information on the cost of training was only reported in 4.5% of studies.There is substantial variability in the reported training process across RCTs of various intervention types, disease areas and sample sizes.


There is an error in affiliation #3 for authors Xiaofan Guo and Hongning Zhou. Affiliation #3 should be: Yunnan Provincial Key Laboratory of Vector-borne Diseases Control and Research (in establishment) of Yunnan Institute of Parasitic Diseases.


Pinus koraiensis mixed forest, the responses of composition and structure of Pinus koraiensis mixed forests to climatic changes are unknown and the key climatic factors controlling the composition and structure of Pinus koraiensis mixed forest are uncertain.Although some studies have indicated that climate changes can affect Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. In order to build the mathematical models for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non-climatic factors, stepwise linear regression analyses were performed, incorporating 14 dependent variables and the linear and quadratic components of 9 factors. All the selected new models were computed under the +2°C and +10% precipitation and +4°C and +10% precipitation scenarios. The Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month were observed to be key climatic factors controlling the stand densities and total basal areas of Pinus koraiensis mixed forest. Increased summer temperatures and precipitations strongly enhanced the stand densities and total basal areas of broadleaf trees but had little effect on Pinus koraiensis under the +2°C and +10% precipitation scenario and +4°C and +10% precipitation scenario.Field survey was conducted in the natural Pinus koraiensis mixed forest. Although the Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitation.These results show that the Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month are key climatic factors which shape the composition and structure of  Pinus koraiensis is a pine species endemic to the region including East Russia, Korea, Japan and Northeast China Pinus koraiensis - broadleaf mixed forest is one of the major vegetation types and the typical conifer - broadleaf mixed forest and plays important role in carbon cycling in Northeast China Pinus koraiensis patches and the expansion of some broadleaf tree species from 1986 to 1994, and indicated that the reason for the shrinkage of Pinus koraiensis patches and the expansion of some broadleaf tree species might be the effects of climate change Pinus koraiensis or its mixed forest Pinus koraiensis would shift Northward under the HadCM2 climatic change scenario and under the average of another five climatic change scenarios  Pinus koraiensis to become broadleaf forests in Changbai Natural Reserve of Northeast China under the CGCM2 climate change scenario Pinus koraiensis mixed forest are uncertain.A field study of the North East China Transect (NECT) has observed the shrinkage of Pinus contorta and Pinus sylvestrisPinus koraiensis reflects the stand age of a Pinus koraiensis mixed forest, because the mean diameter of Pinus koraiensis in a stand naturally increases over time Linear or quadratic regression models can be built to simulate the relationships of compositional and structural attributes of plant communities with climatic and non-climatic factors, and such studies have been conducted in grasses, tropical trees, According to the recent CMIP5 (phase five of the Coupled Model Inter-comparison Project) climate change scenarios, the global temperature averaged in 2081–2100 is projected to likely exceed 2°C (RCP6.0 and RCP8.5 emission scenarios) above 1850–1900; although unlikely to exceed 4°C in all other RCP emission scenarios than RCP8.5 Pinus koraiensis mixed forests to spatial climatic changes, a field survey was conducted in the natural Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. The mathematical models were built for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non-climatic factors, and two scenarios of the +2°C and +10% precipitation and +4°C and +10% precipitation were used to predict the possible changes of composition and structure in Pinus koraiensis mixed forests under the future global climatic change. The objectives of this study are to: (1) build mathematical models to quantify the responses of the composition and structure of Pinus koraiensis mixed forests to the climatic factors; (2) discover the key climatic factors which control the composition and structure of Pinus koraiensis mixed forest. Additionally, we hypothesized that the composition and structure of Pinus koraiensis mixed forests would significantly be affected and Pinus koraiensis mixed forests would be overtaken by broadleaf-dominated forests in the region under the future global warming and increased precipitation.To examine the responses of composition of and structure of All necessary permits were obtained for the described field studies. This study was approved by State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, the Chinese Academy of Sciences; Shengshan National Nature Reserve; Liangshui National Nature Reserve; Dongsheng Forestry Bureau; Changbai National Nature Reserve and Kuandian National Nature Reserve.Pinus koraiensis mixed forests without recent disturbance. All the broadleaved trees are deciduous and most of the conifers are evergreen (except for Larix) in the study region. From June to August is the warmest quarter (summer) and January is the coldest month of the year in the study region. Rainy season begins at May or June and ends at September, and the summer (from June to August) precipitation occupies 60% of annual precipitation This study was conducted in the Augusts of 2010 and 2012 in Northeast China, including ten sites: Kuandian, Dongsheng, Liangshui, Shengshan and Changbai from A to F . The forIn each plot, every living tree higher than 1.4 m was identified to species and then measured for its circumference with a tape measure at its breast height (1.3 m). The measured circumference of each tree was converted into its diameter at breast height (DBH) and calculated into its basal area using the circle formulas.Pinus koraiensis mixed forest were extracted from each plot. The fifteen attributes were: Mean DBH of Pinus koraiensis (MeanDBHPinus), Total Basal Area of Pinus koraiensis , Stand Density of Pinus koraiensis (StandDensityPinus), Total Basal Area of Acer and Fraxinus , Stand Density of Acer and Fraxinus (StandDensityAcer-Fraxinus), Total Basal Area of Quercus , Stand Density of Quercus (StandDensityQuercus), Total Basal Area of Abies and Picea , Stand Density of Abies and Picea (StandDensityAbies-Picea), Total Basal Area of Larix , Stand Density of Larix (StandDensityLarix), Total Basal Area of Ulmus , Stand Density of Ulmus (StandDensityUlmus), Total Basal Area of Betula  and Stand Density of Betula (StandDensityBetula) (Fifteen attributes of yBetula) .One-way ANOVA and correlation and regression analyses were performed using SPSS 13.0. Standard errors within sites were detected by one-way ANOVA with descriptive options. Significant differences (p<0.05) between sites were detected using One-way ANOVA with post-Duncan's test.Pinus koraiensis mixed forest. The independent factors used in the regressions were linear and quadratic components of Max Temperature of Warmest Month (TempWarmestMonth), Min Temperature of Coldest Month (TempColdestMonth), Mean Temperature of Warmest Quarter (TempWarmestQuarter), Mean Temperature of Coldest Quarter (TempColdestQuarter), Precipitation of Wettest Month (PrecipWettestMonth), Precipitation of Driest Month (PrecipDriestMonth), Precipitation of Wettest Quarter (PrecipWettestQuarter), Precipitation of Driest Quarter (PrecipDriestQuarter) and MeanDBHPinus. The 14 dependent variables were BasalAreaPinus, StandDensityPinus, BasalAreaAcer-Fraxinus, StandDensityAcer-Fraxinus, BasalAreaQuercus, StandDensityQuercus, BasalAreaAbies-Picea, StandDensityAbies-Picea, BasalAreaLarix, StandDensityLarix, BasalAreaUlmus, StandDensityUlmus, BasalAreaBetula and StandDensityBetula  included in its regression model.Pinus values under current climate, under the +2°C and +10% precipitation scenario and under the +4°C and +10% precipitation scenario. In order to examine the concordances between the simulated and observed values under current climate, scatter plots with simple error bars and regressions were generated using Sigmaplot 10.0. To represent the variations of stand densities and basal areas of Pinus koraiensis, other conifers and broadleaves under current climate under the +2°C and +10% precipitation scenario and under the +4°C and +10% precipitation scenario, vertical bar charts with error bars were generated using Sigmaplot 10.0.The selected models were computed using the currently observed MeanDBHPinus koraiensis mixed forest    were predicted to be zero  firstly increased and then decreased with increasing latitude, while the stand density of broadleaved trees decreased with increasing latitude and altitude , while Acer and Fraxinus and Pinus koraiensis serve as late successional species during the succession of Pinus koraiensis mixed forest Pinus (which represents the stand age of a Pinus koraiensis forest) Pinus and BasalAreaAcer-Fraxinus, suggesting that Pinus koraiensis and Acer and Fraxinus are late successional species and naturally increase in their total basal areas over time. However, negative relationship existed between MeanDBHPinus and StandDensityPinus when MeanDBHPinus was below 47.6 cm  Pinus koraiensis but the negative effects of summer temperatures on other conifers (Abies and/or Picea and Larix) and the positive effects of summer temperatures on some broadleaved trees (Acer and/or Fraxinus and Quercus) were observed (Pinus koraiensis trees compared with other conifer trees (Abies and/or Picea and Larix); (2) increased summer (growing-season) temperatures may enhance the growths of many broadleaved trees (Acer and/or Fraxinus and Quercus).Climate warming has positive and negative effects on plants. Prolonged growing seasons and increased growing-season temperatures have been found to enhance the growth of some plants, especially the growth of many deciduous broadleaved trees observed . Our resPinus koraiensis were observed (Pinus koraiensis populations. We suggest that the Pinus koraiensis in the region may not necessarily maintain itself under the +2°C and +10% precipitation and +4°C and +10% precipitation scenarios if proper migrations of local populations do not occur in time.A wide-ranged pine species is usually composed of many genetically-different local populations. Each local population has evolved to adapt to its local climate, and has its unique response curve to climate change observed , and thePinus koraiensis within 150 years in current Pinus koraiensis mixed forest under climate warming scenarios Pinus koraiensis could persist for at least 300 years under the warming climate Pinus koraiensis would persist, while the broadleaf trees would overtake Pinus koraiensis to become dominant species under either of the two warming scenarios (Studies using a forest gap model alone usually predicted the extinction of cenarios .Pinus koraiensis mixed forests to the climatic factors. TempWarmestMonth, TempWarmestQuarter and PrecipWettestMonth strongly affected the stand densities and total basal areas in Pinus koraiensis mixed forest and therefore they are suggested to be key climatic factors which shape the composition and structure of Pinus koraiensis mixed forest. The composition and structure of Pinus koraiensis mixed forests were significantly affected, and although Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitations.These results show that some mathematical models were successfully built to quantify the responses of the composition and structure of


Magnetic Resonance Imaging of the Small Bowel  is becoming increasingly popular as the first imaging modality for the diagnosis and follow-up of small bowel diseases. The aim of this work was to evaluate the role of recent MRI sequences and techniques in evaluation of small bowel disease.The study population included 24 patients who were referred to multiple radiology centers by gastroenterologist for magnetic resonance enterography (MRE) for evaluation. The examination was done on 1.5 Tesla superconducting magnet MRI.All studied patients had small bowel lesions. 15 patients were neoplastic (64%) and 9 patients were inflammatory (36%). Among 15 cases of small-bowel neoplasm; 12 were malignant; and 3 were benign. The malignant cases were classified as follows; lymphoma (6 patients); adenocarcinoma (4 patients); GIST (1 patients) and carcinoid tumour(1 patient). Nine patients out of 24 had inflammatory bowel diseases. Eight cases out of 9 proved to be specific inflammatory disease and 1 chronic non specific ileocolitis. Seven cases out of 8 proved to be Crohn’s disease and 1 proved pathologically to be TB of small bowel. The final diagnosis was confirmed by surgical or endoscopic data and follow up.MRE is accurate non-invasive modalities in assessing the intra-luminal, parietal and extra-luminal small bowel tumour without the need for ionizing radiation. MR signal appearances of the lesions, combined with the contrast enhancement behavior and the characteristic of the stenosis, can help in differentiating neoplastic from other non-neoplastic diseases of small bowel.


The presence of joint inflammation in juvenile idiopathic arthritis (JIA) patients can be made by physical examination and confirmed by imaging. The discrepancy between physical examination and MRI for evaluation of synovitis in a target joint is possibly explained by the fact that clinical measures mostly reflect overall disease activity instead of measures specific for the joint imaged by MRI.To compare clinical disease activity of the major target joint upon physical examination with a validated MRI score for the knee in JIA.MRI datasets and corresponding clinical parameters of disease activity of the knee were analyzed in 167 JIA patients . Local physical examination of the knee included absence or presence of swelling, warmth, pain or limitation-of-motion (LOM) as assessed by experienced pediatric rheumatologists. A blinded radiologist (6 years of experience in MRI in JIA) analyzed synovial hypertrophy (SH) on a scale from 0-12 on all MRI datasets following the validated Juvenile Arthritis MRI Scoring system (JAMRIS). SH was ‘present’ when the total JAMRIS score was >2. Diagnostic accuracy of the local physical examination parameters for detection of arthritis was determined with MRI as reference standard.Sensitivity and specificity of the parameters scored by local physical examination compared with MRI varied from 39-71%. The overall positive predictive value for synovitis was very low (21-28%), while the negative predictive value was relatively good (71-74%). Median time between the clinical assessment and the MRI was 38 days (IQR 28-53 days). Subgroup analysis on 51 patients with <31 days (median 25 days) between clinical assessment and MRI did not improve the diagnostic accuracy.The presence of swelling, warmth, pain or LOM on physical examination did not predict the presence of synovitis upon MRI. The time between clinical assessment and MRI appeared to have no influence on the diagnostic accuracy of the physical examination inflammation parameters. While the discrepancy between physical examination and MRI persists, follow-up studies are warranted to unravel the difficulties in assessment of disease activity.None declared.


For multimodal pain therapy (MPT), a bio-psycho-social therapy approach for patients suffering from chronic pain, a core outcome set (COS) is currently lacking. Following the recommendations from initiatives such as Outcome Measures in Rheumatology (OMERACT) and Harmonizing Outcome Measures for Eczema (HOME), the study “Validation and Application of a patient relevant core set of outcome domains to assess multimodal PAIN therapy” (VAPAIN) aims to develop an accepted and valid COS for MPT.An online survey consisting of two rounds was conducted using the mOMEnt software provided by the COMET initiative. 25 stakeholders in MPT  were nominated by their associations and asked to participate. During both rounds, participants were asked to rate the importance of proposed domains regarding a) effectiveness trials (ES) and b) daily record keeping (DRK). Domains to be rated were identified through a systematic review of reported outcomes in MPT studies. During round 1, survey participants were allowed to name additionally relevant outcomes and were asked to name the number of minimal/maximal number of outcome domains to be included in the COS. During round 2 participants received feedback regarding their own previous ratings and also regarding ratings from other participants had to name which outcomes should be included in the COS.All participants completed round 1, but only 22 round 2 (88% response rate). The maximal and minimal number of outcome domains to be included in the COS ES was 9 and 4, and for the COS DRK 6 and 3. Pain intensity/severity (18/22), health-related quality of life (17/22), and pain-related disability (11/22) was named most frequently by the survey participants as being part of the COS for ES. Pain intensity (15/22), psychological distress (9/22) and both analgesic medication intake and pain-related disability (7/22) were named for the COS DRK.The results of this online survey regarding outcomes in studies evaluating MPT are mostly in line with the results from the preceding systematic review on outcome domains. Furthermore, the domains for the COS for effectiveness trials and daily record keeping were not fundamentally different. The identified preliminary outcome domains will be consented during a face-to-face meeting (consensus conference) in a moderated group discussion to determine a COS for MPT.


Rationale. Visual impairment is one of the most common clinical manifestations of multiple sclerosis (MS). Some multiple sclerosis patients complain of poor vision although the Snellen visual acuity is 20/20. This study reveals that sensitive measurements like visual evoked potential (VEP) and optical coherence tomography (OCT) can evidence subclinical disturbances of visual pathway. These methods examine the relation between the visual function (VEP) and retinal nerve fiber layer (RNFL) thickness, as a structural biomarker for axonal loss in patients with multiple sclerosis (MS). The findings in this study indicate the utility of combining structural and functional testing in clinical research on patients with MS.Purpose. To detect visual impairment in a population of visually asymptomatic patients affected by clinically definite multiple sclerosis (MS) and to compare the utility of optical coherence tomography (OCT) versus visual evoked potentials (VEP).Material and methods. Fourteen patients (28 eyes) affected by clinically definite MS, without a history of optic neuritis and asymptomatic for visual disturbances, were initially fully examined  from an ophthalmic point of view and then measured by OCT (RNFL thickness) and VEP.Patients with a history of glaucoma or other retinal or optic nerve disease were excluded.Results. Of fourteen patients (28 eyes), VEP was abnormal in 11 cases  and OCT (RNFL thickness) was abnormal in 5 cases , while 3 patients had no abnormalities on neither tests.Conclusions. Optical coherence tomography (OCT) is less sensitive than visual evoked potentials (VEPs) in detecting visual subclinical impairment in patients with multiple sclerosis (MS). VEP remains the preferred test for the detection of clinical and subclinical optic neuritis. OCT may provide complementary information to VEP in cases with clinical definite MS and represent a valuable research instrument for the study of optic nerve disease in populations. The findings in this study reveal the utility of combining structural and functional testing in clinical research on patients with MS.Abbreviations: multiple sclerosis = MS, optical coherence tomography = OCT, visual evoked potential = VEP, retinal nerve fiber layer = RNFL, best corrected visual acuity = BCVA. Just over a decade ago, MS clinical trials did not include visual outcomes, but experts recognized the need for more sensitive measures of visual function . Optical coherence tomography is used to monitor retinal ganglion cell axon loss in glaucoma, diabetic retinopathy, traumatic optic neuropathy, chiasmal lesions and optic neuritis [4-8]. Recently, OCT has been studied in patients with multiple sclerosis (MS). Two studies showed that the eyes without a history of optic neuritis among MS patients have decreased RNFL thickness compared with the eyes of control subjects, suggesting that retinal ganglion cell axonal loss occurs separately from acute optic neuritis in MS patients .Optical coherence tomography (OCT) is a noninvasive high-resolution technique that uses near-infrared light to generate cross-sectional tomographic images of tissues, including the retinal nerve fiber layer (RNFL) .This suggests that OCT can be used to monitor axonal injury and visual dysfunction in MS and may be an useful outcome measure in clinical trials [15]. In this study, we compared OCT versus VEP in the detection of visual dysfunctions in a population of visually asymptomatic patients with clinically definite MS.The alteration in visual evoked potential (VEP) latencies by using pattern stimuli is considered one of the most characteristic electrophysiological signs observed in patients with MS .The retinal nerve fiber layer (RNFL) measurements were obtained after 3 consecutive scans centered on the optic nerve head. OCT software Cirrus, Carl Zeiss Meditec generated a mean RNFL thickness measurement for 360 degrees around the optic disc, four retinal quadrants and 12 clock for our segment (30 degrees for each hour position). All scans were performed without pupil dilatation [VEPs were elicited by checkerboards reversing at 2 Hz  on a television monitor located 1 m from the patient.15].VEP measurements were obtained with the patient wearing a visual aid, if needed and the fellow eye was occluded. A fixation spot was used on the center of the screen during stimulation. The latency of the first major positive peak in the VEP (P100 wave) was measured. Most investigators currently interpreted pattern reversal VEP based almost entirely on the latency of P100. A P100 latency >115ms was considered abnormal .Multiple sclerosis is a progressive disease in which subclinical RNFL thinning may occur, even in patients who have not been clinically diagnosed with optic neuritis [20]. Visual evoked potentials (VEP) remain the preferred test for the detection of clinical and subclinical optic neuritis [1].The alteration of the visual evoked potential (VEP) latencies during pattern stimulation is considered one of the most characteristic electrophysiological signs in patients with MS, visually affected or unaffected [20].The study showed that in patients affected by MS with no history of optic neuritis and no visual symptoms, there is a large prevalence of visual pathway involvement [2]. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye [1].Clinically, it will be helpful to establish the baseline RNFL thickness and functional measurements in all MS patients at the time of the MS diagnosis. Change in RNFL thickness and/or visual function over time is likely the best approach in monitoring the disease progression [3].Based on OCT studies in MS, RNFL thickness is reduced significantly among patients (92 µm) versus controls (105 µm) and is particularly reduced in MS eyes with a history of optic neuritis (85 µm) [3].Combining information from structural and functional tests and following individuals longitudinally is probably the best strategy for assessing and monitoring the optic nerve involvement in patients with MS [4]. Imaging the RNFL allows a direct measurement of the unmyelinated axons of the central nervous system. The capacity to image central nervous system axons quickly and noninvasively, to minimize expense, and to correlate structural abnormalities with visual dysfunction add to the appeal of OCT as an imaging biomarker and outcome measure in clinical trials .The validation of OCT as an imaging biomarker in MS is important because several aspects of the information it generates are unique [The important correlation between the functional and anatomic aspect confirms the value of VEP and OCT to appreciate the subclinical involvement of the optic nerve.


The management of Adhesive Capsulitis(AC) is controversal. Both capsular distension after intraarticular injection and mobilization therapy are known as highly effective treatment of painful and limited shoulder joint. The aim of this study was to determine the synergistic effect of intensive mobilization technique combined with capsular distension for patients with adhesive capsulitis in improving shoulder ROM, pain and function.A total of 28 subjects suffering from AC were randomized into two groups. Group A received fluoroscopically guided capsular distension with steroid injection followed by intensive mobilization technique twice per week for 4 weeks and group B only received capsular distension with steroid injection.Patients were assessed using the Shoulder Pain and Disability Index (SPADI), Constant-Murley Shoulder Function Assessment Score (CS), Active Range of Motion(AROM) and Verbal Numeric Score(VNS). All measurements were obtained before injection and mobilization and 4 weeks after the procedures in order to compare with effects of the treatments.All measured value was significantly difference in group A and B(P<.05). Only external rotation ROM was not significantly difference in group B. The statistical differences were observed between group A and B in SPADI, CS, AROM and VNS (P<.01).Treatment using steroid injection with distension followed by intensive mobilization technique is recommended rather than injection treatment alone for the treatment of AC. In order to maximize the effectiveness of the two treatments further studies for optimal mobilization techniques will be needed.


Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and following  Hypoxic and ischemic (HI) brain injuries which result from lacking of oxygen or blood supply lead to permanent neuron damage and neurological deficit. During birth, HI insults in developing brain, such as asphyxia and ischemic stroke, are the leading cause of neonatal mortality and lifelong functional loss among newborns . The und ex vivo expanded EPCs or ECs showed therapeutic effect in several disease models, including neonatal HI brain injury, stroke, myocardial infarction, and vascular injury after angioplasty [Endothelial progenitor cells (EPCs) in circulation system are positively correlated with the outcome of hypoxic brain injury, and the more EPCs in circulation showed better recovery . The defioplasty –17. The ioplasty .Although the usage of EPCs is promising in brain therapy, the shortage of autologous EPCs limits its clinical application. We previously demonstrate the induction of endothelial differentiation by synergistic biochemical and biomechanical stimulations in human placenta-derived multipotential cells (PDMCs) . The appHuman liposuction aspirates were obtained from healthy donors with informed consent to protect the information and rights of patients as approved in accordance with procedures of the institutional review board of the National Cheng Kung University Hospital (NCKUH). The human ASCs were isolated following the protocol described previously . Briefly2) for 24 hours immediately after the EGM induction. The LSS was created by a flow chamber which allowed medium to flow through the cell-seeding glass slide and applied LSS to cells [The combined chemical and mechanical stimulation was used to induce the ELCs as previously established induction protocols . For theto cells . The endto cells . The lev5 cells) were trypsinized and resuspended with 1 mL complete medium and added onto the polymerized Matrigel (BD Biosciences). After incubation in 5% CO2 incubator for 5 hours, the formation of tube-like structure was observed and quantified in the tube length using phase contrast microscope.Forming tube-like structure which is an important indicator of endothelial function was measured in ASCs, early EPCs, and ELCs as previously described . In brie5 cells/100 μL each time. The pups returned to dam for recovery for one week before the brain samples were harvested.The Sprague-Dawley (SD) rats were provided by the animal center in NCKU with the approval of the experiment procedure by the Institutional Animal Care and Use Committee at NCKU. Neonatal HI brain injury is created according to previous study . Conciseμm-thick slice for the following staining. The corresponding plates 15, 18, 27, 31, and 39 in rat brain according to the rat brain atlas were stained with 0.1% cresyl violet solution for 1 hour to reveal neurons [Damage severity of brain was determined by the volume of ischemic region on outer surface and Nissl staining at P14. The rat brains were perfused with normal saline and 4% paraformaldehyde. Upon isolation, each brain was given a score based on the lesion size of outer surface of brain. The size of the lesion was divided into 3 grades, score one (lesion size less than 1/3 hemisphere), score two (the lesion size greater than 1/3 but lesser than 1/2), and score three (the lesion size greater than 1/2 hemisphere) . After d neurons .The integrity of neurovascular structure was assessed by immunofluorescence staining. The brain slices were incubated with the primary antibodies against neuronal nuclear antigen  for identifying neuron and against rat endothelial cell antigen-1  for identifying vessels. To further verify the mechanism of the protection effect of different treatment, the marker of angiogenesis, isolectin IB4 antibody , was used to visualize new forming vessels. The antihuman nuclei antibody  was utilized to recognize transplanted human cells in rat brain. The primary antibodies were labeled by fluorescent-labeled secondary antibodies , and the signals were observed at excitation-emission wavelengths of nm 470 to 505 nm and 596 to 615 with a tissue scanning fluorescent microscope  using a 20x objective lens.4 per well) are loaded into the upper compartment of Boyden chamber; the migration ability of the cells through 8 μm-pore membranes (Neuro Probe) to the lower compartment which filled with medium with or without hypoxia mimetic reagent desferrioxamine  will be measured. The cells are cultured in Boyden chamber for 6 hours, and then the cells on the lower surface of membrane will be fixed by 4% paraformaldehyde (Sigma) and stained with Giemsa to quantify the transmigrated cell numbers. To further clarify the mechanism of boosting migration ability of ELCs under hypoxic condition, the ELCs were pretreated with neuropilin-1 (NRP1) blocking peptide  or inhibitor of VEGFR  1 hour before being loaded into the chamber. The migrating cell area was quantified by ImageJ software.The ability of stem cells to migrate into lesion site is important for tissue protection and regeneration. The injured brain area will release environmental cue to trigger the migration of the stem cells. We use Boyden chamber assay to compare the chemotaxis and transmigration ability of different cells. Shortly, different cells (2 × 10 in vitro hypoxic condition was achieved by treating the ASCs or ELCs with 50 mM DFO. The cells were cultured in hypoxic condition for 6 hours with or without the pretreatment of DG2 (20 μM) for 1 hour, followed by the collection of cell lysates. The gene expression level of VEGFR1, VEGFR2, CD31, vWF, angiopoietin 1 (ANG1), and neuropilin 1 (NRP1) was measured using RT-PCR with the primer sequence listed in previous study [β-actin  [To further illustrate the underlying signaling under hypoxic condition, theus study . The act, Sigma) . The p-Ap < 0.05.For all experiments at least 3 independent groups were performed to demonstrate the consistency outcome. All data were expressed as the mean ± standard SEM. Statistical analysis was performed using the one-way analysis of variance (ANOVA) with Fisher's test of the Origin statistic software . The statistical significance was defined as The endothelial differentiation for early EPCs and ELCs was induced from human ASCs using biochemical and biomechanical stimulations. After EGM induction, the early EPCs did not show obvious change in morphology and remained spindle shaped which was similar to undifferentiated ASCs . InsteadThe therapeutic effect of ASCs and ELCs was tested using neonatal HI brain injury model in rats. The severity of brain injury was compared among the rat pups receiving different treatments, including PBS, ASCs, and ELCs. The brain score determined based on infarction size on the outer surface of brain showed sever damage after HI insult in PBS group . TransplWe further investigated the integrity of neurovascular structure by immunofluorescence staining of specific antibodies against neuron (NeuN)  and vess in vivo local hypoxic environment that may have different responses in ASCs and ELCs. We further used in vitro Boyden chamber assay to investigate themigration ability of various cells under normal and hypoxic conditions. The transmigrated cells were labeled in dark blue color after migrating from the loaded upper compartment of chamber to the lower compartment with or without adding DFO for studying the cell mobility in normoxia (vehicle) and hypoxia (DFO) (The HI injured brain created ania (DFO) . The ELCia (DFO) . To illuia (DFO) . The chaia (DFO) . The levia (DFO) . The resTo confirm the role of NRP1 and VEGFR2 in promoting ELCs migration and remaining of endothelial differentiation under hypoxic condition, blockage of NRP1 or VEGFR signals in ELCs was tested by using specific NRP1 blocking peptides (DG2) or a small molecular targeting tyrosine kinase receptor (BIBF1120), respectively. Under regular condition (normoxia), the transmigration ability of ELCs was slightly decreased with the inhibition of NRP1 (DG2) or VEGFR (BIBF1120) signaling . The enhTo further confirm the signaling in brain tissue after receiving different therapeutic cells, the p-VEGFR2 and p-Akt were coimmunofluorescent staining with the angiogenesis marker IB4 . The appIn this study, we demonstrated the ASCs can be differentiated into endothelial lineage by synergistic stimulation of growth factor and shear stress. The therapeutic effects of both ASCs and ELCs were tested in HI injured brain. Main finding of present study supported that transplantation of ELCs showed better capacity than ASCs in preserving neurovascular structure after HI brain injury in rats. The ELCs were able to migrate and incorporate into the vascular structure in brain tissue. In addition, the ELCs can promote the angiogenesis in the impaired area as compared to ASCs. The involvement NRP1 and VEGFR2 is important for ELCs to facilitate the migration ability under hypoxic condition through Akt pathway.The angiogenic potential in early EPCs and late EPCs is comparable; there is divergence in their functions . Early EThe cell-based therapy using EPCs shows protective effect on restoring blood flow and preventing tissue damage. Upon transplantation, the EPCs home the ischemic site and incorporate into the damaged vessel structure. Studies address the fact that there are two main mechanisms for the therapeutic effect of EPCs therapy. First, the EPCs have potential to differentiate into mature ECs . After aThe crosstalk between ECs and neuron are prominent for the normal structure and function of nervous system. The ECs in central nerve system are highly specialized which connect tightly with each other and form blood barrier . The bloSeveral chemoattractants will be secreted in the injured tissue after HI insult to recruit circulating cells into the damaged area. VEGF is an important chemotactic factor for EPCs to participate in cell mobilization . VEGF acThe current study demonstrates the importance of chemical and mechanical factors in inducing the differentiation of ELCs from ASCs and the potential of using ELCs in protecting rat neonatal HI brain injury. Both ASCs and ELCs therapies can prevent the brain from HI insult by decreasing the infarction volume. Yet, ELCs showed a promising outcome in protecting the architecture and integrity of neurovascular unit. The transplantation of ELCs preserved not only the networks of vascular structure, but also the number of neurons. The mechanism for protective effect in ELCs may act through the increase of migration capacity and neovascularization after HI injury. The increase of NRP1 and VEGFR2 was identified with phosphorylation of Akt signaling in ELCs under hypoxic condition. Inhibition of NRP1 signal diminished the promotion of ELCs transmigration and Akt phosphorylation under hypoxia. Inhibition of VEGFR2 totally abolished the cell migration and endothelial differentiation in ELCs. Taken together, these results indicate that shear stress induced ELCs can be a promising cell resource for autologous cell therapy in HI brain injury.


To The Editor: Woodrats (Neotoma spp.) are natural hosts of Whitewater Arroyo virus (WWAV) and other Tacaribe serocomplex viruses (family Arenaviridae) in the western United States and northern Mexico . Virtually all serum samples were acute-phase specimens, and a specific diagnosis was achieved for only 55 (31.8%) of the 173 study participants.Serum samples were tested for IgG against WWAV, Amaparí virus (AMAV), an arenavirus that is antigenically closely related to the Tacaribe serocomplex viruses known to cause hemorrhagic fever  of the 173 study participants. None of the 173 study participants were positive for IgG against AMAV or LCMV. The IgG titers against WWAV in the positive samples were 320 (n = 1), 1,280 (n = 3), and ≥5,120 (n = 4). WWAV was the apparent homologous virus in the 7 persons with antibody titers ≥1,280. The apparent homologous virus in the person with the titer of 320 could not be determined from ELISA data. The presence of IgG against WWAV in acute-phase serum samples  implied past infection with WWAV or an arenavirus antigenically closely related to WWAV.The state of residence , sex ratio , and mean age  of antibody-positive persons reflected the characteristics of the entire study population. The clinical features in each of the antibody-positive persons included fever, headache, myalgia, and thrombocytopenia. The diagnoses given for these persons were acute parvovirus infection (n = 1) by IgM assay, adult respiratory distress syndrome (n = 1) by clinical progression, and not determined (n = 6).The results of this study indicate that a small fraction of the adult population in the southwestern United States has been infected with North American Tacaribe serocomplex virus(es). We note that the dominant epitopes in ELISA for IgG against arenaviruses are associated with the viral nucleocapsid (N) protein, and that amino acid sequence of the N protein of WWAV and amino acid sequences of N proteins of other Tacaribe arenaviruses from Arizona or New Mexico showed differences as high as 15.1% in a previous study (,It might be the case that human IgG against some Tacaribe serocomplex viruses in the southwestern United States does not react strongly against WWAV in ELISA. If so, the true prevalence of antibody against North American Tacaribe serocomplex viruses in this study might be >4.6%. Accordingly, future work should include development of broadly reactive assays for detection of human IgM and human IgG against North American Tacaribe serocomplex viruses, including those associated with wild rodents in Mexico (


Non-alcoholic fatty liver disease (NAFLD) affects almost one third of adults in European countries. A well-known factor of influence is overnutrition and insulin resistance . In conRecently, Marta Benet and colleagues from Barcelona and Valenica in Spain have published a transcriptomic signature to identify compounds with an increased risk of inducing steatosis . ). in vitIn this context the identification of the steatogenic FOXA1/HEX/SREBP1C signature by Benet and colleagues (2014[


Brown adipose tissue (BAT) has long been known to dissipate energy as heat and contribute to energy expenditure, but its presence and physiological role in adult human physiology has been questioned for years. Recent demonstrations of metabolically active brown fat depots in adult humans have revolutionized current therapeutic approaches for obesity-related diseases. The balance between white adipose tissue (WAT) and BAT affects the systemic energy balance and is widely believed to be the key determinant in the development of obesity and related metabolic diseases. Members of the transforming growth factor-beta (TGF-β) superfamily play an important role in regulating overall energy homeostasis by modulation of brown adipocyte characteristics. Inactivation of TGF-β/Smad3/myostatin (Mst) signaling promotes browning of white adipocytes, increases mitochondrial biogenesis and protects mice from diet-induced obesity, suggesting the need for development of a novel class of TGF-β/Mst antagonists for the treatment of obesity and related metabolic diseases. We recently described an important role of follistatin (Fst), a soluble glycoprotein that is known to bind and antagonize Mst actions, during brown fat differentiation and the regulation of cellular metabolism. Here we highlight various investigations performed using different  Obesity is a major health problem spreading at an epidemic pace throughout the world without any sign of abatement. According to the World Health Organization report, more than 1 billion adults (~ 15% of world population) are overweight [body mass index (BMI) > 25]  lineage and are called beige cells or brite (brown-in-white) cells  have recently been identified in adult humans  superfamily is comprised of over 30 members that include several structurally dimeric cytokines such as TGF-β, activins, and bone morphogenic proteins (BMPs)/growth and differentiation factors (GDFs) which are evolutionarily highly conserved , also termed as growth/differentiation factor-8 (GDF-8) is a member of the TGF-β superfamily that regulates skeletal muscle mass  is a secreted glycoprotein that has been recognized for many years as a high affinity binding and neutralizing protein for several members of the TGF-β superfamily including activins and Mst  entitled “Composition and methods for treating or preventing metabolic syndrome disorders” is in process. Authors declare no other potential conflict of interest.


OnabotulinumtoxinA (OnabotA) was approved for treatment of chronic migraine (CM) following the PREEMPT trials, 2, and Written informed consent to publication was obtained from the patient(s).


Mycobacterium tuberculosis, innovations in TB drug discovery and evolving strategies to bring new agents with best performance is an essential investigation. Taking this into account, there is a pressing need to develop new and more effective anti tubercular agents. The coordination of metal with organic drugs is a promising strategy that has been successful in many cases with different pharmacological activities. The emergence of new cases and the adverse effects of first and second-line antituberculosis drugs have led to renewed research interest in metal drug complexes in the hope of discovering new antituberculosis drugs. The aim of the present study is to assess the antituberculosis activity of Ni (II) and Cu (II) complexes of polymer ligand poly (3-nitrobenzylidene-1-naphthylamine-co-methacrylic acid).Tuberculosis (TB) is a disease that produces several million deaths annually. With the appearance of multi drug resistant microbial strains of M. tuberculosis H37 Rv strain by microplate alamar blue assay (MABA) method using pyrazinamide as standard.Antituberculosis activities of the ligand and its complexes were assessed against The minimum inhibitory concentration values of the ligand and its complexes on comparison with standard  indicate that the complexes exhibit promising antituberculosis activity. Cu (II) complex shows more activity (10 µg/ mL) followed by Ni (II) complex (20µg/ mL) and ligand (35 µg/ mL).Among the synthesized compounds, the Cu (II) complex may be used as therapeutic substitute in the treatment of tuberculosis by replacing the routine drugs.


Unequal distribution of dermal collagen and elastic fibers in different orientations is reported to be one of the multi focal causes of scar related complications.To study the correlation pattern between the variables of dermal collagen in horizontal (CH) and in vertical (CV) directions as well as that of dermal elastic fibers in horizontal (EH) and vertical (EV) directions.Current research comprised of histo-morphometrical study of 120 skin samples collected in horizontal and vertical orientations from anterior chest area and lateral chest areas of formalin embalmed human cadavers (n = 30). The quantitative fraction of dermal collagen and elastic fiber content was obtained by tissue-quant image analysis. Spearman correlation coefficient (r) was computed to determine the linear association between the variables (CH/CV/EH/EV). The results were interpreted according to the degree of association after taking into consideration the significant correlation (p < 0.01 or p < 0.05) with respect to coefficient (r) values.Significant positive correlation between CH and CV and between EH and EV were observed in both anterior  and lateral chest areas . However, the negative correlations were observed between CH and EH for anterior chest area (r = -.55) and between CV and EV at lateral chest area (r = -.43).Positive correlation among dermal collagen and elastic fibers between horizontal and vertical directions, and their negative correlation within same direction could be one of the factors for the speckled behavior of scar related complications in the chest area.


Provisional evidence-based classification criteria for Familial Mediterranean Fever (FMF), Cryopyrin Associated Periodic Syndrome (CAPS), Tumor Necrosis factor Receptor Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency (MKD) have been recently developed based on data coming from the Eurofever registry. However, no consensus on how to combine clinical criteria with results of molecular analysis has been reached so far.To understand how physicians involved in the clinical care of patients with Autoinflammatory diseases (AIDs) classify patients with inherited periodic fever in daily practice.By using the Delphi and Nominal Group Technique, we started a process made of three consecutive e-mail surveys. In the first survey, clinicians/biologists and other health professionals working in the field of autoinflammation were asked to identify the variables that they consider as important, in their clinical practice, for the diagnosis of patients with inherited periodic fever. This survey was open not to influence the experts.We sent the first survey to 124 experts. The overall rate of response was 107 (86%): 101 experts responded to be interested in the survey and 88 completed and confirmed it for at least one disease; 6 experts responded not to be interested. No clinical variable was chosen by all the experts for any disease the five most cited clinical variables for FMF were recurrent fever (80% of experts), abdominal pain (67%), arthritis (53%), thoracic pain (47%) and arthralgia (36%). The five most cited clinical variables for CAPS were fever (75%), urticarial rash (71%), hearing loss (49%), ocular involvement (40%) and arthralgia (35%). The five most cited clinical variables for TRAPS were long lasting fever (92%), rash (84%), periorbital edema (59%), myalgia/myositis (57%), and abdominal pain (55%) while the five most cited clinical variables for MKD were abdominal pain (61%), fever (59%), skin rash (41%), diarrhea (43%) and arthralgia (39%). A confirmatory genetic test resulted a relevant element for the diagnosis of FMF, TRAPS, CAPS and MKD while the response to treatment for FMF and CAPS.The preliminary results of the first Eurofever Delphi Survey show a high rate of response by Expert, underlying the interest of the scientific community in this topic. A wide heterogeneity in their response was observed. At the end of the Delphi process, we will obtain different set of clinical criteria whose performance will be tested in comparison to already existing criteria in a cohort of patients affected by AIDs. The final step will be a Consensus among experts (geneticists and clinicians) in order to define the best combination of clinical and genetic data for the definitive classification of patients with inherited periodic fevers.


Medical errors are particularly frequent in Neonatal Intensive Care Units (NICUs) , increasWe carried out our study from 2011 and 2012 in Department of Medical and Surgical Neonatology of Bambino Gesù Children’s Hospital. We recorded throughout retrospective methods nursing reports to detect an error or incidents. We used voluntary reporting, non punitive, of medical errors by health care providers.From 2011 and 2012 we detected 29 adverse events in Neonatal Department; 15 (58%)of whom were therapeutic errors concerning of drug process: 2 (13%) order, 1 (7%) preparation, 7 (46%) prescription, 5 (33%) administration (Figure The voluntary reporting system represents the best option to detect the human errors. In our experienced the introduction of shared protocols, of the nurse staff training, and the following of the JCHAO directives have been achieved to identify all procedures performed for patient care. To reduce the ADRs the Paediatric Investigation Plans should be required by the Paediatric Committed to guarantee safer and tolerated drugs, especially for newborns.