Miracle-dz/UniFAR-FTUs huggingface dataset:
How does strength training and balance training affect gait and fatigue in patients with Multiple Sclerosis? A study protocol of a randomized controlled trial.

INTRODUCTION Multiple sclerosis (MS) is characterized by a demyelination that results in reduced conductivity in the somatosensory nervous system, decreased muscle strength, vestibular alteration, and severe fatigue. Progressive resistance training (PRT) has proven to be a promising intervention showing a positive effect on muscle strength. Another promising intervention frequently used in neuro-rehabilitation is task specific training where also Balance and Motor Control Training (BMCT) are incorporated. Interestingly, the principles of BMCT do fundamentally contrast the principles of PRT in terms of variation in movement pattern, loading and repetitions. Consequently, knowledge of any diverse effect would be of clinical relevance. AIM To evaluate the effects of PRT and BMCT on gait, balance and fatigue in persons with MS. METHOD A three-armed multi-center, single-blinded cluster randomized controlled trial with two intervention groups (1. PRT of the lower extremities. 2. BMCT that challenges gait function) and a control group that receives usual care while on a waitlist for a combined PRT + BMCT intervention performed after the two interventions groups have completed their interventions. The interventions last ten weeks with two sessions per week, in groups of 3-6 participants. Number of participants is 30 per intervention - 90 in total. Primary outcome measures for gait function are the Timed 25 Foot Walk (T25FW) and the Six Spot Step Test (SSST). Secondary outcomes are fatigue, perceived gait function, temporo-spatial gait characteristics, balance and strength.Inclusion criteria are: EDSS 2-6, SSST >8 sec and T25FW >5 sec. Exclusion: Recent attacks and ongoing intensive rehabilitation. ANALYSIS The effects in the three groups are examined in a mixed effects regression analysis with group and time as fixed effects and center and patient within center as random effects. Spearman or Pearson correlation analysis will be conducted on baseline data to determine associations between the primary outcomes on gait function and the secondary outcomes on fatigue, spatial gait parameters, balance and patient reported measures. TRIAL REGISTRATION The study is approved by the Regional ethical committee and registered at clinicaltrials.gov, NCT02870023.
The establishment of active promoters in chromatin

The organization of eukaryotic genomes as chromatin provides the framework within which regulated transcription occurs in the nucleus. The association of DNA with chromatin proteins required to package the genome into the nucleus is, in general, inhibitory to transcription, and therefore provides opportunities for regulated transcriptional activation. Granting access to the cis‐acting elements in DNA, a prerequisite for any further action of the trans‐acting factors involved, requires the establishment of local heterogeneity of chromatin and, in some cases, extensive remodeling of nucleosomal structures. Challenging problems relate to the establishment of this heterogeneity at the level of the single nucleosome and to the mechanisms that operate when nucleosomal arrays are reorganized. Recent developments indicate that chromatin reconstitution in cell‐free systems allows the biochemical analysis of the interplay between transcription factors and chromatin components that brings about regulated transcription.
Structure-Based Approaches to Improve Selectivity: CDK2-GSK3beta Binding Site Analysis

An evaluation and comparison of two different approaches, GRID/CPCA and GRIND/CPCA (CPCA = consensus principal component analysis; GRIND = GRid-INdependent Descriptors), suitable for visualizing the structural differences between related proteins is presented. Ten crystal structures of CDK2/cyclin A and GSK3beta solved in-house with different inhibitors were compared with the aim of highlighting regions that could be potential sites for gaining selectivity for CDK2 versus GSK3beta. The analyses pointed out remarkable differences in the backs of the CDK2-GSK3beta ATP binding pockets that guided the optimization toward a selective benzodipyrazole CDK2 inhibitor. The gain in selectivity can be associated with the two main differences in the ATP pocket between the enzymes. Phe80 of CDK2, the so-called gatekeeper residue often exploited for the design of kinase selective ligands, is replaced by a leucine in GSK3beta, and Ala144 is replaced by a cysteine. As a consequence of these mutations, CDK2 has a less elongated and less flat buried region at the back of the ATP pocket.
Advances in Primary Recovery: Centrifugation and Membrane Technology

Significant and continual improvements in upstream processing for biologics have resulted in challenges for downstream processing, both primary recovery and purification ( 1 ). Given the high cell densities achievable in both microbial and mammalian cell culture processes, primary recovery can be a significant bottleneck in both clinical and commercial manufacturing. The combination of increased product titer and low viability leads to significant relative increases in the levels of process impurities such as lipids, intracellular proteins and nucleic acid versus the product. In addition, cell culture media components such as soy and yeast hydrolysates have been widely applied to achieve the cell culture densities needed for higher titers ( 2 , 3 ). Many of the process impurities can be negatively charged at harvest pH and can form colloids during the cell culture and harvest processes. The wide size distribution of these particles and the potential for additional particles to be generated by shear forces within a centrifuge may result in insufficient clarification to prevent fouling of subsequent filters. The other residual process impurities can lead to precipitation and increased turbidity during processing and even interference with the performance of the capturing chromatographic step. Primary recovery also poses significant challenges owing to the necessity to execute in an expedient manner to minimize both product degradation and bioburden concerns. Both microfiltration and centrifugation coupled with depth filtration have been employed successfully as primary recovery processing steps. Advances in the design and application of membrane technology for microfiltration and dead‐end filtration have contributed to significant improvements in process performance and integration, in some cases allowing for a combination of multiple unit operations in a given step. Although these advances have increased productivity and reliability, the net result is that optimization of primary recovery processes has become substantially more complicated. Ironically, the application of classical chemical engineering approaches to overcome issues in primary recovery and purification (e.g., turbidity and trace impurity removal) are just recently gaining attention ( 4 ). Some of these techniques (e.g., membrane cascades, pretreatment, precipitation, and the use of affinity tags) are now seen almost as disruptive technologies ( 5 ). This paper will review the current and potential future state of research on primary recovery, including relevant papers presented at the 234th American Chemical Society (ACS) National Meeting in Boston.
[Value of a clinical test for assessing physical activity in children].

BACKGROUND An appropriate measurement of physical activity (PA) in children is useful, since inactivity is associated to obesity, cardiovascular and metabolic risk. AIM To assess the reliability of the INTA questionnaire of PA, to compare the derived PA score with accelerometry and to assess its ability to identify excessively inactive children. MATERIAL AND METHODS One hundred eighty children aged 8 to 13 years answered an interviewer-administered questionnaire about their usual PA, consisting in 5 items (recumbent, seated, walking, playing outdoor, sports). The answers were converted to a PA score with a 0-10 points scale. Reliability was tested in 87 children by test/retest conducted 3-5 days apart. The PA score was compared with 3-day accelerometry in 77 of 93 children (35 obese and 42 non obese). Receiver operating characteristic (ROC) curves were used to determine the optimal cut-point for identify an excessively sedentary child. RESULTS The test/retest reliability of the questionnaire was 0.69 to 0.93 (Lin coefficient). Accelerometry was significantly associated with PA score (RHO: 0.60, p =0.008), outdoor plays (RHO: 0.37, p =0.0009) and practicing of sports (RHO: 0.33, p =0.003). Obese children were less active than non obese children, according both to PA score and to accelerometry. The optimal cut-point for classifying a child as too sedentary was a score of 5 (sensitivity =0.89). CONCLUSIONS The INTA-test is a valuable instrument for measuring usual PA in clinical practice and is easy to administer.
Impact of lesion segmentation metrics on computer-aided diagnosis/detection in breast computed tomography

Abstract. Evaluation of segmentation algorithms usually involves comparisons of segmentations to gold-standard delineations without regard to the ultimate medical decision-making task. We compare two segmentation evaluations methods—a Dice similarity coefficient (DSC) evaluation and a diagnostic classification task–based evaluation method using lesions from breast computed tomography. In our investigation, we use results from two previously developed lesion-segmentation algorithms [a global active contour model (GAC) and a global with local aspects active contour model]. Although similar DSC values were obtained (0.80 versus 0.77), we show that the global + local active contour (GLAC) model, as compared with the GAC model, is able to yield significantly improved classification performance in terms of area under the receivers operating characteristic (ROC) curve in the task of distinguishing malignant from benign lesions. [Area under the ROC curve (AUC)=0.78 compared to 0.63, p≪0.001]. This is mainly because the GLAC model yields better detailed information required in the calculation of morphological features. Based on our findings, we conclude that the DSC metric alone is not sufficient for evaluating segmentation lesions in computer-aided diagnosis tasks.
Herpes Simplex Virus Latency-Associated Transcript Encodes a Protein Which Greatly Enhances Virus Growth, Can Compensate for Deficiencies in Immediate-Early Gene Expression, and Is Likely To Function during Reactivation from Virus Latency

ABSTRACT Herpes simplex virus types 1 and 2 (HSV1 and HSV2) enter and reactivate from latency in sensory neurons, although the events governing these processes are little understood. During latency, only the latency-associated transcripts (LATs) are produced. However, although the LAT RNAs were described ≈10 years ago, their function remains ambiguous. Mutations affecting the LATs have minimal effects other than a small reduction in establishment of and reactivation from latency in some cases. Mutations in putative LAT-contained open reading frames (ORFs) have so far shown no effect. The LATs consist of a large species from which smaller (≈2 kb), nuclear, nonlinear LATs which are abundant during latency are spliced. Thus, translation of ORFs in these smaller LATs would not usually be expected to be possible, and if expressed at all, their expression might be tightly regulated. Here we show that deregulated expression of the largest HSV1 2-kb LAT-contained ORF in various cells of neuronal and nonneuronal origin greatly enhances virus growth in a manner specific to HSV1—the HSV1 LAT ORF has no effect on the growth of HSV2. Similar results of enhanced growth were found when the HSV1 LAT ORF was constitutively expressed from within the HSV1 genome. The mechanism of LAT ORF action was strongly suggested to be by substituting for deficiencies in immediate-early (IE) gene expression (particularly ICP0), because deregulated LAT ORF expression, as well as enhancing wild-type virus growth, was also found to allow efficient growth of viruses with mutations in ICP0 or VMW65. Such viruses otherwise exhibit considerable growth defects. IE gene expression deficiencies are often the block to productive infection in nonpermissive cells and are also evident during latency. These results, which we show to be protein- rather than RNA-mediated effects, strongly suggest a function of the tightly regulated expression of a LAT ORF-encoded protein in the reactivation from HSV latency.
A polarizable empirical force field for molecular dynamics simulation of liquid hydrocarbons

Electronic polarizability is usually treated implicitly in molecular simulations, which may lead to imprecise or even erroneous molecular behavior in spatially electronically inhomogeneous regions of systems such as proteins, membranes, interfaces between compounds, or mixtures of solvents. The majority of available molecular force fields and molecular dynamics simulation software packages does not account explicitly for electronic polarization. Even the simplest charge‐on‐spring (COS) models have only been developed for few types of molecules. In this work, we report a polarizable COS model for cyclohexane, as this molecule is a widely used solvent, and for linear alkanes, which are also used as solvents, and are the precursors of lipids, amino acid side chains, carbohydrates, or nucleic acid backbones. The model is an extension of a nonpolarizable united‐atom model for alkanes that had been calibrated against experimental values of the density, the heat of vaporization and the Gibbs free energy of hydration for each alkane. The latter quantity was used to calibrate the parameters governing the interaction of the polarizable alkanes with water. Subsequently, the model was tested for other structural, thermodynamic, dielectric, and dynamic properties such as trans/gauche ratios, excess free energy, static dielectric permittivity, and self‐diffusion. A good agreement with the experimental data for a large set of properties for each considered system was obtained, resulting in a transferable set of polarizable force‐field parameters for CH2, CH3, and CH4 moieties. © 2014 Wiley Periodicals, Inc.
Long-term follow up of secundum atrial septal defect closure with the amplatzer septal occluder.

BACKGROUND During the past 15 years, closure of a secundum atrial septal defect (ASD) has moved from a surgical to a percutaneous transcatheter approach. Few long-term studies of the efficacy and safety of closure of an ASD by an Amplatzer septal occluder (ASO) exist. METHODS To examine the long-term results of secundum ASD closure using the ASO, data on 94 patients who underwent secundum ASD closure with the ASO between 1998 and 2002 were available and reviewed. Data regarding residual shunt, chest pain, palpitations, arrhythmias, headaches, transient ischemic attacks, cerebrovascular accidents, and mortality were collected. RESULTS Seven (7.4%) subjects had residual shunts immediately following ASO placement. During follow-up, 4 residual shunts closed for a complete closure rate of 97%. Eighteen (19%) patients reported chest pain during the follow-up period. Twenty-three patients (24%) reported palpitations during the follow up period, 7 were documented arrhythmias, including supraventricular tachycardia, atrial fibrillation, and premature ventricular beats. Migraine headaches were new-onset in 4 patients. Migraine cessation occurred in 2 patients after secundum ASD closure. One child died from a cerebral vascular event 18 months following device placement. Only 1 patient developed mild aortic insufficiency. CONCLUSION These data indicate that for up to 120 months of patient follow-up, the ASO continues to be a safe device. Residual shunts and arrhythmias have low incidence post-ASO placement. Given the mortality in one high-risk patient, further investigation into anti-platelet therapy after device placement is warranted.
Neurons and Glia Modify Receptor Protein-tyrosine Phosphatase ζ (RPTPζ)/Phosphacan with Cell-specific O-Mannosyl Glycans in the Developing Brain*

Background: The neural extracellular matrix protein RPTPζ/phosphacan is abnormally glycosylated in models of congenital muscular dystrophies (CMDs). Results: RPTPζ/phosphacan is invested with unique and cell-specific O-mannosyl carbohydrate structures. Conclusion: RPTPζ/phosphacan is a major substrate for O-mannosyl glycosylation, which is a pathway critical in CMDs. Significance: Abnormal glycosylation of RPTPζ/phosphacan is neural cell-specific and may play a role in CMDs. Protein O-mannosylation is a glycan modification that is required for normal nervous system development and function. Mutations in genes involved in protein O-mannosyl glycosylation give rise to a group of neurodevelopmental disorders known as congenital muscular dystrophies (CMDs) with associated CNS abnormalities. Our previous work demonstrated that receptor protein-tyrosine phosphatase ζ (RPTPζ)/phosphacan is hypoglycosylated in a mouse model of one of these CMDs, known as muscle-eye-brain disease, a disorder that is caused by loss of an enzyme (protein O-mannose β-1,2-N-acetylglucosaminyltransferase 1) that modifies O-mannosyl glycans. In addition, monoclonal antibodies Cat-315 and 3F8 were demonstrated to detect O-mannosyl glycan modifications on RPTPζ/phosphacan. Here, we show that O-mannosyl glycan epitopes recognized by these antibodies define biochemically distinct glycoforms of RPTPζ/phosphacan and that these glycoforms differentially decorate the surface of distinct populations of neural cells. To provide a further structural basis for immunochemically based glycoform differences, we characterized the O-linked glycan heterogeneity of RPTPζ/phosphacan in the early postnatal mouse brain by multidimensional mass spectrometry. Structural characterization of the O-linked glycans released from purified RPTPζ/phosphacan demonstrated that this protein is a significant substrate for protein O-mannosylation and led to the identification of several novel O-mannose-linked glycan structures, including sulfo-N-acetyllactosamine containing modifications. Taken together, our results suggest that specific glycan modifications may tailor the function of this protein to the unique needs of specific cells. Furthermore, their absence in CMDs suggests that hypoglycosylation of RPTPζ/phosphacan may have different functional consequences in neurons and glia.
Age- and sex-related growth patterns of the craniofacial complex in European children aged 3–6 years

Abstract Background: Craniofacial growth changes in young children are not yet completely understood. Up-to-date references for craniofacial measurements are crucial for clinical assessment of orthodontic anomalies, craniofacial abnormalities and subsequent planning of interventions. Aim: To provide normal reference data and to identify growth patterns for craniofacial dimensions of European boys and girls aged 3–6 years. Subjects and methods: Using standard anthropometric methodology, body weight, body height and 23 craniofacial measurements were acquired for a cross-sectional sample of 681 healthy children (362 boys and 319 girls) aged 3–6 years from Germany, Italy and Lithuania. Descriptive statistics, correlation coefficients, percentage annual changes and percentage growth rates were used to analyse the dataset. Results: Between the ages of 3–6 years, craniofacial measurements showed age- and sex-related patterns independent from patterns observed for body weight and body height. Sex-related differences were observed in the majority of craniofacial measurements. In both sexes, face heights and face depths showed the strongest correlation with age. Growth patterns differed by craniofacial measurement and can be summarised into eight distinct age- and sex-related patterns. Conclusion: This study provided reference data and identified sex- and age-related growth patterns of the craniofacial complex of young European children, which may be used for detailed assessment of normal growth in paediatrics, maxillofacial reconstructive surgery and possibly for forensic age assessment.
The effect of herbal, essential oil and chlorhexidine mouthrinse on de novo plaque formation.

BACKGROUND Brushing and flossing are the most widely accepted procedures, the 'gold standard', for controlling bacterial plaque, but these mechanical methods have limitations. Based on results derived from several clinical trials, essential oil (EO) mouthrinse (Listerine(®)) and a chlorhexidine mouthrinse have been accepted by ADA to be used as an adjunct to routine mechanical oral hygiene measures however, both of them are associated with side effects, therefore, the present study was undertaken to evaluate the antiplaque efficacy of a new herbal formulation as compared to an EO and chlorhexidine rinse. MATERIALS AND METHOD The study was a single blind parallel randomized controlled trial involving four groups. 48 volunteers refrained from all oral hygiene measures for 4 days, but rinsed instead twice daily with 10 ml of a herbal (HM), EO, chlorhexidine (CHX) or a placebo (PL) solution. Plaque index and plaque area (PA) was assessed on Day 4. RESULTS The HM and EO showed a significant inhibition of plaque regrowth compared to PL (P<0.001), but the lowest values of PI and PA were obtained with CHX. Statistically significant difference in plaque parameters was observed when CHX was compared to HM and EO, and HM to EO rinse. CONCLUSION The new herbal mouthrinse had a promising plaque inhibitory potential but it not as efficacious as chlorhexidine in preventing plaque regrowth.
Phase II study of neoadjuvant docetaxel, vinorelbine, and trastuzumab followed by surgery and adjuvant doxorubicin plus cyclophosphamide in women with human epidermal growth factor receptor 2-overexpressing locally advanced breast cancer.

PURPOSE To evaluate the combination of docetaxel, vinorelbine, and trastuzumab as neoadjuvant therapy for human epidermal growth factor receptor 2 (HER2)--overexpressing breast cancer. PATIENTS AND METHODS Patients with stage IIB or III breast cancer, including inflammatory disease, and HER2 overexpression (determined by fluorescent in situ hybridization) were treated with six cycles of docetaxel 60 mg/m2 and vinorelbine 45 mg/m2 administered every 14 days with granulocyte colony-stimulating factor and quinolone prophylaxis. Trastuzumab was administered as a 4 mg/kg loading dose followed by 2 mg/kg weekly for 12 weeks. The primary efficacy end point was pathologic complete response (pCR) in the breast. RESULTS Of 31 enrolled patients, 68% had T3 or T4 tumors and 90% were clinically node positive. Twelve patients (39%; 95% CI, 21.6% to 55.9%) achieved pCR in the breast and lymph nodes and 14 patients (45%; 95% CI, 27.6% to 62.7%) achieved pCR in the breast alone, and 19 patients (61%; 95% CI, 44.1% to 78.4%) were node negative after neoadjuvant therapy. Clinical response was documented in 29 patients (94%; 95% CI, 78.6% to 99.2%) with 26 complete responses (84%; 95% CI, 70.9% to 96.8%). The most commonly reported grade 3/4 toxicities were neutropenia (97%), febrile neutropenia (22%), anemia (6%), mucositis/stomatitis (6%), constipation (6%), and skin rash (6%). CONCLUSION With clinical response and pCR rates of 94% and 39%, respectively, docetaxel, vinorelbine, and trastuzumab is a highly active neoadjuvant therapy for HER2-overexpressing locally advanced breast cancer. Although well tolerated overall, significant febrile neutropenia was observed despite prophylactic measures; therefore, evaluating a similar regimen using lower docetaxel and/or vinorelbine doses is warranted.