Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus from Latin America

Abstract Objective: This post hoc analysis evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) from Latin America. Research design and methods: Analyses were performed in subgroups of patients from Latin America based on data from three individual, 26-week, placebo-controlled studies of canagliflozin (monotherapy [n = 116/584], add-on to metformin [n = 199/918], and add-on to metformin plus sulfonylurea [n = 76/469]) and three individual, 52-week, active-controlled studies of canagliflozin (add-on to metformin versus sitagliptin [n = 240/1101], add-on to metformin versus glimepiride [n = 155/1450], and add-on to metformin plus sulfonylurea versus sitagliptin [n = 156/755]). Main outcome measures: Changes from baseline in HbA1c, body weight, and systolic blood pressure (BP) with canagliflozin 100 and 300 mg versus placebo or active comparator (i.e., sitagliptin or glimepiride) were evaluated in the overall study populations and Latin American subgroups. Safety was assessed based on adverse event (AE) reports. Results: Canagliflozin 100 and 300 mg provided reductions in HbA1c, body weight, and systolic BP across studies in patients from Latin America that were generally similar to those seen in the overall populations of patients with T2DM. The AE profile in patients from Latin America was equivalent to that in the overall populations; higher rates of genital mycotic infections and osmotic diuresis–related AEs were seen with canagliflozin versus comparators. Limitations of this study include the post hoc analysis of data and the small sample size of patients from Latin America. Conclusion: Canagliflozin improved glycemic control, reduced body weight and systolic BP, and was generally well tolerated in patients with T2DM from Latin America. Clinical trial registration: NCT01081834; NCT01106677; NCT01106625; NCT00968812; NCT01137812.
Forced Alignment of Mesenchymal Stem Cells Undergoing Cardiomyogenic Differentiation Affects Functional Integration With Cardiomyocyte Cultures

Alignment of cardiomyocytes (CMCs) contributes to the anisotropic (direction-related) tissue structure of the heart, thereby facilitating efficient electrical and mechanical activation of the ventricles. This study aimed to investigate the effects of forced alignment of stem cells during cardiomyogenic differentiation on their functional integration with CMC cultures. Labeled neonatal rat (nr) mesenchymal stem cells (nrMSCs) were allowed to differentiate into functional heart muscle cells in different cell-alignment patterns during 10 days of coculture with nrCMCs. Development of functional cellular properties was assessed by measuring impulse transmission across these stem cells between 2 adjacent nrCMC fields, cultured onto microelectrode arrays and previously separated by a laser-dissected channel (230±10 &mgr;m) for nrMSC transplantation. Coatings in these channels were microabraded in a direction (1) parallel or (2) perpendicular to the channel or were (3) left unabraded to establish different cell patterns. Application of cells onto microabraded coatings resulted in anisotropic cell alignment within the channel. Application on unabraded coatings resulted in isotropic (random) alignment. After coculture, conduction across seeded nrMSCs occurred from day 1 (perpendicular and isotropic) or day 6 (parallel) onward. Conduction velocity across nrMSCs at day 10 was highest in the perpendicular (11±0.9 cm/sec; n=12), intermediate in the isotropic (7.1±1 cm/sec; n=11) and lowest in the parallel configuration (4.9±1 cm/sec; n=11) (P<0.01). nrCMCs and fibroblasts served as positive and negative control, respectively. Also, immunocytochemical analysis showed alignment-dependent increases in connexin 43 expression. In conclusion, forced alignment of nrMSCs undergoing cardiomyogenic differentiation affects the time course and degree of functional integration with surrounding cardiac tissue.
Determination of nerve conduction velocity distribution from sampled compound action potential signals

The sampled compound action potential (CAP) data sequence was expressed as the circular convolution of the delay sequence and the sampled single fiber action potential (SFAP) data sequence. An algorithm, based on Hirose's method (1986) was then developed to separate the delay sequence from the sampled CAP data sequence, and the nerve conduction velocity distribution (NCVD) was consequently calculated from the delay sequence. The NCVD was found to be the product of the amplitude of the SFAP and the number of fibers. Simulations show that the estimated results were in good agreement with the calculated results. Experiments were performed on ten sciatic nerves from five bullfrogs (Rana pipens) using two independent variables: interelectrode distance and stimulus current strength. The results estimated from CAP's recorded under each condition reflect the corresponding feature of NCVD of the condition. The advantage of the technique is to provide detailed information about both slow and fast conducting fibers. This technique also offers the possibility to directly calculate the nerve fiber diameter distribution from the sampled CAP data sequences.
Incidence of alpha-1 antitrypsin Z and S alleles in patients with granulomatosis with polyangiitis--pilot study.

INTRODUCTION Inherited alpha-1 antitrypsin (AAT) deficiency is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. It has also been suggested that AAT deficiency might be instrumental vasculitis associated with the anti-neutrophil cytoplasm antibodies (cANCA) and subsequent lung tissue injury. MATERIAL AND METHODS We present the results from a pilot study involving 51 patients with granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis (GPA), 43 of whom were cANCA positive. The control group consisted of 658 individuals. AAT blood concentration assessment by nephelometry, phenotyping by isoelectrofocusing and real-time PCR genotyping were performed. RESULTS Deficiency alleles PI*Z and PI*S were detected in 3 (5.88%) and in 2 patients (3.92%) with GPA, respectively. All of them were cANCA positive. In the controls, PI*Z was observed in 2.8% while PI*S in 1.5% of cases. Accordingly, the increased incidence of main deficiency alleles was demonstrated in GPA, and particularly in cANCA+GPA patients, when compared to the controls. The estimated frequency for PI*Z in GPA, cANCA+GPA patients and controls was, respectively, 29.4/1000, 34.9/1000 and 13.7/1000, whereas for PI*S it was 19.2/1000, 23.2/10,00 and 7.6/1000. However, the observed differences did not reach statistical significance due to the considerable size disproportion between groups. CONSCLUSIONS: We believe that our preliminary data confirm the clinical importance of AAT deficiency in GPA patients and the need to screen for AAT deficiency alleles. The study is on-going.
Differences in MEG/EEG Epileptic Spike Yields Explained by Regional Differences in Signal-to-Noise Ratios

Controversy remains regarding the preferred modality, magnetoencephalography (MEG) or EEG, for the presurgical evaluation of patients with epilepsy. In general, it appears that the spike yields for MEG and EEG are similar in patients with temporal lobe epilepsy, and that for neocortical epilepsy the MEG spike yields may be larger than for EEG. In general, MEG/EEG spike yields depend on factors such as (1) the number of sensors, (2) the source depth and orientation, (3) the background activity, and (4) the smearing of the potential fields due to variations in skull resistivity in EEG. Because the contribution of all these factors are of the same order of magnitude, the authors took them all into account to predict the signal-to-noise ratio (SNR) of hypothetical spikes in different brain areas. In this study, it was assumed that spike sensitivity (and therefore the spike yield) increases with SNR. The estimated SNR values at temporal areas were comparable for MEG and EEG, which is in agreement with clinical findings that spike yields in temporal lobe epilepsy are similar. Furthermore, the SNR of MEG was substantially higher in the frontal area, indicating that in frontal lobe epilepsy MEG may be highly relevant to prescreening of epilepsy patients. This model-based approach indicates that SNR mapping clarifies differences between MEG and EEG findings that are difficult to understand on the basis of patient studies only.
Koral: A Glass Box Profiling System for Individual Components of Distributed RDF Stores

In the last years, scalable RDF stores in the cloud have been developed increasing the complexity of RDF stores running on a single computer. In order to gain a deeper understanding how, e.g., the data placement or the distributed query execution strategies affect the performance, we have developed the modular glass box proﬁling system Koral. With its help, it is possible to test the behaviour of already existing or newly created strategies tackling the challenges caused by the distribution in a realistic distributed RDF store. Thereby, the design goal of Koral is that only the evaluated component needs to be exchanged and the adaptation of other components is aimed to be minimal. The wide variety of measurements allow for an in-depth investigation of the performance. With Koral we analyse the impact of the three most commonly used data placement strategies and found out that balancing query workload reduces the query execution time more than reducing the data transfer.
Cholinergic Excitation of Septohippocampal GABA But Not Cholinergic Neurons: Implications for Learning and Memory

The medial septum/diagonal band (MSDB), which gives rise to the septohippocampal pathway, is a critical locus for the mnemonic effects of muscarinic drugs. Infusion of muscarinic cholinergic agonists into the MSDB enhance learning and memory processes both in young and aged rats and produce a continuous theta rhythm in the hippocampus. Intraseptal muscarinic agonists also alleviate the amnesic syndrome produced by systemic administration of muscarinic receptor antagonists. It has been presumed, but not proven, that the cellular mechanisms underlying the effects of muscarinic agonists in the MSDB involve an excitation of septohippocampal cholinergic neurons and a subsequent increase in acetylcholine (ACh) release in the hippocampus. Using a novel fluorescent labeling technique to selectively visualize live septohippocampal cholinergic neurons in rat brain slices, we have found that muscarinic agonists do not excite septohippocampal cholinergic neurons, instead they inhibit a subpopulation of cholinergic neurons. In contrast, unlabeled neurons, confirmed to be noncholinergic, septohippocampal GABA-type neurons using retrograde marking and double-labeling techniques, are profoundly excited by muscarine. Thus, the cognition-enhancing effects of muscarinic drugs in the MSDB cannot be attributed to an increase in hippocampal ACh release. Instead, disinhibitory mechanisms, caused by increased impulse flow in the septohippocampal GABAergic pathway, may underlie the cognition-enhancing effects of muscarinic agonists.
Presynaptic inhibition upon CB1 or mGlu2/3 receptor activation requires ERK/MAPK phosphorylation of Munc18‐1

Presynaptic cannabinoid (CB1R) and metabotropic glutamate receptors (mGluR2/3) regulate synaptic strength by inhibiting secretion. Here, we reveal a presynaptic inhibitory pathway activated by extracellular signal‐regulated kinase (ERK) that mediates CB1R‐ and mGluR2/3‐induced secretion inhibition. This pathway is triggered by a variety of events, from foot shock‐induced stress to intense neuronal activity, and induces phosphorylation of the presynaptic protein Munc18‐1. Mimicking constitutive phosphorylation of Munc18‐1 results in a drastic decrease in synaptic transmission. ERK‐mediated phosphorylation of Munc18‐1 ultimately leads to degradation by the ubiquitin–proteasome system. Conversely, preventing ERK‐dependent Munc18‐1 phosphorylation increases synaptic strength. CB1R‐ and mGluR2/3‐induced synaptic inhibition and depolarization‐induced suppression of excitation (DSE) are reduced upon ERK/MEK pathway inhibition and further reduced when ERK‐dependent Munc18‐1 phosphorylation is blocked. Thus, ERK‐dependent Munc18‐1 phosphorylation provides a major negative feedback loop to control synaptic strength upon activation of presynaptic receptors and during intense neuronal activity.
A new strategy based on recombinant viruses for assessing the replication capacity of HIV‐1

In heavily pretreated patients, resistance mutations arise in both protease (PR) and reverse transcriptase (RT) sequences; however, the relative impact of PR and RT mutations on viral fitness cannot be evaluated with the majority of systems. To address this issue we have developed a model based on recombinant viruses (RVs) that allows the analysis of the replication capacity (RC) of viral populations in which PR and RT are cloned either in combination or separately.
Phenotypic and molecular characteristics of hyperplastic polyposis.

BACKGROUND & AIMS Patients with hyperplastic polyposis are reported to have multiple and/or large hyperplastic polyps (HPs) and an increased risk of colorectal cancer, but the phenotype and genetic alterations in hyperplastic polyposis have not been studied in detail. METHODS We evaluated clinical-pathological and molecular characteristics of 129 HPs, 6 serrated adenomas, and 3 admixed hyperplastic-adenomatous polyps from 13 patients with hyperplastic polyposis (more than 20 HPs), 5 patients with a large HP (>/=1 cm in diameter), and 5 patients with multiple HPs (5-10 HPs). RESULTS HPs in the right colon in contrast to the left colorectum had more frequent topographic dysregulation of p21(Waf-1/Cip1) expression (94% vs. 76%, P = 0.03) and of proliferation (92% vs. 53%, P = 0. 0001), but less frequent allelic loss of chromosome 1p (4% vs. 17%, P = 0.03). K-ras mutation was present in 8% of HPs, p53 gene product overexpression in none, and microsatellite instability in 3% without relationship to microsatellite instability in synchronous cancer. Patients with a large HP differed from those with multiple HPs in having a high frequency of right-sided HP (63% vs. 22%, P = 0.01) and of right-sided colon cancer (100% vs. 8%, P = 0.003). Hyperplastic polyposis was associated with a family history of colorectal cancer (P = 0.01) and with loss of chromosome 1p in HP (21% vs. 0%, P = 0.001). CONCLUSIONS A hyperplastic polyp/dysplasia-to-adenocarcinoma sequence can be manifested in 3 distinct phenotypes consisting of patients with hyperplastic polyposis and chromosome 1p allelic loss in some HPs, in contrast to patients who have large, right-sided HPs or small numbers of HPs that lack 1p loss.
Hybrid bio-based composites from nano-reinforced bio-petro polymer blends and natural fibers

Natural fiber composites or biocomposites have recently gained much attention due to their low cost, environmental friendliness, and their potential to compete with glassfiber composites. However, the use of all-natural resins is limited due to performance concern, and hence the blending bio-resins in petroleum resins has gained importance due to their improved toughness and environmental friendliness. Nevertheless, addition of bio-resins generally compromises stiffness, barrier and thermal properties. The enhancement of polymer stiffness and barrier properties with small concentrations of layered silicates is well established. With this context, the paper presents the development and thermo-physical characterization of a hybrid composite material with increased environmental friendliness that can retain stiffness without sacrificing toughness, barrier and thermal properties. Hybrid biocomposites were made from biobased resins (blends of unsaturated polyester and epoxidized soya bean oil) reinforced with organo-nanoclays and natural fibers (unprocessed industrial hemp). Results show that an optimum material design that maximizes the synergy of the constituents is possible and provide an initial benchmark in identifying such balance.
Myths and Truths of Stretching

IN BRIEF: Stretching recommendations are clouded by misconceptions and conflicting research reports. This review of the current literature on stretching and range-of-motion increases finds that one static stretch of 15 to 30 seconds per day is sufficient for most patients, but some require longer durations. Heat and ice improve the effectiveness of static stretching only if applied during the stretch. Physicians should know the demands of different stretching techniques on muscles when making recommendations to patients. An individualized approach maybe most effective based on intersubject variation and differences between healthy and injured tissues.
Stochastic Capacitated Lot Sizing Subject to Maximum Acceptable Risk Level of Overutilization

Stochastic capacitated lot sizing problem is considered in the presence of probabilistic processing times and demand in this paper. A two-step hierarchical methodology is developed. First, stochastic capacity requirements are determined with statistical analysis & Monte-Carlo simulation. Second, a stochastic nonlinear mixed integer mathematical model is developed to solve the problem.
Bilateral Impact between Dairy Cattle and Global Warming

Although water vapour is the largest and essential greenhouse gas inclusive of ozone in the stratosphere, the mitigation of anthropogenic six greenhouse gases such as carbon dioxide, methane, nitrous oxide, sulphur hexafluoride, hydrofluorocarbons and perfluorocarbons have been established as legally binding commitments in The Kyoto Protocol. Important greenhouse gases attributed to ruminant livestock are methane and nitrous oxide. When the greenhouse effect of carbon dioxide is set to 1, the impact of the greenhouse effect of methane and nitrous oxide is 21-fold and 310-fold higher than carbon dioxide respectively
Models of Competitive Price Promotions: Some Empirical Evidence from the Coffee and Saltine Crackers Markets

I present tests of a competitive rationale for price promotions. In a model with a population of informed and uninformed customers, price competition yields a static equilibrium in which each seller draws a price from a specified density function. Price data on coffee and saltine crackers products are used to test whether the sample of prices on each product could have possibly come from the theoretically specified density function. The results suggest that some markets are indeed consistent with the marginal distributions of prices predicted by the model. Furthermore, in the process of testing this rationale for price promotions, estimates are obtained for the marginal cost of each product, the number of competing goods, and the percentage of informed consumers. The resulting excess variability of these estimates across competing brands can also raise questions with respect to the empirical validity of the model. Copyright 1995 by MIT Press.
The Effects of Accentuated Eccentric Loading During Drop Jumps on Strength, Power, Speed and Exercise-Induced Muscle Damage

iii List of Figures . ix List of Tables. x Attestation of Authorship . xi Co-Authored Works . xii Acknowledgements . xiv Ethics Approval . xv Chapter 1 .
New Insight in Loss of Gut Barrier during Major Non-Abdominal Surgery

Background Gut barrier loss has been implicated as a critical event in the occurrence of postoperative complications. We aimed to study the development of gut barrier loss in patients undergoing major non-abdominal surgery. Methodology/Principal Findings Twenty consecutive children undergoing spinal fusion surgery were included. This kind of surgery is characterized by long operation time, significant blood loss, prolonged systemic hypotension, without directly leading to compromise of the intestines by intestinal manipulation or use of extracorporeal circulation. Blood was collected preoperatively, every two hours during surgery and 2, 4, 15 and 24 hours postoperatively. Gut mucosal barrier was assessed by plasma markers for enterocyte damage (I-FABP, I-BABP) and urinary presence of tight junction protein claudin-3. Intestinal mucosal perfusion was measured by gastric tonometry (PrCO2, Pr-aCO2-gap). Plasma concentration of I-FABP, I-BABP and urinary expression of claudin-3 increased rapidly and significantly after the onset of surgery in most children. Postoperatively, all markers decreased promptly towards baseline values together with normalisation of MAP. Plasma levels of I-FABP, I-BABP were significantly negatively correlated with MAP at ½ hour before blood sampling (−0.726 (p<0.001), −0.483 (P<0.001), respectively). Furthermore, circulating I-FABP correlated with gastric mucosal PrCO2, Pr-aCO2-gap measured at the same time points (0.553 (p = 0.040), 0.585 (p = 0.028), respectively). Conclusions/Significance This study shows the development of gut barrier loss in children undergoing major non-abdominal surgery, which is related to preceding hypotension and mesenterial hypoperfusion. These data shed new light on the potential role of peroperative circulatory perturbation and intestinal barrier loss.
Efficient Second Order Online Learning by Sketching

We propose Sketched Online Newton (SON), an online second order learning algorithm that enjoys substantially improved regret guarantees for ill-conditioned data. SON is an enhanced version of the Online Newton Step, which, via sketching techniques enjoys a running time linear in the dimension and sketch size. We further develop sparse forms of the sketching methods (such as Oja's rule), making the computation linear in the sparsity of features. Together, the algorithm eliminates all computational obstacles in previous second order online learning approaches.
Regulatory Circuit of Human MicroRNA Biogenesis

miRNAs (microRNAs) are a class of endogenous small RNAs that are thought to negatively regulate protein production. Aberrant expression of many miRNAs is linked to cancer and other diseases. Little is known about the factors that regulate the expression of miRNAs. We have identified numerous regulatory elements upstream of miRNA genes that are likely to be essential to the transcriptional and posttranscriptional regulation of miRNAs. Newly identified regulatory motifs occur frequently and in multiple copies upstream of miRNAs. The motifs are highly enriched in G and C nucleotides, in comparison with the nucleotide composition of miRNA upstream sequences. Although the motifs were predicted using sequences that are upstream of miRNAs, we find that 99% of the top-predicted motifs preferentially occur within the first 500 nucleotides upstream of the transcription start sites of protein-coding genes; the observed preference in location underscores the validity and importance of the motifs identified in this study. Our study also raises the possibility that a considerable number of well-characterized, disease-associated transcription factors (TFs) of protein-coding genes contribute to the abnormal miRNA expression in diseases such as cancer. Further analysis of predicted miRNA–protein interactions lead us to hypothesize that TFs that include c-Myb, NF-Y, Sp-1, MTF-1, and AP-2α are master-regulators of miRNA expression. Our predictions are a solid starting point for the systematic elucidation of the causative basis for aberrant expression patterns of disease-related (e.g., cancer) miRNAs. Thus, we point out that focused studies of the TFs that regulate miRNAs will be paramount in developing cures for miRNA-related diseases. The identification of the miRNA regulatory motifs was facilitated by a new computational method, K-Factor. K-Factor predicts regulatory motifs in a set of functionally related sequences, without relying on evolutionary conservation.