Miracle-dz/UniFAR-FTUs huggingface dataset:
Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.

BACKGROUND In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up. METHODS We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events. RESULTS The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively. CONCLUSIONS The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).
Computational fluid dynamic simulations of aortic coarctation comparing the effects of surgical‐ and stent‐based treatments on aortic compliance and ventricular workload

Objectives: In this work, we examine the effects of stent‐induced aortic stiffness on cardiac workload and blood pressure using computational fluid dynamic simulations. Background: Treatment of aortic coarctation (CoA) consists of either open, surgical repair or angioplasty with or without stenting. Although stenting is a minimally invasive alternative to surgery, aortic stiffness increases in the stented section. Concern over this increased stiffness has long been argued to be detrimental to the overall vascular health of the patient. Methods: MR imaging was performed on a 15‐year‐old female with CoA. A 3D model of the large thoracic arteries was created, and the heart and downstream vasculature were represented by lumped parameter models at the model inlet and outlets, respectively. A deformable wall assumption was used in conjunction with variable wall properties and tissue support, and 3D velocity, pressure, and wall dynamics were computed. The lumped parameter values and wall properties were tuned to match the mean flow and aortic deformation as measured by MRI. The CoA was then virtually removed from the model representing an end‐to‐end surgical correction. In a second model, the repaired section was prescribed to be nearly rigid, representing stenting. All other variables remained the same. Results: When compared to surgery, stenting resulted in clinically negligible increases in cardiac work (0.4%) and no change in mean blood pressure. Conclusions: This pilot study suggests CoA stenting may not affect cardiac work to any significant degree as is commonly believed in the clinical community. © 2011 Wiley‐Liss, Inc.
Systematic 16S rRNA Gene Sequencing of Atypical Clinical Isolates Identified 27 New Bacterial Species Associated with Humans

ABSTRACT Clinical microorganisms isolated during a 5-year study in our hospital that could not be identified by conventional criteria were studied by 16S rRNA gene sequence analysis. Each isolate yielded a ≥1,400-bp sequence containing <5 ambiguities which was compared with the GenBank 16S rRNA gene library; 1,404 such isolates were tested, and 120 were considered unique (27 isolates) or rare (≤10 cases reported in the literature) human pathogens. Eleven new species, “Actinobaculum massiliae,” “Candidatus Actinobaculum timonae,” Paenibacillus sanguinis, “Candidatus Bacteroides massiliae,” Chryseobacterium massiliae, “Candidatus Chryseobacterium timonae,” Paenibacillus massiliensis, “Candidatus Peptostreptococcus massiliae,” “Candidatus Prevotella massiliensis,” Rhodobacter massiliensis, and “Candidatus Veillonella atypica” were identified. Sixteen species were obtained from humans for the first time. Our results show the important role that 16S rRNA gene sequence-based bacterial identification currently plays in recognizing unusual and emerging bacterial diseases.
Analysis of growth kinetics by division tracking

Cell division tracking using fluorescent dyes, such as carboxyfluorescein diacetate succinimidyl ester, provides a unique opportunity for analysis of cell growth kinetics. The present review article presents new methods for enhancing resolution of division tracking data as well as derivation of quantities that characterize growth from time‐series data. These include the average time between successive divisions, the proportion of cells that survive and the proliferation per division. The physical significance of these measured quantities is interpreted by formulation of a two‐compartment model of cell cycle transit characterized by stochastic and deterministic cell residence times, respectively. The model confirmed that survival is directly related to the proportion of cells that enter the next cell generation. The proportion of time that cells reside in the stochastic compartment is directly related to the proliferation per generation. This form of analysis provides a starting point for more sophisticated physical and biochemical models of cell cycle regulation.
Drosophila Avoids Parasitoids by Sensing Their Semiochemicals via a Dedicated Olfactory Circuit

Detecting danger is one of the foremost tasks for a neural system. Larval parasitoids constitute clear danger to Drosophila, as up to 80% of fly larvae become parasitized in nature. We show that Drosophila melanogaster larvae and adults avoid sites smelling of the main parasitoid enemies, Leptopilina wasps. This avoidance is mediated via a highly specific olfactory sensory neuron (OSN) type. While the larval OSN expresses the olfactory receptor Or49a and is tuned to the Leptopilina odor iridomyrmecin, the adult expresses both Or49a and Or85f and in addition detects the wasp odors actinidine and nepetalactol. The information is transferred via projection neurons to a specific part of the lateral horn known to be involved in mediating avoidance. Drosophila has thus developed a dedicated circuit to detect a life-threatening enemy based on the smell of its semiochemicals. Such an enemy-detecting olfactory circuit has earlier only been characterized in mice and nematodes.
Orthopedics and biofilm – what do we know? A review

Summary Bacteria have been found to grow predominantly in biofilms. The initial stage includes the attachment of bacteria to the substratum. Bacterial growth and division then leads to the colonization of the surrounding area and the formation of the biofilm. The environment in a biofilm is not homogeneous; the bacteria in a multispecies biofilm are not randomly distributed, but rather are organized to best meet their needs. Although there is an initial understanding on the mechanisms of biofilm-associated antimicrobial resistance, this topic is still under investigation. A variety of approaches are being explored to overcome biofilm-associated antimicrobial resistance. A greater understanding of biofilm processes should lead to novel, effective control strategies for biofilm control and a resulting improvement in patient management.
Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self- antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.
Should Statins Be Paused or Discontinued After Thrombolysis or Acute Intracerebral Hemorrhage? No!

A 78-year-old male patient arrives at the emergency department 3 hours after sudden onset of aphasia and right-sided sensorimotor hemiparesis (National Institutes of Health Stroke Scale=8). There is a medical history of coronary artery disease, hypertension, and hyperlipidemia. Prior medication consists of 100 mg aspirin, 5 mg bisoprolol, and 40 mg simvastatin. Initial blood glucose is 5.6 mmol/L and blood pressure is 150/90 mm Hg. Computed tomography does not reveal any pathology. Intravenous recombinant tissue-plasminogen activator (rt-PA) is rapidly administered 225 minutes after symptom onset. There is uncertainty about how to proceed with preexisting statin treatment in the acute setting of thrombolysis. Several studies linked statin treatment with an increased risk of intracerebral hemorrhage (ICH) after stroke, and additional studies recently indicated an increased risk for ICH after thrombolysis.1–4 This is in line with earlier epidemiological evidence showing an inverse correlation of cholesterol and ICH risk.5,6 Should statin treatment be discontinued following the principle “primum nil nocere” (Latin: first of all, do not harm)? On the contrary, there is strong evidence that discontinuation of statin therapy during acute vascular events, including ischemic as well as hemorrhagic stroke, impairs vascular function and dramatically decreases the chances of good outcome and survival.7–10 In this opinion article, we would like to make a strong case that preexisting statin treatment should not be paused or abruptly discontinued, either in acute ischemic stroke patients receiving rt-PA or in patients with acute ICH. What is the evidence that stroke patients on statins have a higher risk of ICH? The evidence for risks and benefits of statins after stroke are mainly derived from the Heart Protection Study and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.1,2 A subgroup analysis of the Heart …
The Dystrophin Complex Controls BK Channel Localization and Muscle Activity in Caenorhabditis elegans

Genetic defects in the dystrophin-associated protein complex (DAPC) are responsible for a variety of pathological conditions including muscular dystrophy, cardiomyopathy, and vasospasm. Conserved DAPC components from humans to Caenorhabditis elegans suggest a similar molecular function. C. elegans DAPC mutants exhibit a unique locomotory deficit resulting from prolonged muscle excitation and contraction. Here we show that the C. elegans DAPC is essential for proper localization of SLO-1, the large conductance, voltage-, and calcium-dependent potassium (BK) channel, which conducts a major outward rectifying current in muscle under the normal physiological condition. Through analysis of mutants with the same phenotype as the DAPC mutants, we identified the novel islo-1 gene that encodes a protein with two predicted transmembrane domains. We demonstrate that ISLO-1 acts as a novel adapter molecule that links the DAPC to SLO-1 in muscle. We show that a defect in either the DAPC or ISLO-1 disrupts normal SLO-1 localization in muscle. Consistent with observations that SLO-1 requires a high calcium concentration for full activation, we find that SLO-1 is localized near L-type calcium channels in muscle, thereby providing a mechanism coupling calcium influx with the outward rectifying current. Our results indicate that the DAPC modulates muscle excitability by localizing the SLO-1 channel to calcium-rich regions of C. elegans muscle.
Similarities and Differences in Smooth Muscle a-Actin Induction by TGF-b in Smooth Muscle Versus Non – Smooth Muscle Cells

Transforming growth factorb (TGF-b) has been shown to stimulate smooth muscle (SM) a-actin expression in smooth muscle cells (SMCs) and non-SMCs. We previously demonstrated that the 2 CArG boxes A and B and a novel TGF-b control element (TCE) located within the first 125 bp of the SM a-actin promoter were required for TGFb inducibility of SM a-actin in SMCs. The aims of the present study were (1) to determine whether the TCE exhibits SMC specificity or contributes to TGFb induction of SM a-actin expression in non-SMCs (ie, endothelial cells and fibroblasts) and (2) to determine whether TGFb can induce expression of multiple TCE-containing SMC differentiation marker genes, such as SM22 a, h1 calponin, and SM myosin heavy chain (SM MHC) in non-SMCs. Results of transient transfection assays demonstrated that mutation of CArG A, CArG B, or the TCE within a 125-bp promoter context completely abolished TGFb inducibility of SM a-actin in endothelial cells and fibroblasts. However, in contrast to observations in SMCs, inclusion of regions upstream from 2155 completely repressed TGFb responsiveness in non-SMCs. Electrophoretic mobility shift assays showed that TGFb enhanced binding of a serum response factor to the CArG elements and the binding of an as-yet-unidentified factor to the TCE in endothelial cells and fibroblasts, but to a much lesser extent compared with SMCs. TGFb also stimulated expression of the SMC differentiation marker SM22a in non-SMCs. However, in contrast to SMCs, TGFb did not induce expression of h 1 calponin and SM MHC in non-SMCs. In summary, these results suggest a conserved role for CArG A, CArG B, and the TCE in TGFb–induced expression of SMa-actin in SMCs and non-SMCs that is modified by a complex interplay of positiveand negative-actingcis elements in a cell-specific manner. Furthermore, observations that TGFb stimulated expression of several early but not late differentiation markers in non-SMCs indicate that TGFb alone is not sufficient to induce transdifferentiation of non-SMCs into SMCs. (Arterioscler Thromb Vasc Biol . 1999;19:2049-2058.)
Erratic Flu Vaccination Emerges from Short-Sighted Behavior in Contact Networks

The effectiveness of seasonal influenza vaccination programs depends on individual-level compliance. Perceptions about risks associated with infection and vaccination can strongly influence vaccination decisions and thus the ultimate course of an epidemic. Here we investigate the interplay between contact patterns, influenza-related behavior, and disease dynamics by incorporating game theory into network models. When individuals make decisions based on past epidemics, we find that individuals with many contacts vaccinate, whereas individuals with few contacts do not. However, the threshold number of contacts above which to vaccinate is highly dependent on the overall network structure of the population and has the potential to oscillate more wildly than has been observed empirically. When we increase the number of prior seasons that individuals recall when making vaccination decisions, behavior and thus disease dynamics become less variable. For some networks, we also find that higher flu transmission rates may, counterintuitively, lead to lower (vaccine-mediated) disease prevalence. Our work demonstrates that rich and complex dynamics can result from the interaction between infectious diseases, human contact patterns, and behavior.
A D.C. Optimization Algorithm for Solving the Trust-Region Subproblem

This paper is devoted to difference of convex functions (d.c.) optimization: d. c. duality, local and global optimality conditions in d. c. programming, the d. c. algorithm (DCA), and its application to solving the trust-region problem. The DCA is an iterative method that is quite different from well-known related algorithms. Thanks to the particular structure of the trust-region problem, the DCA is very simple (requiring only matrix-vector products) and, in practice, converges to the global solution. The inexpensive implicitly restarted Lanczos method of Sorensen is used to check the optimality of solutions provided by the DCA. When a nonglobal solution is found, a simple numerical procedure is introduced both to find a feasible point having a smaller objective value and to restart the DCA at this point. It is shown that in the nonconvex case, the DCA converges to the global solution of the trust-region problem, using only matrix-vector products and requiring at most 2m+2 restarts, where m is the number of distinct negative eigenvalues of the coefficient matrix that defines the problem. Numerical simulations establish the robustness and efficiency of the DCA compared to standard related methods, especially for large-scale problems.
Addressing the Challenges of Tuberculosis: A Brief Historical Account

Tuberculosis (TB) is a highly contagious disease that still poses a threat to human health. Mycobacterium tuberculosis (MTB), the pathogen responsible for TB, uses diverse ways in order to survive in a variety of host lesions and to subsequently evade immune surveillance; as a result, fighting TB and its associated multidrug resistance has been an ongoing challenge. The aim of this review article is to summarize the historical sequence of drug development and use in the fight against TB, with a particular emphasis on the decades between World War II and the dawn of the twenty first century (2000).
Calcium Regulation of Calcineurin Phosphatase Activity by Its B Subunit and Calmodulin

Calcineurin (CaN) contains an autoinhibitory element (residues 457-482) 43 residues COOH-terminal of the calmodulin-binding domain (Hashimoto, Y., Perrino, B. A., and Soderling, T. R.(1990) J. Biol. Chem.265, 1924-1927) that regulates the Ca-dependent activation of its phosphatase activity. Substitution of Arg and Arg or Asp to Ala in the autoinhibitory peptide 457-482 significantly decreased its inhibitory potency. CaN A subunits with these residues mutated to Ala were co-expressed with the Ca-binding B subunit using the baculovirus/Sf9 cell system. Kinetic analysis showed that although the purified mutants had no activity in the absence of calcium, they were less dependent than the wild-type enzyme on calcium and calmodulin for activity. To determine if additional autoinhibitory motifs were present in the COOH terminus of calcineurin, the A subunit was truncated at residues 457 or 420 and co-expressed with B subunit. The Vmax values of both truncation mutants with or without Ca were increased relative to wild-type calcineurin. The increased Ca-independent activity of CaN relative to CaN indicates the presence of additional autoinhibitory element(s) within residues 420-457. CaN had similar high Vmax values with or without Ca, but the K value for peptide substrate was increased 5-fold to 125 μM in the absence of Ca. The K values of all the expressed calcineurin species were increased in the absence of Ca. The CaN A or CaN A subunits alone have low Vmax and high K (115 μM) values even in the presence of Ca. These results indicate that 1) there are several autoinhibitory motifs between the CaM-binding domain and the COOH terminus that are relieved by Ca binding to CaM and the B subunit, 2) Ca binding to the B subunit also regulates enzyme activity by lowering the K of the catalytic subunit for substrate, 3) binding of the B subunit is required for high Vmax values even after removal of the autoinhibitory domain. These results are consistent with synergistic activation of calcineurin by Ca acting through both CaM and the B subunit.
The Clinical Utility of the Combination of T Stage and Venous Invasion to Predict Survival in Patients Undergoing Surgery for Colorectal Cancer

Objective:To examine the clinical utility of improved detection of venous invasion (VI) in patients undergoing potentially curative resection of colorectal cancer. Background:VI is a feature of colorectal cancer (CRC) progression. Elastica staining can be used to improve detection of VI and correspondingly its prediction of patient survival. Methods:A single-center, observational study of pathology variables, including detection of VI by staining for elastica, using 631 stage I to III CRC specimens, collected from 1997 to 2009 (176 analyzed retrospectively and 455 analyzed prospectively), was performed. Results:VI was detected in 56% of patients with CRC. Over a median follow-up period of 73 months, 238 patients died (134 from cancer). On multivariate analysis, VI by elastica staining was associated with a shorter survival duration, independent of other pathology features, in all cases [hazard ratio (HR) = 3.94, 95% confidence interval (CI): 2.33–6.65, P < 0.001] and in node-negative cases (HR = 3.55, 95% CI: 1.81–6.97; P < 0.001). In the absence of elastica-detected VI, with the exception of T stage, no other pathology features were associated with survival time. Therefore, the combination of T stage and VI (TVI) on survival was examined. Five-year cancer mortality could be stratified between 100% and 54% for patients with node-negative tumors and between 100% and 33% for patients with node-positive tumors. In all cases, the TVI had similar predictive value as that of T stage and node status (TNM). In node-negative disease, TVI had superior predictive value. Conclusions:The results of the present study have prompted the development of a novel tumor staging system based on TVI. The TVI has clinical utility, especially in node-negative disease, in predicting outcome following curative resection for CRC.