Miracle-dz/UniFAR-FTUs huggingface dataset:
Corticosteroid Pharmacokinetics in the Inner Ear Fluids: An Animal Study Followed by Clinical Application

Objective: Autoimmune disease (e.g., Cogan syndrome) and other inflammatory inner ear diseases may ravage the labyrinth if not treated aggressively with antiinflammatory medication. Corticosteroids are the mainstay of treatment, yet, partly because of the existence of the blood—labyrinthine barrier, the ideal drug, dose, and route of administration are currently unknown. Study Design: In the present study, we established cochlear fluid pharmacokinetic profiles of hydro‐cortisone, methylprednisolone, and dexamethasone in the guinea pig following oral, intravenous, and topical (intratympanic) administration. High‐performance liquid chromatography was used to determine the drug concentrations, and comparisons were made with simultaneous pharmacokinetic profiles from blood and cerebrospinal fluid. Results: Our findings demonstrated a much higher penetration of all three drugs into the cochlear fluids following topical application as compared with systemic administration, with methylprednisolone showing the best profile. Discussion: The results suggested that intratympanic administration of corticosteroids might be more efficacious while avoiding high blood levels and therefore the deleterious side effects of systemic use. Clinical Application: Thirty‐seven patients with various inner ear disorders causing sensorineural hearing loss were subsequently treated using intratympanic corticosteroids, 20 with dexamethasone, and 17 with methlyprednisolone. Patients with immune‐mediated hearing losses showed the best results, with notable improvement also seen in several cases of a “sudden deafness. ” No benefit was seen in patients with cochlear hydrops or those with sudden deterioration of a preexisting hearing loss. Three patients developed a transient otitis media related to the treatments, easily controlled with antibiotics. There were no cases of treatment‐induced hearing loss and no permanent tympanic membrane perforations. Conclusions: Overall, injection of intratympanic corticosteroids for the treatment of hearing loss in inner ear disorders appears to be both safe and highly effective for certain disorders. The concept of this technique is supported by animal experimental data. The findings from the present study warrant further clinical application and experimental investigation.
Reduced Coronary Flow Reserve and Early Diastolic Filling Abnormalities in Patients with Nephrotic Syndrome

Background. Increased cardiovascular disease risk is very well known in nephrotic syndrome. Coronary flow reserve measurement by trans-thoracic echocardiography reflects coronary microvascular and endothelial function. However, diastolic filling abnormalities by echocardiography may indicate diastolic dysfunction. Our aim was to evaluate endothelial and diastolic functions by trans-thoracic echocardiography in nephrotic syndrome. Methods. Eighteen patients with nephrotic syndrome (five females, 34 ± 17 years) and 30 controls (10 females, 35 ± 10 years) were evaluated in this cross-sectional observational study. Age, weight, lipid profile, glucose, blood urea nitrogen, creatinine, serum albumin, total protein, C-reactive protein, erythrocyte sedimentation rate, blood pressures, 24-hour urine volume, and protein were recorded. Glomerular filtration rate was estimated by Cockcroft-Gault Formula. Doppler flow and other echocardiographic parameters were measured by Vivid 7 echocardiography. Results. Coronary flow reserve was significantly lower in patients than controls (p < 0.001) and was negatively correlated with proteinuria (p < 0. 001), creatinine levels (p = 0.03), total cholesterol (p = 0.02), C-reactive protein (p = 0.02), and erythrocyte sedimentation rate (p = 0.005). E/A ratio was significantly lower in patients than in controls (p = 0.005). DT was significantly higher in patients than in controls (p = 0.01) and isovolumic relaxation time was similar in both groups. Conclusion. Coronary flow reserve and left ventricular diastolic filling are significantly impaired in nephrotic syndrome. Proteinuria, serum creatinine, total cholesterol and inflammation may have all contributory effects on endothelial dysfunction. Early evaluation of patients with nephrotic syndrome should include coronary flow and diastolic function by echocardiography.
No Evidence for a Role of Adipose Tissue-Derived Serum Amyloid A in the Development of Insulin Resistance or Obesity-Related Inflammation in hSAA1+/− Transgenic Mice

Obesity is associated with a low-grade inflammation including moderately increased serum levels of the acute phase protein serum amyloid A (SAA). In obesity, SAA is mainly produced from adipose tissue and serum levels of SAA are associated with insulin resistance. SAA has been described as a chemoattractant for inflammatory cells and adipose tissue from obese individuals contains increased numbers of macrophages. However, whether adipose tissue-derived SAA can have a direct impact on macrophage infiltration in adipose tissue or the development of insulin resistance is unknown. The aim of this study was to investigate the effects of adipose tissue-derived SAA1 on the development of insulin resistance and obesity-related inflammation. We have previously established a transgenic mouse model expressing human SAA1 in the adipose tissue. For this report, hSAA1+/− transgenic mice and wild type mice were fed with a high fat diet or normal chow. Effects of hSAA1 on glucose metabolism were assessed using an oral glucose tolerance test. Real-time PCR was used to measure the mRNA levels of macrophage markers and genes related to insulin sensitivity in adipose tissue. Cytokines during inflammation were analyzed using a Proinflammatory 7-plex Assay. We found similar insulin and glucose levels in hSAA1 mice and wt controls during an oral glucose tolerance test and no decrease in mRNA levels of genes related to insulin sensitivity in adipose tissue in neither male nor female hSAA1 animals. Furthermore, serum levels of proinflammatory cytokines and mRNA levels of macrophage markers in adipose tissue were not increased in hSAA1 mice. Hence, in this model we find no evidence that adipose tissue-derived hSAA1 influences the development of insulin resistance or obesity-related inflammation.
Boosting Probabilistic Graphical Model Inference by Incorporating Prior Knowledge from Multiple Sources

Inferring regulatory networks from experimental data via probabilistic graphical models is a popular framework to gain insights into biological systems. However, the inherent noise in experimental data coupled with a limited sample size reduces the performance of network reverse engineering. Prior knowledge from existing sources of biological information can address this low signal to noise problem by biasing the network inference towards biologically plausible network structures. Although integrating various sources of information is desirable, their heterogeneous nature makes this task challenging. We propose two computational methods to incorporate various information sources into a probabilistic consensus structure prior to be used in graphical model inference. Our first model, called Latent Factor Model (LFM), assumes a high degree of correlation among external information sources and reconstructs a hidden variable as a common source in a Bayesian manner. The second model, a Noisy-OR, picks up the strongest support for an interaction among information sources in a probabilistic fashion. Our extensive computational studies on KEGG signaling pathways as well as on gene expression data from breast cancer and yeast heat shock response reveal that both approaches can significantly enhance the reconstruction accuracy of Bayesian Networks compared to other competing methods as well as to the situation without any prior. Our framework allows for using diverse information sources, like pathway databases, GO terms and protein domain data, etc. and is flexible enough to integrate new sources, if available.
Nucleotide Distribution Patterns in Insect Genomes

This work analyzed genome-wide nucleotide distribution patterns in ten insect genomes. Two internal measures were applied: (i) GC variation and (ii) third codon nucleotide preference. Although the genome size and overall GC level did not show any correlation with insect order, the internal measures usually displayed higher levels of consistency. GC variations in genomes of hymenopteran insects, honeybee and wasp, ranked highest among all eukaryotic genomes analyzed by us. Genomes of honeybee and beetle, insects of different orders with similar overall GC levels, showed significant internal differences. Honeybee genome stood out as unusual due to its high GC variation and 'left-handed' gene locations.
Norepinephrine and cyclic adenosine 3′:5′‐cyclic monophosphate enhance a nifedipine‐sensitive calcium current in cultured rat astrocytes

We employed two microelectrode current‐clamp and voltage‐clamp methods to examine the modulation of Ca++ channels by norepinephrine and cyclic AMP (cAMP) in cultured astrocytes from the rat cerebral cortex. Currents owing to Ca++ channels were maximized by replacing Ca++ with Ba++ in the extracellular solution and pharmacologically blocking K+ and Na+ currents. In current‐clamp experiments, we observed that norepinephrine, isoproternol (an agonist of β‐receptors for norepinephrine), or dibutyryl cAMP (dbcAMP, a membrane permeant analogue of cAMP) induced or enhanced slow Ba++‐dependent action potentials in the cells. In voltage‐clamp experiments, we confirmed that the slow action potentials were generated by a voltage‐activated and Ba++‐dependent inward current. This current was mediated by channels that resembled L‐type calcium channels (cf. McCleskey et al., Journal of Experimental Biology 124:177–190, 1986) in their voltage‐activation range, slow inactivation, and sensitivity to blockage by Co++, Cd++, and nifedipine. DbcAMP, or isoproterenol, enhanced the Ba++ current. Modulation of Ca++ channel function in glial cells could have functional implications.
Induction Kinetics of the l-Arabinose Operon of Escherichia coli

After addition of l-arabinose to growing Escherichia coli, the l-ribulokinase (EC 2.7.1.16) and l-arabinose isomerase (EC 5.3.1.4) first appear at about 0.7 and 1.4 min, respectively. These times are consistent with the distances of the genes from the ribonucleic acid polymerase initiation site in the operon. The kinetics of appearance of these enzymes as well as those of β-galactosidase (EC 3.2.1.23) in the same strain are consistent with a peptide elongation rate of no less than 14 amino acids per second. A measurement of the average peptide elongation rate made by measuring the kinetics of radioactive amino acid appearance in completed polypeptides yielded a rate of about 12 amino acids per s. Convenient assays of the arabinose isomerase and ribulokinase are also given.
Effect of Chronic Rapid Ventricular Pacing on Total Vascular Capacitance

Background Rapid right ventricular pacing (RRVP) at 250 bpm for 3–6 weeks produces chronic heart failure manifested by a reduction in cardiac output and increases in right atrial, pulmonary artery, and capillary wedge pressures. Methods and Results One week after splenectomy and pacemaker placement, vascular capacitance, unstressed volume, and compliance were determined in 19 anesthetized dogs from pressure-volume curves using transient circulatory arrests induced by acetylcholine. Nine dogs were restudied 31±1 days later without RRVP, and 10 dogs underwent RRVP at 250 bpm and were restudied at 23±8 and 38±8 days in cardiac failure and after 1 and 2 weeks of postpacing recovery. Control animals had no changes in vascular capacitance or compliance. Dogs undergoing RRVP exhibited a marked increase in mean circulatory filling pressure (5.4±0.4 to 10.5±1.5 mm Hg) during the development of cardiac failure with a reduction in unstressed volume (81.9±5.7 to 43.9±8.1 ml kg−1) without changing total vascular compliance. Total blood volume decreased (95.4±6.2 to 66.7±6.5 ml kg−1) primarily due to a reduction in packed cell volume. The pressure gradient for venous return and overall venous resistance was unaltered. Central blood volume as a proportion of total blood volume increased (93±1.7% to 16.0±2.7%). Arterial compliance and capacity and pulmonary vascular compliance were reduced. In the 2-week postpacing period, except for a reduced cardiac response to a volume load, all of these parameters returned to baseline values. Conclusions Chronic RRVP induced cardiac failure with a marked reduction in total vascular capacitance due to a reduction in unstressed volume without altering compliance. The rise in mean circulatory filling pressure was limited by a reduction in total blood volume.
Effects of Epitope Modification on T Cell Receptor–Ligand Binding and Antigen Recognition by Seven H-2Kd–restricted Cytotoxic T Lymphocyte Clones Specific for a Photoreactive Peptide Derivative

We tested for antigen recognition and T cell receptor (TCR)–ligand binding 12 peptide derivative variants on seven H-2Kd–restricted cytotoxic T lymphocytes (CTL) clones specific for a bifunctional photoreactive derivative of the Plasmodium berghei circumsporozoite peptide 252– 260 (SYIPSAEKI). The derivative contained iodo-4-azidosalicylic acid in place of PbCS S-252 and 4-azidobenzoic acid on PbCS K-259. Selective photoactivation of the N-terminal photoreactive group allowed crosslinking to Kd molecules and photoactivation of the orthogonal group to TCR. TCR photoaffinity labeling with covalent Kd–peptide derivative complexes allowed direct assessment of TCR–ligand binding on living CTL. In most cases (over 80%) cytotoxicity (chromium release) and TCR–ligand binding differed by less than fivefold. The exceptions included (a) partial TCR agonists (8 cases), for which antigen recognition was fivetenfold less efficient than TCR–ligand binding, (b) TCR antagonists (2 cases), which were not recognized and capable of inhibiting recognition of the wild-type conjugate, (c) heteroclitic agonists (2 cases), for which antigen recognition was more efficient than TCR–ligand binding, and (d) one partial TCR agonist, which activated only Fas (CD95), but not perforin/granzymemediated cytotoxicity. There was no correlation between these divergences and the avidity of TCR–ligand binding, indicating that other factors than binding avidity determine the nature of the CTL response. An unexpected and novel finding was that CD8-dependent clones clearly incline more to TCR antagonism than CD8-independent ones. As there was no correlation between CD8 dependence and the avidity of TCR–ligand binding, the possibility is suggested that CD8 plays a critical role in aberrant CTL function.
Gene Therapy in a Patient with Sickle Cell Disease.

Sickle cell disease results from a homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like–globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 ClinicalTrials.gov number, NCT02151526.)
Splash generation and evolvement in the laser ablation with liquid working substance

Splash generation and evolvement have been observed with ns-shadowgraphy time resolved method on the laser micro ablation with liquid working substance. The flow visualization method of splash phenomenon is introduced and the shock wave and particle front velocity were measured and analyzed to research the relationship between material characteristics and splash dynamics. Three different laser energy densities and four different doped mass fractions are adopted for the comparison to find out the energy intensity density and work substance doped mass fraction influence on the splash generation and evolvement. The results show that: the carbon doped in the liquid working substance could weaken the splash process with the smaller droplets and shorter duration time.
A lightweight software fault‐tolerance system in the cloud environment

With the development of cloud computing, the demand of high availability for services is growing. Unfortunately, software failures greatly reduce system availability. This paper presents a lightweight software fault‐tolerance system, called SHelp, which can effectively recover programs from many types of software bugs in the cloud environment. With error virtualization techniques, it proposes ‘weighted’ rescue points techniques to effectively survive software failures through bypassing the faulty path. For multiple application instances running on different virtual machine, a three‐level storage hierarchy with several comprehensive cache updating algorithms for rescue points management is adopted to share error handling information. On the one hand, SHelp can reduce the redundancy for multiple application instances; on the other hand, it can more effectively and quickly recover from faults caused by the same bugs. A Linux prototype is implemented on an open‐source virtual machine monitor platform, Xen, and evaluated using four Web server applications that contain various types of bugs. The experimental results show that SHelp can recover server applications from these bugs in just a few seconds with modest performance overhead. Copyright © 2013 John Wiley & Sons, Ltd.
TrkB expression and phospho‐ERK activation by brain‐derived neurotrophic factor in rat spinothalamic tract neurons

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin implicated in the phenomena of synaptic plasticity in the adult. It is found in terminals of nociceptive primary afferents. Following a pain‐related stimulus, it is released in the spinal cord, where it activates its high‐affinity receptor TrkB, leading to the phosphorylation of the mitogen‐activated protein kinase (MAPK) extracellular signal‐regulated kinase (ERK). A large body of evidence suggests that BDNF has a positive neuromodulatory effect on glutamate transmission in the spinal cord. However, none of these studies examined anatomically whether projection neurons known to be involved in transmission of nociceptive inputs express BDNF's receptor. Because the spinothalamic tract (STT) is a well‐characterized pathway for its role in the transfer and integration of sensory and nociceptive informations, this study in rats aimed to 1) determine whether neurons of the STT pathway express the TrkB receptor, 2) establish the rostrocaudal and laminar distribution of STT‐TrkB neurons in the whole spinal cord, and 3) test the potential functionality of TrkB expression in these cells by investigating the ability of BDNF to activate the MAP kinase ERK. Using tract tracing coupled to immunofluorescent labeling for TrkB, we observed that in all levels of the spinal cord most STT neurons were immunoreactive for TrkB. Furthermore, microinjections of BDNF into the spinal cord or release of endogenous BDNF by intraplantar injection of capsaicin activated ERK phosphorylation in TrkB‐containing STT neurons. These data suggest an important role for BDNF in nociception as an activator of spinothalamic projection neurons. J. Comp. Neurol. 489:59–68, 2005. © 2005 Wiley‐Liss, Inc.
The Conduction System in Acute Myocardial Infarction Complicated by Heart Block

Detailed histological examination of the conduction system in 29 cases of acute myocardial infarction complicated by heart block has been carried out. In 24 cases posterior infarction was present and occlusion had occurred in the artery from which the blood supply to the A-V node was ultimately derived. In these cases major structural damage to the conduction system was rare, but when present, involved the bundle branches. A-V block in posterior infarction is therefore usually due to hypoxia or other reversible factors rather than structural damage to the conduction system. These findings are consistent with the high incidence of transient heart block in survivors.In five cases anterior infarction alone was present. The blood supply of the A-V node was not compromised, but massive infarction had caused major damage to both bundle branches.Since major structural damage to the conduction system is uncommon in myocardial infarction, only a minority of survivors will have permanent heart block. In those cases in which there is extensive damage to the bundle branches there is a risk of high mortality and permanent block particularly when the infarct is anteroseptal.
Pattern of road traffic injuries in Ghana: Implications for control

Road traffic injuries and fatalities are increasing in Ghana. Police-collected crash and injury data for the period 1994-1998 were aggregated and analyzed using the MAAP5 accident analysis package developed by the Transport Research Laboratory, U.K. Published results of recent transport-related epidemiological and other surveys provided an additional data source. According to the 1994-1998 police data, road traffic crashes were a leading cause of death and injuries in Ghana. The other leading causes of death and injuries are occupational injuries which involve nonmechanized farming and tribal conflicts. The majority of road traffic fatalities (61.2%) and injuries (52.3%) occurred on roads in rural areas. About 58% more people died on roads in the rural areas than in urban areas, and generally more severe crashes occurred on rural roads compared with urban areas. Pedestrians accounted for 46.2% of all road traffic fatalities. The majority of these (66.8%) occurred in urban areas. The second leading population of road users affected was riders in passenger-ferrying buses, minibuses and trucks. The majority of these (42.8%) were killed on roads that pass through rural areas. Pedestrian casualties were overrepresented (nearly 90%) in five regions located in the southern half of the country. Efforts to tackle pedestrian safety should focus on the five regions of the country where most pedestrian fatalities occur in urban areas. Policies are also needed to protect passengers in commercially operated passenger-ferrying buses, minibuses and trucks because these vehicles carry a higher risk of being involved in fatal crashes.