Miracle-dz/UniFAR-FTUs huggingface dataset:
The lymphocyte homing receptors: gatekeepers of the multistep paradigm

Purpose of reviewLymphocyte trafficking is regulated by adhesion molecules mediating the initial shear-resistant binding of circulating cells to target tissue endothelium (Step 1). This review focuses on the current and emerging perspectives of the biology of these ‘homing receptors. ’ Recent findingsThe conventional multistep paradigm holds that leukocyte migration represents a cascade of events, initiated by tethering and rolling interactions of leukocytes on the endothelial surface (Step 1). These interactions are indispensable, required to dampen velocities sufficiently to allow cells to sense the local chemokines and/or other inflammatory signals resulting in activation of integrin adhesiveness (Step 2), with ensuing firm adherence on the vessel wall (Step 3) followed by endothelial transmigration (Step 4). Mechanistic studies now suggest that some effectors of Step 1 interactions themselves activate integrin adhesiveness and trigger transmigration - in some cases by forming complexes with integrins - thus bypassing the need for chemokine signaling. These findings force a reconsideration of the multistep paradigm, and shift focus now to identifying all relevant effectors of Step 1 interactions using adherence assays performed under shear stress to mimic the dynamic conditions of blood flow. SummaryRecent findings suggest that homing receptors are not merely molecular brakes. The cross-talk among the homing receptors and integrins opens a new ‘avenue’ to lymphocyte migration, suggesting that homing receptors may be sufficient alone, in some cases, to perform the function the name implies.
Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction

Binding of alpha interferon (IFNalpha) to its receptors induces rapid tyrosine phosphorylation of the receptor subunits IFNaR1 and IFNaR2, the TYK2 and JAK1 tyrosine kinases, and the Stat1 and Stat2 transcription factors. Previous studies have demonstrated that TYK2 directly and specifically binds to and tyrosine phosphorylates IFNaR1 in vitro. We now report a detailed analysis of the TYK2 binding domain on the IFNaR1 subunit. First, we used an in vitro binding assay to identify the TYK2 binding motif in IFNaR1 as well as the critical residues within this region. The most striking feature is the importance of a number of hydrophobic and acidic residues. A minor role is also ascribed to a region resembling the proline-rich "box 1" sequence. In addition, mutations which disrupt in vitro binding also disrupt the coimmunoprecipitation of the receptor and TYK2. We also provide direct evidence that the binding region is both necessary and sufficient to activate TYK2 in vivo. Specifically, mutations in the binding domain act in a dominant-negative fashion to inhibit the IFNalpha-induced tyrosine phosphorylation of TYK2 and Stat2. Further, introduction of dimerized glutathione S-transferase-IFNaR1 fusion proteins into permeabilized cells is sufficient to induce phosphorylation of TYK2 and the receptor, confirming the role of the binding domain in IFNalpha signal transduction. These studies provide clues to the sequences determining the specificity of the association between JAK family tyrosine kinases and cytokine receptors as well as the functional role of these kinases in cytokine signal transduction.
Mitochondrial injury and cognitive function in HIV infection and methamphetamine use

Objective:In this work, we evaluated the association of human immunodeficiency virus (HIV) infection and methamphetamine (METH) use with mitochondrial injury in the brain and its implication on neurocognitive impairment. Design:Mitochondria carry their genome (mtDNA) and play a critical role in cellular processes in the central nervous system. METH is commonly used in HIV-infected populations. HIV infection and METH use can cause damage to mtDNA and lead to neurocognitive morbidity. We evaluated HIV infection and METH use with mitochondrial injury in the brain. Methods:We obtained white and gray matter from Brodmann areas 7, 8, 9, 46 of the following: HIV-infected individuals with history of past METH use (HIV+METH+, n = 16), HIV-infected individuals with no history of past METH use (HIV+METH−, n = 11), and HIV-negative controls (HIV−METH−, n = 30). We used the ‘common deletion’, a 4977 bp mutation, as a measurement of mitochondrial injury, and quantified levels of mtDNA and ‘common deletion’ by droplet digital PCR, and evaluated in relation to neurocognitive functioning [Global Deficit Score (GDS)]. Results:Levels of mtDNA and mitochondrial injury were highest in white matter of Brodmann area 46. A higher relative proportion of mtDNA carrying the ‘common deletion’ was associated with lower GDS (P < 0.01) in HIV+METH+ but higher GDS (P < 0.01) in HIV+METH−. Conclusions:Increased mitochondrial injury was associated with worse neurocognitive function in HIV+METH− individuals. Among HIV+METH+ individuals, an opposite effect was seen.
Acute alcohol intoxication-induced microvascular leakage.

BACKGROUND Alcohol intoxication can increase inflammation and worsen injury, yet the mechanisms involved are not clear. We investigated whether acute alcohol intoxication increases microvascular permeability and investigated potential signaling mechanisms in endothelial cells that may be involved. METHODS Conscious rats received a 2.5 g/kg alcohol bolus via gastric catheters to produce acute intoxication. Microvascular leakage of intravenously administered fluorescein isothiocyanate (FITC)-conjugated albumin (FITC-albumin) from the mesenteric microcirculation was assessed by intravital microscopy. Endothelial-specific mechanisms were studied using cultured endothelial cell monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function, before and after treatment with alcohol or its metabolite acetaldehyde. Pharmacologic agents were used to test the roles of alcohol metabolism, oxidative stress, p38 mitogen-activated protein kinase (MAPK), myosin light-chain kinase (MLCK), rho kinase (ROCK), and exchange protein activated by cAMP (Epac). VE-cadherin localization was investigated to assess junctional integrity. Rac1 and RhoA activation was assessed by ELISA assays. RESULTS Alcohol significantly increased FITC-albumin extravasation from the mesenteric microcirculation. Alcohol also significantly decreased TER and disrupted VE-cadherin organization at junctions. Acetaldehyde significantly decreased TER, but inhibition of alcohol dehydrogenase or application of a superoxide dismutase mimetic failed to prevent alcohol-induced decreases in TER. Inhibition of p38 MAPK, but not MLCK or ROCK, significantly attenuated the alcohol-induced barrier dysfunction. Alcohol rapidly decreased GTP-bound Rac1 but not RhoA during the drop in TER. Activation of Epac increased TER, but did not prevent alcohol from decreasing TER. However, activation of Epac after initiation of alcohol-induced barrier dysfunction quickly resolved TER to baseline levels. CONCLUSIONS Our results suggest that alcohol intoxication increases microvascular permeability to plasma proteins. The data also suggest the endothelial-specific mechanism involves the p38 MAPK, Rac1, and reorganization of VE-cadherin at junctions. Last, activation of Epac can quickly resolve alcohol-induced endothelial barrier dysfunction.
Direct and quantitative evaluation of the human CYP3A4 contribution (fm) to drug clearance using the in vitro SILENSOMES model

Abstract 1. Among the different in vitro studies recommended by the regulatory agencies, no gold-standard model can easily and directly measure the quantitative CYP450 contributions to drug biotransformation. In this article, we propose an original strategy, called SilensomesTM, to produce human liver microsomes silenced for one specific CYP450, thanks to specific mechanism-based inhibitors (MBI). 2. Using azamulin as a specific CYP3A4 MBI, we demonstrated the proof of concept that CYP3A4 can be totally, specifically (even against 3A5) and permanently (at least for six years) inhibited by our process. Thus, comparing clearance in control and CYP3A4-SilensomesTM, CYP3A4 contributions were determined for 11 CYP3A4 substrates which correlated with known in vivo contributions and revealed accuracy with less than 10% error. In comparison, contributions determined using recombinant human CYP450 (rhCYP450s) were less accurate (more than 10% error for 30% of the tested CYP3A4 substrates). 3. This easy and ready-to-use in vitro method combines the advantages of existing models (specificity of rhCYP450s and representativeness of HLM) without their drawbacks. The same strategy could be used to silence other major CYP450s one-by-one to provide a complete direct CYP450 quantitative phenotyping kit.
Left ventricular myocardial performance index change for detection of acute cellular rejection in pediatric heart transplantation

EMB, the gold standard for diagnosis of ACR, poses unique risks in children. Limited cross‐sectional data have associated LV MPI with ACR. We hypothesize that a relative change in MPI from baseline without ACR to the time of ACR will better detect ACR than an absolute threshold LV MPI value. We identified 40 children with ACR ≥60 days post‐transplant matching them by age and time from transplantation to 40 children without ACR. There was a significant increase in LV MPI at time of ACR vs. baseline (0.59 ± 0.17 vs. 0.41 ± 0.11; p < 0.001). There was no difference in LV MPI between baseline and follow‐up (0.41 ± 0.11 vs. 0.42 ± 0.11; p = 0.65). An absolute increase in LV MPI of ≥0.47 had 82.5% sensitivity and 85% specificity for ACR, whereas an increase in LV MPI from baseline of ≥20.4% was 90% sensitive and 100% specific. Serial measurement of LV MPI appears to be a sensitive and specific marker of ACR. LV MPI shows good interobserver agreement and increases at the time of EMB‐proven ACR with subsequent resolution to baseline measurements upon EMB‐proven resolution of ACR. Future studies in larger, prospective cohorts should be undertaken to validate these findings.
Inheritance of Total Serum IgE in the Isolated Tangier Island Population from Virginia: Complexities Associated with Genealogical Depth of Pedigrees in Segregation Analyses

Objectives: This study was aimed at performing a segregation analysis of total serum immunoglobulin E (tIgE) in an isolated population using maximal genealogical information permitted by current software and computer capacities, while assessing the reliability of the best-fitting model of inheritance for tIgE through simulations. Methods: All current Tangier Island, VA, residents (n = 664) belonged to one large extended pedigree (n = 3,501) spanning 13 generations, with an average inbreeding coefficient of 0.009. Phenotype data were obtained on 453 (68.2%) of the residents using a population-based recruitment scheme. Due to computational limitations resulting from the extremely complex pedigree structure, analysis on only two pedigree reconstructions was feasible: a reduced pedigree retaining all phenotyped individuals and their parents as 57 distinct families, and 922 nuclear families. Results: Familial correlations and heritability calculations reveal a significant genetic component to tIgE in these data (heritability = 26%). The most parsimonious model to explain tIgE distribution indicated by the reduced pedigree structure was a two-distribution Mendelian model. However, larger and non-genetic models could not be rejected. Simulations over 200 replicates performed to evaluate the reliability of this model, indicated that using restricted genealogical information had minimal impact on results of segregation anal yses performed here.
Adjunctive hyperbaric oxygen therapy in the treatment of atrophic tibial nonunion with Ilizarov external fixator: a radiographic and scintigraphic study in rabbits.

OBJECTIVE The aim of this experimental study was to determine the effects of adjunctive hyperbaric oxygen therapy (HBO) on atrophic tibial nonunion treatment using Ilizarov external fixator. METHODS Twenty New Zealand white rabbits were randomly divided into two equal groups. A circular external fixator was applied to the right tibia of all the rabbits. A 5-mm bone block was resected and a tibial pseudarthrosis was obtained after a 6-month waiting period. The experimental group rabbits (n=10) underwent daily 2.5 ATA HBO therapy for 2 hours for 20 days and the control group rabbits (n=10) did not receive any corresponding treatment. Osteoblastic activity was evaluated with bone scintigraphy on days 30 and 90. Fracture healing was evaluated by plain radiographs on days 30 and 90. RESULTS On Day 30, radiological scores were statistically similar in both groups (p=0.167). However, on Day 90, the experimental group displayed significantly higher radiological scores (p<0.001). Osteoblastic activity was also higher in the experimental group on both scintigraphic assessments (p=0.005 and p=0.001). CONCLUSION The results of this study suggest that HBO can be used as a supplementary therapy in the management of atrophic tibial nonunion.
Preliminary study of disfluency in school-aged children with autism.

BACKGROUND In recent years, there has been increased identification of disfluencies in individuals with autism, but limited examination of disfluencies in the school-age range of this population. We currently lack information about whether the disfluencies of children with autism represent concomitant stuttering, normal disfluency, excessive normal disfluency, or some form of disfluency unique to the school-age population of children with autism. AIMS This paper explores the nature of disfluencies in school-aged children with autism in comparison with matched children who stutter and controls. It explores stuttering-like disfluencies, non-stuttering-like disfluencies and word-final disfluencies. METHODS & PROCEDURES This study compared disfluency patterns in 11 school-aged children with Asperger's syndrome (AS), 11 matched children who stutter (CWS), and 11 matched children with no diagnosis (ND). Analyses were based on speech samples collected during an expository discourse task. OUTCOMES & RESULTS Results reveal statistically significant differences between children with AS and CWS and between children with AS and those with ND for the percentage of words containing stuttering-like disfluencies. In the AS group, four out of 11 (36%) met the common diagnostic criteria for a fluency disorder. Disfluencies in the AS group differed qualitatively and quantitatively from the CWS, and included a larger distribution of word-final disfluencies. CONCLUSIONS & IMPLICATIONS This study provides initial data regarding patterns of disfluency in school-aged children with AS that, with careful consideration and the cautious application of all findings, can assist therapists in making more evidence-based diagnostic decisions. Findings offer evidence that when working with children with AS, disfluencies both similar and dissimilar to those of CWS may be identified in at least a subset of those with AS. Therefore, children with AS should be screened for fluency disorders during their initial evaluation and treated if it is determined that the fluency disorder negatively impacts the effectiveness of communication.
PCR analysis is superior to histology for diagnosis of Whipple’s disease mimicking seronegative rheumatic diseases

Objectives: The diagnosis of Whipple’s disease (WD) is commonly confirmed by histology demonstrating Periodic Acid Schiff (PAS)-positive macrophages in the duodenal mucosa. Analysis of intestinal tissue or other specimens using polymerase chain reaction (PCR) is a more sensitive method. However, the relevance of positive PCR findings is still controversial. Therefore, we evaluated the relevance of histology and PCR findings to establishing the diagnosis of WD in a series of WD patients initially presenting with suspected rheumatic diseases. Method: Between 2006 and 2014, 20 patients with seronegative rheumatic diseases tested positive for Tropheryma whipplei (Tw) by PCR and/or histology and were enrolled in a retrospective analysis of the diagnostic value of both procedures. Results: Seven of the 20 cases (35%) were diagnosed with ‘classic’ WD as indicated by PAS-positive macrophages. In the remaining 13 patients, the presence of Tw was detected by intestinal (n = 10) or synovial PCR analysis (n = 3). Two of the 20 patients (10%) with evidence of Tw did not respond to antibiotic therapy. They were not considered to suffer from WD. Therefore, relying only on histological findings of intestinal biopsies would have missed 11 (61%) of the 18 patients with WD in our cohort. In comparison, PCR of intestinal biopsies detected Tw-DNA in 14 (93%) of the 15 WD patients evaluated. Patients with a positive histology did not differ from PCR-positive patients with regard to sex, age, or duration of disease, but more often presented with gastrointestinal symptoms. Conclusions: A substantial number of WD patients present without typical intestinal histology findings. Additional PCR analysis of intestinal tissue or synovial fluid increased the sensitivity of the diagnostic evaluation and should be considered particularly in patients presenting with atypical seronegative rheumatic diseases and a high-risk profile for WD.
Modeling of Magnetoresistive-Based Electrical Current Sensors: A Technological Approach

The utilization of modeling tools can, in many cases, help us in the design and final prototyping of any sort of sensors. In this paper, we describe a finite-element method (FEM) model applied to a hybrid technology involving a full Wheatstone bridge spin-valve-based electrical current sensor. After validating the model against experimental results, we focus our studies on geometrical aspects of the sensor configuration, in order to detect possible deviations that may have occurred during the fabrication process. In this regard, the characteristics of the behavior of the sensor depending on lateral displacements and inclination are included. Moreover, the frequency response of the sensor is also analyzed, thus enlarging the scope of the model.
Percutaneous Lumbar and Thoracic Pedicle Screws: A Trauma Experience

Design: Retrospective case study. Objective: Percutaneous pedicle screw (PPS) techniques do not allow direct visualization and may lead to erroneous screw placement. A technique utilizing only fluoroscopy is described. Verification of its accuracy and morphometric validation are presented. Background: Minimally invasive spine surgical techniques, particularly PPS placement, have been growing in popularity. The purported benefits of minimally invasive spine surgical stated may be even more advantageous in the trauma setting. Methods: Jamshidi needles were docked in the typical starting position verified with posterior-anterior image. Jamshidi needle (20 mm) was advanced ensuring that the tip remained lateral to the medial pedicle wall. A Kirschner (K-wire) was placed through the needle. Once all the K-wires were placed, a lateral image was taken confirming the correct trajectory and that the wire passed the posterior vertebral body wall. Patients with PPS fixation were retrospectively studied with postoperative computed tomography to verify screw accuracy. Screw grade was assessed as grade I when completely within the pedicle, II <2 mm, III 2–4 mm, and IV >4 mm outside the pedicle. Morphometrically, 40 thoracic and lumbar computed tomography scans of patients (<40 y) without spine fractures were reviewed. The pedicle length was defined as the distance from the dorsal cortical margin to the posterior vertebral body in the pedicle’s midaxis. Results: A total of 172 screws were placed. Eighteen percent were found to have cortical breach, but only 2.9% were found to have >grade II breach. The morphometric study demonstrated the pedicle length to range from 14.4 to 22.1 mm. The shortest was in the upper thoracic and the longest at L1–L2. Conclusions: The morphometric study demonstrates if a K-wire is placed 20 mm into the bone and remains lateral to the medial pedicle wall and the tip just engages the vertebral body, the screw trajectory is safe particularly in the lower thoracic and upper lumbar spine. A smaller distance may be utilized in the upper thoracic. Breach rates are similar to other reports using other techniques; none were clinically significant. The advantage of this technique is the use of only PA fluoroscopy for placing all the wires percutaneously.
Scarless hepatectomy: natural orifice specimen extraction after left lateral sectionectomy

Background The use of laparoscopy in liver surgery is well established and considered as the gold standard for small resections. The laparoscopic resections have lower morbidity and better cosmetic results, but still require an incision to remove the surgical specimen. The possibility of remove the specimen through natural orifices and avoid an abdominal incision may further improve the benefits offered by minimally invasive procedures. Aim To describe the technique of transvaginal extraction of the specimen after laparoscopic liver left lateral sectionectomy. Method The laparoscopic liver resection is performed in a standard fashion. After completing the resection, the specimen is placed into a retrieval plastic bag. To perform de extraction, a vaginal colpotomy is performed, guided by a 12 mm trocar introduced through the vagina. Then the extraction bag is removed pulling the bag through the extended incision in the posterior wall of the vagina. After the extraction, the colpotomy incision is closed laparoscopically. Results This technique was performed in a 74-year-old woman with a 3 cm lesion between liver segments 2 and 3. She had a fast and uneventful recovery. Conclusion This technique appears to be feasible, safe and avoid the complications of an abdominal incision.
Electromyographic and kinematic analysis of the flexion-rotation trunk test.

While most trunk endurance field protocols are performed in the sagittal or frontal planes, the flexion-rotation trunk (FRT) test combines trunk flexion with rotation, which may be relevant to rotation-related sports. The aim of this study was to describe the trunk and hip muscle activation and fatigue and the range of hip flexion of this test. Twenty-seven physically active males and females performed the FRT test after a period of practice. Electromyographic (EMG) signals were bilaterally collected from the rectus abdominis (RA), internal oblique (IO), and rectus femoris (RF), and hip flexion amplitude was measured using a biaxial electrogoniometer. Since the fast Fourier transform algorithm requires stationary EMG signals, participants performed a 6-s isometric trunk flexion-rotation repetition just before and just after the test execution (pre- and post-execution repetitions, respectively). RA showed the highest mean activation levels (about 30% maximal voluntary isometric contractions [MVC]) in the pre-execution repetition, followed by IO (about 20% MVC). Also, the mean power frequency (MPF) significantly decreased from the pre- to the post-execution repetition for RA and IO, which shows abdominal muscle fatigue. Although each trunk flexion rotation repetition involved an average 8-14° hip flexion, the RF activation was lower than 10% MVC, and no significant MPF reduction (i.e. no muscle fatigue) was observed for this muscle. Additionally, significant negative correlations were found between the FRT test scores and the normalised EMG amplitudes of RF. Based on these results, the FRT test seems a valid field protocol to assess abdominal muscle endurance in trunk flexion-rotation exertions.