Miracle-dz/UniFAR-FTUs huggingface dataset:
Laminar inflammatory gene expression in the carbohydrate overload model of equine laminitis.

REASONS FOR PERFORMING STUDY There is a need to assess the laminar inflammatory response in a laminitis model that more closely resembles clinical cases of sepsis-related laminitis than the black walnut extract (BWE) model. OBJECTIVES To determine if a similar pattern of laminar inflammation, characterised by proinflammatory cytokine expression, occurs in the CHO model of laminitis as has been previously reported for the BWE model. METHODS Sixteen horses administered 17.6 g of starch (85% corn starch/15% wood flour)/kg bwt via nasogastric (NG) tube were anaesthetised either after developing a temperature>38.9°C (DEV group, n=8) or at onset of Obel grade 1 lameness (OG1 group, n=8). Control horses (CON group, n=8) were anaesthetised 24 h after NG administration of 6 l of deionised water. Laminar tissue was collected from horses while under anaesthesia, followed by humane euthanasia. Real time-quantitative PCR was used to assess laminar mRNA concentrations of genes involved in inflammatory signalling. RESULTS Increased mRNA concentrations (P<0.05) for IL-1β, IL-6, IL-12p35, COX-2, E-selectin and ICAM-1 were present in laminae from horses with OG1 lameness but not at the DEV time, when compared to the CON horses. No differences between the groups were found for IL-2, IL-4, IL-10, TNF-α, IFN-γ or COX-1 at either the DEV or OG1 time points. CONCLUSIONS There was a notable difference in the temporal pattern of inflammatory events between the BWE and CHO models, with the majority of laminar inflammatory events appearing to occur at or near the onset of lameness in the CHO model, whereas many of these events peak earlier in the developmental stages in the BWE model. This suggests that, in addition to circulating inflammatory molecules, there may be a local phenomenon in the CHO model resulting in the simultaneous onset of multiple laminar events including endothelial activation, leucocyte emigration and proinflammatory cytokine expression. POTENTIAL RELEVANCE The similar (although somewhat delayed) inflammatory response in the CHO model of laminitis indicates that inflammatory signalling is a consistent entity in the pathophysiology of laminitis.
BACTERIAL INTERACTIONS WITH CELLS OF THE INTESTINAL MUCOSA: TOLL-LIKE RECEPTORS AND NOD2

Toll-like receptors (TLR) and NOD2 are emerging as key mediators of innate host defence in the intestinal mucosa, crucially involved in maintaining mucosal as well as commensal homeostasis. Recent observations suggest new (patho-) physiological mechanisms of how functional versus dysfunctional TLRx/NOD2 pathways may oppose or favour inflammatory bowel disease (IBD). In health, TLRx signalling protects the intestinal epithelial barrier and confers commensal tolerance whereas NOD2 signalling exerts antimicrobial activity and prevents pathogenic invasion. In disease, aberrant TLRx and/or NOD2 signalling may stimulate diverse inflammatory responses leading to acute and chronic intestinal inflammation with many different clinical phenotypes.
Structural and degradation characteristics of an innovative porous PLGA/TCP scaffold incorporated with bioactive molecular icaritin

Phytomolecules may chemically bind to scaffold materials for medical applications. The present study used an osteoconductive porous poly(l-lactide-co-glycolide)/tricalcium phosphate (PLGA/TCP) to incorporate an exogenous phytoestrogenic molecule icaritin to form a PLGA/TCP/icaritin composite scaffold material with potential slow release of icaritin during scaffold degradation. Accordingly, the present study was designed to investigate its in vitro degradation characteristics and the release pattern of icaritin at three different doses (74 mg, 7.4 mg and 0.74 mg per 100 g PLGA/TCP, i.e. in the PLGA/TCP/icaritin-H, -M and -L groups, respectively). A PLGA/TCP/icaritin porous composite scaffold was fabricated using a computer-controlled printing machine. The PLGA/TCP/icaritin scaffolds were incubated in saline at 37 °C for 12 weeks and the pure PLGA/TCP scaffold served as a control. During the 12 weeks in vitro degradation, the scaffolds in all four groups showed changes, including a decrease in weight, volume and pore size of the composite scaffold, while there was a decrease in acidity and an increase in Ca and lactic acid concentrations in the degradation medium, especially after 7 weeks. The rate of degradation was explained by the relationship with the content of icaritin incorporated into the scaffolds. The higher the icaritin content in the scaffolds, the slower the degradation could be observed during 12 weeks. After 12 weeks, the SEM showed that the surface of the PLGA/TCP and PLGA/TCP/icaritin-L groups was relatively smooth with a gradual decrease in number and size of the micropores, while the porous morphology on the surface of the PLGA/TCP/icaritin-M and PLGA/TCP/icaritin-H groups was partly maintained, accompanied by a decrease in phosphate (P) and calcium (Ca) contents at the surface. Though the mechanical property of the PLGA/TCP/icaritin scaffold decreased after degradation, its porous structure was maintained, which was essential for cell migration and ingrowth of newly regenerated tissues in vivo. The controlled release of icaritin from the composite scaffold reached about 70% of the incorporated icaritin into the degradation medium after 12 weeks. The above findings suggested that the structural and degradation properties of the porous composite PLGA/TCP/icaritin scaffold were dependent on icaritin concentrations. This innovative composite porous scaffold material developed in the present study may be used as a good scaffold material for enhancing bone repair, especially at high concentrations of icaritin. In vivo confirmation is, however, needed to substantiate our in vitro findings.
Review of Cerebral Microangiopathy and Alzheimer’s Disease: Relation between White Matter Hyperintensities and Microbleeds

Although Alzheimer’s disease (AD) is basically considered to be a neurodegenerative disorder, cerebrovascular disease is also involved. The role of vascular risk factors and vascular disease in the progression of AD remains incompletely understood. With the development of brain MRI, it is now possible to detect small-vessel disease, whose prevalence and severity increase with age. The first types of small-vessel disease to be described were white matter hyperintensities (WMHs). More recently, small areas of signal loss on T2*-weighted images, also called microbleeds (MBs), have been reported. Cerebral MBs are focal deposits of hemosiderin that indicate prior microhemorrhages around small vessels, related to either ruptured atherosclerotic microvessels or amyloid angiopathy. Consequently, using brain MRI for the detection of microangiopathy may prove useful to improve our understanding of the impact of the vascular burden in AD pathology. The relationship between microangiopathy and the clinical course of AD or the conversion of mild cognitive impairment to AD remains questionable in terms of cognitive or affective symptoms, particularly if we consider MBs.
Pharmacogenetic differences between warfarin, acenocoumarol and phenprocoumon

Summary Coumarin oral anticoagulant drugs have proven to be effective for the prevention of thromboembolic events. World-wide, warfarin is the most prescribed drug. In Europe, acenocoumarol and phenprocoumon are also administered. Yet it has been proven that variant alleles of theVKORC1 and CYP2C9 genotypes influence the pharmacokinetics and pharmacodynamics of these drugs. The combination of these two variant genotypes is a major cause of the inter-individual differences in coumarin anticoagulant drug dosage. Individuals who test positive for both variant genotypes are at increased risk of major bleeding. The impact of the CYP2C9 andVKORC1 genotype is most significant during the initial period of coumarin anticoagulant therapy. The effect ofVKORC1 allelic variants is relatively similar for all three VKAs. The CYP2C9 polymorphism is associated with delayed stabilisation for coumarin anticoagulants. The effects of CYP2C9 polymorphisms on the pharmacokinetics and anticoagulant response are least pronounced in the case of phenprocoumon. In the long term, patients using phenprocoumon have more often international normalised ratio (INR) values in the therapeutic range, requiring fewer monitoring visits. This leads us to conclude that in the absence of pharmacogenetic testing, phenprocoumon seems preferable for use in long-term therapeutic anti-coagulation. Pharmacogenetic testing before initiating coumarin oral anticoagulants may add to the safety of all coumarin anticoagulants especially in the elderly receiving multiple drugs.
Myofibre damage in human skeletal muscle: effects of electrical stimulation versus voluntary contraction

Disruption to proteins within the myofibre after a single bout of unaccustomed eccentric exercise is hypothesized to induce delayed onset of muscle soreness and to be associated with an activation of satellite cells. This has been shown in animal models using electrical stimulation but not in humans using voluntary exercise. Untrained males (n= 8, range 22–27 years) performed 210 maximal eccentric contractions with each leg on an isokinetic dynamometer, voluntarily (VOL) with one leg and electrically induced (ES) with the other leg. Assessments from the skeletal muscle were obtained prior to exercise and at 5, 24, 96 and 192 h postexercise. Muscle tenderness rose in VOL and ES after 24 h, and did not differ between groups. Maximal isometric contraction strength, rate of force development and impulse declined in the VOL leg from 4 h after exercise, but not in ES (except at 24 h). In contrast, a significant disruption of cytoskeletal proteins (desmin) and a rise of myogenic growth factors (myogenin) occurred only in ES. Intracellular disruption and destroyed Z‐lines were markedly more pronounced in ES (40%) compared with VOL (10%). Likewise, the increase in satellite cell markers [neural cell adhesion molecule (N‐CAM) and paired‐box transcription factor (Pax‐7)] was more pronounced in ES versus VOL. Finally, staining of the intramuscular connective tissue (tenascin C) was increased equally in ES and VOL after exercise. The present study demonstrates that in human muscle, the delayed onset of muscle soreness was not significantly different between the two treatments despite marked differences in intramuscular histological markers, in particular myofibre proteins and satellite cell markers. An increase in tenascin C expression in the midbelly of the skeletal muscle in both legs provides further evidence of a potential role for the extracellular matrix in the phenomenon of delayed onset of muscle soreness.
Structure-function analysis of human cytochrome P450 3A4 using 7-alkoxycoumarins as active-site probes.

The oxidation of a series of seven alkyl ethers of 7-hydroxycoumarin by cytochrome P450 3A4 (CYP3A4) has been studied to probe the active site of the enzyme. TLC of the reaction mixture showed formation of metabolites other than 7-hydroxycoumarin. The separation and characterization of the different metabolites of the C4 to C7 compounds were achieved using a combination of TLC, HPLC, and gas chromatography-electron impact mass spectra. Among the 7-alkoxycoumarins, 7-hexoxycoumarin was found to be the most suitable candidate for investigating the active site of cytochrome CYP3A4, due to the well-separated metabolite peaks on TLC and HPLC. 7-hexoxycoumarin was found to produce three side-chain hydroxylated products besides 7-hydroxycoumarin: 7-(5-hydroxyhexoxy)coumarin, 7-(4-hydroxyhexoxy)coumarin, and 7-(3-hydroxycoumarin). The substitution of residues from substrate recognition sites -1, -4, -5, and -6 of CYP3A4 showed a strong influence on the product profile of 7-hexoxycoumarin, the most prominent effects observed with mutants at residues 119, 301, 305, 370, 373, and 479. The docking of 7-hexoxycoumarin into a molecular model of CYP3A4 also confirmed the presence of these residues within 5 A of the substrate. A comparative study of cytochrome P450 2B1 showed that the active-site mutants F206L, T302V, V363A, and S478G but not V363L exhibited a dramatic decrease in total 7-hexoxycoumarin hydroxylation. The study suggests that although the electronic nature of the substrate is important, enzymatic constraints significantly contribute to CYP3A4 selectivity.
JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects.

CONTEXT The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. OBJECTIVE Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. DESIGN, SETTINGS, AND PATIENTS A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. RESULTS We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. CONCLUSIONS clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.
Molecular prevalence and risk factors for the occurrence of canine monocytic ehrlichiosis.

Evaluation of blood samples collected from 214 dogs from Ludhiana, Punjab (India) was performed for the presence of Ehrlichia canis using PCR-based assays targeting a portion of the 16S rRNA gene. Of the total samples subjected to routine blood smear examination, the morulae of E. canis were detected in 2.34% samples. Nested PCR assay produced amplicons of expected size (389 bp) specific for E. canis in 41.59% (89/214) of samples. The results of multivariate analysis showed that the prevalence of E. canis was higher in the summer as compared to the winter season (P = 0.031) and in dogs younger than six-month-old as compared to older dogs (P < 0.001), while breed and sex of the host were not significantly associated with the occurrence of the disease.
A simple and objective marker for stress

Abstract Objective: To examine the association between pressure pain sensitivity (PPS) at sternum and various well established physiological stress measures among opera singers during a performance as a measure for transitional stress, and resting values in out-clinic patients as a measure for persistent stress. Methods: Changes in PPS on the index finger and sternum, middle blood pressure (MAP), heart rate (HR), pressure-rate-product (PRP) and salivary cortisol (SCO) were recorded in 26 opera solo singers during a performance. Resting PPS, HR, MAP, PRP and presence of a noxious withdrawal reflex (NWR) were recorded in 181 out-clinic patients. Results: During opera performance, the PPS on sternum changed concomitantly with MAP (correlation coefficient (r) r=0.42, p<0.005), HR (r=0.55, p<0.001), PRP (r=0.54, p<0.001) and SCO (r=0.26, p=0.066). During rest, a significant correlation was found between PPS on sternum and HR, PRP and presence of noxious withdrawal reflex (all p<0.01). Conclusions: The PPS measurement at sternum was associated with well established physiological stress measures and may represent a simple, objective and reliable measure of physiological stress used by both non-professional and professionals.
Does Immigration into Their Neighborhoods Incline Voters Toward the Extreme Right? The Case of the Freedom Party of Austria

This paper explores one potentially important channel through which immigration may drive support for extreme right-wing parties: the presence of immigrants in one’s neighborhood. We study the case of the Freedom Party of Austria (FPO). Under the leadership of Jorg Haider, this party increased its share of votes from less than 5 percent in the early 1980s to 27 percent by the year 1999. Using past regional settlement patterns as a source of exogenous variation, we find a significantly positive effect of the residential proximity of immigrants on FPO votes, explaining roughly a quarter of the cross-community variance in FPO votes. It is the presence of low- and medium-skilled immigrants that drives this result; high-skilled immigrants have no (or even a negative) effect on FPO votes.
Persistent cognitive deficits in adult women with Turner syndrome

Background: Turner syndrome (TS) has a characteristic neurocognitive profile. Verbal abilities are, in general, normal; however, women with TS, as a group, have specific deficits in visual-spatial abilities, visual-perceptual abilities, motor function, nonverbal memory, executive function, and attentional abilities. Observed deficits could be caused by genetic or endocrine factors. Objective: To evaluate the specific cognitive deficits that appear to persist in adulthood, are not estrogen-responsive, and may be genetically determined. Methods: The cognitive performance of adult women with TS (n = 71) who were estrogen repleted was compared with verbal IQ– and socioeconomic status–matched female controls (n = 50). Sixty-one women with TS had ovarian failure and received estrogen replacement and 10 had preserved endogenous ovarian function and were not receiving estrogen replacement at the time of evaluation. Results: Similar to children and adolescents with TS, adults with TS have normal verbal IQ but have relative difficulty on measures of spatial/perceptual skills, visual-motor integration, affect recognition, visual memory, attention, and executive function despite estrogen replacement. These deficits are apparent in women with TS despite apparently adequate estrogen effect, either endogenous or by hormone replacement. Conclusion: The cognitive phenotypes of adults with TS, with or without ovarian failure, are similar, indicating that estrogen replacement does not have a major impact on the cognitive deficits of adults with TS.
The influence of a sensitive period for auditory-visual integration in children with cochlear implants.

PURPOSE Children who experience long periods of auditory deprivation are susceptible to large-scale reorganization of auditory cortical areas responsible for the perception of speech and language. One consequence of this reorganization is that integration of combined auditory and visual information may be altered after hearing is restored with a cochlear implant. Our goal was to investigate the effects of reorganization in a task that examines performance during multisensory integration. METHODS Reaction times to the detection of basic auditory (A), visual (V), and combined auditory-visual (AV) stimuli were examined in a group of normally hearing children, and in two groups of cochlear implanted children: (1) early implanted children in whom cortical auditory evoked potentials (CAEPs) fell within normal developmental limits, and (2) late implanted children in whom CAEPs were outside of normal developmental limits. Miller's test of the race model inequality was performed for each group in order to examine the effects of auditory deprivation on multisensory integration abilities after implantation. RESULTS Results revealed a significant violation of the race model inequality in the normally hearing and early implanted children, but not in the group of late implanted children. CONCLUSION These results suggest that coactivation to multi-modal sensory input cannot explain the decreased reaction times to multi-modal input in late implanted children. These results are discussed in regards to current models for coactivation to redundant sensory information.
Mental Fatigue Modulates Dynamic Adaptation to Perceptual Demand in Speeded Detection

When stimulus intensity in simple reaction-time tasks randomly varies across trials, detection speed usually improves after a low-intensity trial. With auditory stimuli, this improvement was often found to be asymmetric, being greater on current low-intensity trials. Our study investigated (1) whether asymmetric sequential intensity adaptation also occurs with visual stimuli; (2) whether these adjustments reflect decision-criterion shifts or, rather, a modulation of perceptual sensitivity; and (3) how sequential intensity adaptation and its underlying mechanisms are affected by mental fatigue induced through prolonged performance. In a continuous speeded detection task with randomly alternating high- and low-intensity visual stimuli, the reaction-time benefit after low-intensity trials was greater on subsequent low- than high-intensity trials. This asymmetry, however, only developed with time on task (TOT). Signal-detection analyses showed that the decision criterion transiently became more liberal after a low-intensity trial, whereas observer sensitivity increased when the preceding and current stimulus were of equal intensity. TOT-induced mental fatigue only affected sensitivity, which dropped more on low- than on high-intensity trials. This differential fatigue-related sensitivity decrease selectively enhanced the impact of criterion down-shifts on low-intensity trials, revealing how the interplay of two perceptual mechanisms and their modulation by fatigue combine to produce the observed overall pattern of asymmetric performance adjustments to varying visual intensity in continuous speeded detection. Our results have implications for similar patterns of sequential demand adaptation in other cognitive domains as well as for real-world prolonged detection performance.
Spaced Learning Enhances Subsequent Recognition Memory by Reducing Neural Repetition Suppression

Spaced learning usually leads to better recognition memory as compared with massed learning, yet the underlying neural mechanisms remain elusive. One open question is whether the spacing effect is achieved by reducing neural repetition suppression. In this fMRI study, participants were scanned while intentionally memorizing 120 novel faces, half under the massed learning condition (i.e., four consecutive repetitions with jittered interstimulus interval) and the other half under the spaced learning condition (i.e., the four repetitions were interleaved). Recognition memory tests afterward revealed a significant spacing effect: Participants recognized more items learned under the spaced learning condition than under the massed learning condition. Successful face memory encoding was associated with stronger activation in the bilateral fusiform gyrus, which showed a significant repetition suppression effect modulated by subsequent memory status and spaced learning. Specifically, remembered faces showed smaller repetition suppression than forgotten faces under both learning conditions, and spaced learning significantly reduced repetition suppression. These results suggest that spaced learning enhances recognition memory by reducing neural repetition suppression.