Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and safety of balloon dilation as palliative treatment for tetralogy of Fallot

Abstract Twenty-six patients requiring palliation for the tetralogy of Fallot were treated by balloon dilation. The mean age at dilation was 8.5 months (range 0.5−20.6) and the mean weight 6.7 kg (range 2.6−10.7). Successful dilation was achieved in 25 patients. The mean ratio of the balloon to the diameter of the pulmonary outflow tract was 1.6 (range 1.2−2.0). The aortic oxygen saturation increased from mean±SD of 80±12.4% before to 91±4.3% after dilation (p<0.05). The pulmonary arterial oxygen saturation rose from 64±10.7% to 80±7.7% (p<0.05). Transient hypotension and arterial desaturation were noted in 19 patients during inflation of the balloon. One patient had a cardiac arrest prior to dilation and died afterwards. Seven patients had cyanotic spells related to the procedure. Attempts to cross the pulmonary valve resulted in infundibular perforation by the guide wire in one patient. Of the 24 survivors who initially had successful dilation procedures, three have needed a Blalock-Taussig shunt. Palliation without a shunt was achieved in the remaining 21 patients. In 12 patients, repeat angiography, 2.5−20 months (mean 9.1) after dilation, showed an increase in the diameter of the outflow tract from 7.1±2.1 mm before to 9.5±2.0 mm after dilation (p<0.05). Diameters of the pulmonary arteries increased from 6.3±2.2 mm on the right and 6.8±1.9 mm on the left before to 9.2±2.2 mm and 9.3±2.5 mm respectively after dilation (p<0.05 for both branches). Surgical correction has been achieved in 22 patients, 21 of these 2−22 months after balloon dilation and the other patient 20 months after construction of a shunt. At operation, the leaflets of the pulmonary valve were noted to be torn in five patients. In 12 patients, there was extensive scarring of the infundibulum. Balloon dilation of the right ventricular outflow tract achieves adequate palliation and may result in an increase in the diameter of the pulmonary valve and branches of the pulmonary trunk. It should be considered as an alternative to shunt procedures in children with tetralogy of Fallot.
Ionic conductances regulating the excitability of colonic smooth muscles

The tunica muscularis of the gastrointestinal (GI) tract contains two layers of smooth muscle cells (SMC) oriented perpendicular to each other. SMC express a variety of voltage‐dependent and voltage‐independent ionic conductance(s) that develop membrane potential and control excitability. Resting membrane potentials (RMP) vary through the GI tract but generally are within the range of −80 to −40 mV. RMP sets the ‘gain’ of smooth muscle and regulates openings of voltage‐dependent Ca2+ channels. A variety of K+ channels contribute to setting RMP of SMC. In most regions, RMP is considerably less negative than the K+ equilibrium potential, due to a finely tuned balance between background K+ channels and non‐selective cation channels (NSCC). Variations in expression patterns and openings of K+ channels and NSCC account for differences of the RMP in different regions of the GI tract. Smooth muscle excitability is also regulated by interstitial cells (interstitial cells of Cajal (ICC) and PDGFRα+ cells) that express additional conductances and are electrically coupled to SMC. Thus, ‘myogenic’ activity results from the integrated behavior of the SMC/ICC/PDGFRα+ cell (SIP) syncytium. Inputs from excitatory and inhibitory motor neurons are required to produce the complex motor patterns of the gut. Motor neurons innervate three cell types in the SIP, and receptors, second messenger pathways, and ion channels in these cells mediate postjunctional responses. Studies of isolated SIP cells have begun to unravel the mechanisms responsible for neural responses. This review discusses ion channels that set and regulate RMP of SIP cells and how neurotransmitters regulate membrane potential.
Dysregulated development of IL‐17‐ and IL‐21‐expressing follicular helper T cells and increased germinal center formation in the absence of RORγt

Interleukin 17‐producing helper T (Th17) cells have been widely defined by the lineage transcription factor retinoid‐related orphan receptor (ROR)γt. Pathophysiologically, these cells play a crucial role in autoimmune diseases and have been linked to dysregulated germinal center (GC) reactions and autoantibody production. In this study, we used gene expression and flow cytometric analyses for the characterization of Rorγt–/– and Rorγt–/–Il21RFP/+ mice to demonstrate a previously unknown transcriptional flexibility in the development of IL‐17‐producing Th‐cell subsets. We found an accumulation of follicular Th (Tfh) cells by 5.2‐fold, spontaneous 13‐fold higher GC formation, decreased frequency of follicular Foxp3+ T‐regulatory (Treg) cells (50%), and a 3.4‐fold increase in the number of proliferating follicular B cells in RORγt‐deficient vs. wild‐type mice. Dysregulated B‐cell responses were associated with enhanced production of IL‐17 (6.4‐fold), IL‐21 (2.2‐fold), and B‐cell‐activating factor (BAFF) (2‐fold) and were partially rescued by adoptive transfer of Treg cells. In an unexpected finding, we detected RORγt‐independent IL‐17 expression in ICOS+CXCR5+Tfh and in ICOS+CXCR5–Th cells. Based on the observed high Irf4 and Batf gene expression, we suggest that CD4+ T‐cell transcription factors other than RORγt can cooperatively induce differentiation of IL‐17‐producing Th cells, including Th17‐like Tfh‐cell subsets. We conclude that the occurrence of aberrant Tfh and follicular Treg cells support spontaneous GC formation and dysregulated B‐cell responses in RORγt‐deficient mice. —Wichner, K. , Stauss, D. , Kampfrath, B. , Krüger, K. , Müller, G. , Rehm, A. , Lipp, M. , Höpken, U. E. Dysregulated development of IL‐17‐ and IL‐21‐expressing follicular helper T cells and increased germinal center formation in the absence of RORγt. FASEB J. 30, 761–774 (2016). www.fasebj. org
Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle

Skeletal muscle mitochondrial content and oxidative capacity are important determinants of muscle function and whole‐body health. Mitochondrial content and function are enhanced by endurance exercise and impaired in states or diseases where muscle function is compromised, such as myopathies, muscular dystrophies, neuromuscular diseases, and age‐related muscle atrophy. Hence, elucidating the mechanisms that control muscle mitochondrial content and oxidative function can provide new insights into states and diseases that affect muscle health. In past studies, we identified Perm1 (PPARGC1‐ and ESRR‐induced regulator, muscle 1) as a gene induced by endurance exercise in skeletal muscle, and regulating mitochondrial oxidative function in cultured myotubes. The capacity of Perm1 to regulate muscle mitochondrial content and function in vivo is not yet known. In this study, we use adeno‐associated viral (AAV) vectors to increase Perm1 expression in skeletal muscles of 4‐wk‐old mice. Compared to control vector, AAV1‐Perm1 leads to significant increases in mitochondrial content and oxidative capacity (by 40‐80%). Moreover, AAV1‐Perm1‐transduced muscles show increased capillary density and resistance to fatigue (by 33 and 31 %, respectively), without prominent changes in fiber‐type composition. These findings suggest that Perm1 selectively regulates mitochondrial biogenesis and oxidative function, and implicate Perm1 in muscle adaptations that also occur in response to endurance exercise. —Cho, Y. , Hazen, B. C. , Gandra, P. G. , Ward, S. R. , Schenk, S. , Russell, A. P., Kralli, A. Perm1 enhances mitochondrial biogenesis, oxidative capacity, and fatigue resistance in adult skeletal muscle. FASEB J. 30, 674‐687 (2016). www.fasebj. org
Molecular Modifications of Imidazole Compounds: Studies of Activity and Synergy in Vitro and of Pharmacology and Therapy of Blastomycosis in a Mouse Model

Three orally administered imidazoles (R34,000, R40,500, and R41,400) were tested in vitro for activity against Blastomyces dermatitidis and in vivo in a mouse model of pulmonary blastomycosis; results of these tests were compared with those of tests with miconazole and amphotericin B. All of these drugs were inhibitory in vitro, and fungicidal activity was demonstrated. The imidazoles had promising pharmacokinetics, with peak blood concentrations that greatly exceeded the MICs and prolonged potentially therapeutic concentrations in serum; all three drugs appeared to be well tolerated. In vivo, however, they prolonged life temporarily but were not curative. After challenge with a sublethal inoculum of B. dermatitidis, R41,400 (ketoconazole) produced clinical cure but not sterilization of the lung. The three drugs were comparable to miconazole in efficacy in the mouse model but were inferior to parenterally administered amphotericin B. In vitro, results of synergy studies with several other orally administered drugs did not suggest that combined therapy is a promising avenue for improved results. The versatility and reproducibility of the mouse model permits study of antifungal drugs in several settings. Ketoconazole appears to be the most promising of the "second generation" of imidazoles, and ketoconazole therapy of longer duration might produce results in this model comparable to those seen in other studies.
Endothelin‐1 as a master regulator of whole‐body Na+ homeostasis

The current study was designed to determine whether vascular endothelial‐derived endothelin‐1 (ET‐1) is important for skin Na+ buffering. In control mice (C57BL/6J), plasma Na+ and osmolarity were significantly elevated in animals on high‐ vs. low‐salt (HS and LS, respectively) intake. The increased plasma Na+ and osmolarity were associated with increased ET‐1 mRNA in vascular tissue. There was no detectable difference in skin Na+:H2O in HS fed mice (0.119 ± 0.005 mM vs. 0.127 ± 0.007 mM; LS vs. HS); however, skin Na+:H2O was significantly increased by blockade of the endothelin type A receptor with ABT‐627 (0.116 ± 0.006 mM vs. 0.137 ± 0.007 mM; LS vs. HS; half‐maximal inhibitory concentration, 0.055 nM). ET‐1 peptide content in skin tissue was increased in floxed control animals on HS (85.9 ± 0.9pg/mg vs. 106.4 ± 6.8 pg/mg; P< 0.05), but not in vascular endothelial cell endothelin‐1 knockout (VEET KO) mice (76.4 ± 5.7 pg/mg vs. 65.7 ± 7.9 pg/mg; LS vs. HS). VEET KO mice also had a significantly elevated skin Na+:H2O (0.113 ± 0.007 mM vs. 0.137 ± 0.005 mM; LS vs. HS; P < 0.05). Finally, ET‐1 production was elevated in response to increasing extracellular osmolarity in cultured human endothelial cells. These data support the hypothesis that increased extrarenal vascular ET‐1 production in response to HS intake is mediated by increased extracellular osmolarity and plays a critical role in regulating skin storage of Na+. —Speed, J. S. , Heimlich, J. B. , Hyndman, K. A. , Fox, B. M. , Patel, V. , Yanagisawa, M. , Pollock, J. S. , Titze, J. M. , Pollock, D. M. Endothelin‐1 as a master regulator of whole‐body Na+ homeostasis. FASEB J. 29, 4937–4944 (2015). www.fasebj. org
Occludin controls HIV transcription in brain pericytes via regulation of SIRT‐1 activation

HIV invades the brain early after infection; however, its interactions with the cells of the blood‐brain barrier (BBB) remain poorly understood. Our goal was to evaluate the role of occludin, one of the tight junction proteins that regulate BBB functions in HIV infection of BBB pericytes. We provide evidence that occludin levels largely control the metabolic responses of human pericytes to HIV. Occludin in BBB pericytes decreased by 10% during the first 48 h after HIV infection, correlating with increased nuclear translocation of the gene repressor C‐terminal‐binding protein (CtBP)‐1 and NFκB‐p65 activation. These changes were associated with decreased expression and activation of the class III histone deacetylase sirtuin (SIRT)‐1. Occludin levels recovered 96 h after infection, restoring SIRT‐1 and reducing HIV transcription to 20% of its highest values. We characterized occludin biochemically as a novel NADH oxidase that controls the expression and activation of SIRT‐1. The inverse correlation between occludin and HIV transcription was then replicated in human primary macrophages and differentiated monocytic U937 cells, in which occludin silencing resulted in 75 and 250% increased viral transcription, respectively. Our work shows that occludin has previously unsuspected metabolic properties and is a target of HIV infection, opening the possibility of designing novel pharmacological approaches to control HIV transcription. —Castro, V. , Bertrand, L. , Luethen, M. , Dabrowski, S. , Lombardi, J., Morgan, L. , Sharova, N. , Stevenson, M. , Blasig, I. E. , Toborek, M. , Occludin controls HIV transcription in brain pericytes via regulation of SIRT‐1 activation. FASEB J. 30, 1234–1246 (2016). www.fasebj. org
Leukotriene B4 receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins

GPCRs are involved in numerous physiologic functions and are important drug targets. Although the epithelial barrier is important for protection from invading pathogens, the correlation between GPCRs and epithelial barrier function remains unknown. Leukotriene B4 (LTB4) receptor type 2 (BLT2), mainly expressed in epithelial cells, is a GPCR for 12(S)‐hydroxyheptadeca‐5Z,8E,10E‐trienoic acid (12‐HHT) and LTB4. In our study, BLT2 localized at the lateral membrane in BLT2‐overexpressing Madin‐Darby canine kidney (MDCK) II cells and in the small intestine of BLT2‐transgenic mice. BLT2‐deficient mice exhibited higher transepidermal water loss and were more sensitive to epicutaneous sensitization. MDCK‐BLT2 cells recovered transepithelial electrical resistance (TER) after a calcium switch faster than did MDCK‐Mock cells, and 12‐HHT stimulation accelerated TER recovery only in MDCK‐BLT2 cells. Quantitative PCR and immunoblot analyses revealed that the 12‐HHT/BLT2 axis up‐regulated claudin‐4 (CLDN4) expression in MDCK‐BLT2 cells and human primary keratinocytes, and CLDN4 knockdown abolished 12‐HHT‐dependent TER recovery. Acceleration of TER recovery and induction of CLDN4 expression by 12‐HHT stimulation were abolished by inhibition of Gαi protein or p38 MAPK. These results show that 12‐HHT/BLT2 enhances epithelial barrier function by increasing CLDN4 expression via the Gαi protein‐p38 MAPK pathway. —Ishii, Y. , Saeki, K. , Liu, M. , Sasaki, F. , Koga, T. , Kitajima, K. , Meno, C. , Okuno, T. , Yokomizo, T. Leukotriene B4 receptor type 2 (BLT2) enhances skin barrier function by regulating tight junction proteins. FASEB J. 30, 933–947 (2016). www.fasebj. org
Primary Sjogren's Syndrome Presenting with Renal Tubular Acidosis and Central Pontine Myelinolysis: A Case Report

©2013 Turkish League Against Rheumatism. All rights reserved. Bu olgu sunumunda siddetli hipokaleminin ortaya cikardigi distal renal tubuler asidoz (RTA) ve normal anyon bosluk metabolik asidozu ve anormal duzeyde asitlesmis idrar ile birlikte seyreden primer Sjogren sendromlu (pSS) 75 yasindaki bir kadin olgu sunuldu. Hastada kuadripleji, hipersomnia ve disfaji ile dogrulanmis beyinsapi lezyonu mevcuttu. Laboratuvar testlerinde anti-Ro/SS-A ve anti-La/SS-B antikorlari pozitifti. Manyetik rezonans goruntuleme ile yapilan beyin taramasinda, santral pontin miyelinolizisin tipik ozelligi olan orta ponlarda T1 ve T2’de hiperintens sinyal goruldu.
Limited expression of heparan sulphate proteoglycans associated with Aβ deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease

N. M. Timmer, M. K. Herbert, J. W. Kleinovink, A. J. Kiliaan, R. M. W. de Waal and M. M. Verbeek (2010) Neuropathology and Applied Neurobiology36, 478–486 Limited expression of heparan sulphate proteoglycans associated with Aβ deposits in the APPswe/PS1dE9 mouse model for Alzheimer's disease
Biomarker assay for residual chronic myeloid leukemia stem/progenitor cells during treatment with ABL-tyrosine kinase inhibitors

The use of tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM) targeted against BCR-ABL has proven successful in chronic myeloid leukemia (CML) and long-term survival has become a reality. However, several mathematical models and ex-vivo examinations suggested that IM-therapy does not eradicate CML stem cells. We recently reported the investigation of residual CML diseases during TKI treatment using FACS-sorting and quantitative RT-PCR of BCR-ABL among each population; total mononuclear cells, hematopoietic stem cells, and myeloid progenitors. Moreover, we need to develop the evaluation method of the residual CML stem cells to establish rational TKI-cessation strategies in CML.
Combined NgR vaccination and neural stem cell transplantation promote functional recovery after spinal cord injury in adult rats

C‐J. Xu, L. Xu, L‐D. Huang, Y. Li, P‐P. Yu, Q. Hang, X‐M. Xu and P‐H. Lu (2011) Neuropathology and Applied Neurobiology37, 135–155 Combined NgR vaccination and neural stem cell transplantation promote functional recovery after spinal cord injury in adult rats
Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol‐A) exposure

Bisphenol‐A (BPA) is an environmentally ubiquitous estrogen‐like endocrine‐disrupting compound. Exposure to BPA in utero has been linked to female reproductive disorders, including endometrial hyperplasia and breast cancer. Estrogens are an etiological factor in many of these conditions. We sought to determine whether in utero exposure to BPA altered the global CpG methylation pattern of the uterine genome, subsequent gene expression, and estrogen response. Pregnant mice were exposed to an environmentally relevant dose of BPA or DMSO control. Uterine DNA and RNA were examined by using methylated DNA immunoprecipitation methylation microarray, expression microarray, and quantitative PCR. In utero BPA exposure altered the global CpG methylation profile of the uterine genome and subsequent gene expression. The effect on gene expression was not apparent until sexual maturation, which suggested that estrogen response was the primary alteration. Indeed, prenatal BPA exposure preferentially altered adult estrogen‐responsive gene expression. Changes in estrogen response were accompanied by altered methylation that preferentially affected estrogen receptor‐a (ERa)–binding genes. The majority of genes that demonstrated both altered expression and ERa binding had decreased methylation. BPA selectively altered the normal developmental programming of estrogen‐responsive genes via modification of the genes that bind ERa. Gene– environment interactions driven by early life xenoestrogen exposure likely contributes to increased risk of estrogenrelated disease in adults. —Jorgensen, E. M. , Alderman, M.H. , III, Taylor, H. S. Preferential epigenetic programming of estrogen response after in utero xenoestrogen (bisphenol‐A) exposure. FASEB J. 30, 3194–3201 (2016). www.fasebj. org
A novel germ cell protein, SPIF (sperm PKA interacting factor), is essential for the formation of a PKA/TCP11 complex that undergoes conformational and phosphorylation changes upon capacitation

Spermatozoa require the process of capacitation to enable them to fertilize an egg. PKA is crucial to capacitation and the development of hyperactivated motility. Sperm PKA is activated by cAMP generated by the germ cell‐enriched adenylyl cyclase encoded by Adcy10. Male mice lacking Adcy10 are sterile, because their spermatozoa are immotile. The current study was designed to identify binding partners of the sperm‐specific (Cα2) catalytic subunit of PKA (PRKACA) by using it as the “bait” in a yeast 2‐hybrid system. This approach was used to identify a novel germ cell‐enriched protein, sperm PKA interacting factor (SPIF), in 25% of the positive clones. Homozygous Spif‐null mice were embryonically lethal. SPIF was coexpressed and coregulated with PRKACA and with t‐complex protein (TCP)‐11, a protein associated with PKA signaling. We established that these 3 proteins form part of a novel complex in mouse spermatozoa. Upon capacitation, the SPIF protein becomes tyrosine phosphorylated in >95% of sperm. An apparent molecular rearrangement in the complex occurs, bringing PRKACA and TCP11 into proximity. Taken together, these results suggest a role for the novel complex of SPIF, PRKACA, and TCP11 during sperm capacitation, fertilization, and embryogenesis. —Stanger, S. J., Law, E. A. , Jamsai, D. , O'Bryan, M. K. , Nixon, B. , McLaughlin, E. A. , Aitken, R. J., Roman, S. D. A novel germ cell protein, SPIF (sperm PKA interacting factor), is essential for the formation of a PKA/TCP11 complex that undergoes conformational and phosphorylation changes upon capacitation. FASEB J. 30, 2777‐2791 (2016). www.fasebj. org
Analysis of Conformational Changes during Activation of Protein Kinase Pak2 by Amide Hydrogen/Deuterium Exchange*

During apoptotic stress, protein kinase Pak2 is cleaved by caspase 3 to form a heterotetramer that is constitutively activated following autophosphorylation. The active protein kinase migrates slightly slower than the inactive holoenzyme when analyzed by gel filtration, suggesting an expanded conformation. Activation of Pak2 comprises a series of structural changes resulting from caspase cleavage, ATP binding, and autophosphorylation of Pak2. Changes at each step were individually analyzed by amide hydrogen/deuterium exchange coupled with mass spectrometry and compared with inactive Pak2. The auto-inhibited form was shown to bind ATP in the active site, with minor changes in the glycine loop and the autoinhibitory domain (AID). Caspase cleavage produced significant changes in solvent accessibility in the AID and upper lobe of the catalytic domain. Cleavage of ATP-bound Pak2 relaxes the allosteric inhibition, as shown by increased solvent accessibility in the upper and lower lobes, including the G-helix, facilitating the autophosphorylation of two sites required for activation, Ser-141 in the regulatory domain and Thr-402 in the catalytic domain. Autophosphorylation increased the amide hydrogen/deuterium exchange solvent accessibility of the contact region between the AID and the G-helix, the E-F loop, and the N terminus. Thus, activation of Pak2 via caspase cleavage is associated with structural relaxation of Pak2 that allows for complete auto-phosphorylation, resulting in a more comprehensive solvent-exposed and conformationally dynamic enzyme.
Clinical Outcome and Life Quality of Patients After Monophasic Encephalitis

Purpose: Acute encephalitis is a rare disease mainly occurring sporadically. Only limited data as to the long-term prognosis, in particular for impact on quality of life, is available. Methods: Patients with a definite or highly probable diagnosis of acute encephalitis were identified through retrospective analysis and invited to undertake a structured interview and to fill in questionnaires regarding their quality of life. People who matched the patients in age, sex, and level of education were used as controls. Results: Seventy-two patients and 57 controls were included. The period between the acute illness and the follow-up amounted to 6 to 93 months. The study showed a favorable outcome with complete or far-reaching functional recovery in most of the patients (83.3%). In cases that progressed in an unfavorable way such that cognitive handicaps were dominant, only 4% were left with extreme physical handicaps. Approximately 22% had postencephalitic epilepsy, which was correlated to a significantly more unfavorable outcome (P < 0.05). Women who have had encephalitis were significantly more depressive than men (P < 0.001) and also noticeably more depressive than female control subjects (P < 0.01). Furthermore, postencephalitic epilepsy was linked with significantly stronger likelihood of depression (P < 0.05). Conclusions: In this study, most patients had a favorable outcome with complete or far-reaching functional recovery. Postencephalitic epilepsy is a risk factor for an unfavorable outcome and a factor that might hinder coping with the sequelae of acute encephalitis in the long term and that has a negative effect on mood.