bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual regeneration of muscle and nerve by intravenous administration of human amniotic fluid–derived mesenchymal stem cells regulated by stromal cell–derived factor-1α in a sciatic nerve injury model
Authors: Yang Dar-Yu , Sheu Meei-Ling , Su Hong-Lin , Cheng Fu-Chou , Chen Ying-Ju , Chen Chun-Jung , Chiu Wen-Ta , Yiin Jia-Jean , Sheehan Jason , Pan Hung-Chuan 
Published: April 2012

Object
Human amniotic fluid–derived mesenchymal stem cells (AFMSCs) have been shown to promote peripheral nerve regeneration. The expression of stromal cell–derived factor-1α (SDF-1α) in the injured nerve exerts a trophic effect by recruiting progenitor cells that promote nerve regeneration. In this study, the authors investigated the feasibility of intravenous administration of AFMSCs according to SDF-1α expression time profiles to facilitate neural regeneration in a sciatic nerve crush injury model.

Methods
Peripheral nerve injury was induced in 63 Sprague-Dawley rats by crushing the left sciatic nerve using a vessel clamp. The animals were randomized into 1 of 3 groups: Group I, crush injury as the control; Group II, crush injury and intravenous administration of AFMSCs (5 × 106 cells for 3 days) immediately after injury (early administration); and Group III, crush injury and intravenous administration of AFMSCs (5 × 106 cells for 3 days) 7 days after injury (late administration). Evaluation of neurobehavior, electrophysiological study, and assessment of regeneration markers were conducted every week after injury. The expression of SDF-1α and neurotrophic factors and the distribution of AFMSCs in various time profiles were also assessed.

Results
Stromal cell–derived factor-1α increased the migration and wound healing of AFMSCs in vitro, and the migration ability was dose dependent. Crush injury induced the expression of SDF-1α at a peak of 10–14 days either in nerve or muscle, and this increased expression paralleled the expression of its receptor, chemokine receptor type-4 (CXCR-4). Most AFMSCs were distributed to the lung during early or late administration. Significant deposition of AFMSCs in nerve and muscle only occurred in the late administration group. Significantly enhanced neurobehavior, electrophysiological function, nerve myelination, and expression of neurotrophic factors and acetylcholine receptor were demonstrated in the late administration group.

Conclusions
Amniotic fluid–derived mesenchymal stem cells can be recruited by expression of SDF-1α in muscle and nerve after nerve crush injury. The increased deposition of AFMSCs paralleled the expression profiles of SDF-1α and its receptor CXCR-4 in either muscle or nerve. Administration of AFMSCs led to improvements in neurobehavior and expression of regeneration markers. Intravenous administration of AFMSCs may be a promising alternative treatment strategy in peripheral nerve disorder.
Microbiological and clinical characteristics of diabetic foot infections in northern India
Authors: Tiwari Shalbha , Pratyush Daliparthy D , Dwivedi Awanindra , Gupta Sanjiv K , Rai Madhukar , Singh Surya K 
Published: April 2012

Introduction: India has the largest diabetic population of 50.8 million that could reach an epidemic proportion by 2030. Diabetic foot infection is one of the dreaded complications of diabetes. Only a few studies that focus on patterns of diabetic foot infection in our region, where diabetic foot care is inadequate, are available. This study evaluated microbial and clinical characteristics of diabetic foot infections that will be helpful in taking appropriate measures for their management. Methodology: In this prospective study conducted during 2008-2009, sixty-two diabetic foot patients underwent detailed history, clinical examination, and laboratory investigations including parameters of systemic infections. Microbial culture and sensitivity were performed at the time of presentation. Results: Among 62 cases, 43.5% had mono-microbial infection, 35.5% had poly-microbial infections, and 21% had sterile culture. Among 82 bacteria isolated, 68% were Gram negative and 32% were Gram positive. Leukocyte counts were higher (16928±9642 versus 14593±6687 cells/mm3) and haemoglobin (7.9±2.4 versus 9.2±2.2 mg/dl) lower in poly-microbial compared to mono-microbial infections. Haemoglobin counts were lower and leukocyte counts higher in Gram-negative compared to Gram-positive infections. Patients with sterile cultures also had clinical evidence of persistent infection. Escherichia coli were the most common isolate and piperacillin/tazobactam showed highest sensitivity. Conclusions: Gram-negative bacteria were most prevalent in diabetic foot infection. It is not uncommon to have culture reports negative despite clinical evidence of infection. This study suggests that piperacillin/tazobactam should be the treatment of choice on an empirical basis prior to a definitive bacteriological study and in cases with negative culture reports.
Astrocytes, but Not Microglia, Rapidly Sense H2O2 via STAT6 Phosphorylation, Resulting in Cyclooxygenase-2 Expression and Prostaglandin Release
Authors: Park Soo Jung , Lee Jee Hoon , Kim Hee Young , Choi Youn Hee , Park Jung Sup , Suh Young Ho , Park Sang Myun , Joe Eun-hye , Jou Ilo 
Published: April 2012

Abstract
Emerging evidence has established that astrocytes, once considered passive supporting cells that maintained extracellular ion levels and served as a component of the blood–brain barrier, play active regulatory roles during neurogenesis and in brain pathology. In the current study, we demonstrated that astrocytes sense H2O2 by rapidly phosphorylating the transcription factor STAT6, a response not observed in microglia. STAT6 phosphorylation was induced by generators of other reactive oxygen species (ROS) and reactive nitrogen species, as well as in the reoxygenation phase of hypoxia/reoxygenation, during which ROS are generated. Src–JAK pathways mediated STAT6 phosphorylation upstream. Experiments using lipid raft disruptors and analyses of detergent-fractionated cells demonstrated that H2O2-induced STAT6 phosphorylation occurred in lipid rafts. Under experimental conditions in which H2O2 did not affect astrocyte viability, H2O2-induced STAT6 phosphorylation resulted in STAT6-dependent cyclooxygenase-2 expression and subsequent release of PGE2 and prostacyclin, an effect also observed in hypoxia/reoxygenation. Finally, PGs released from H2O2-stimulated astrocytes inhibited microglial TNF-α expression. Accordingly, our results indicate that ROS-induced STAT6 phosphorylation in astrocytes can modulate the functions of neighboring cells, including microglia, through cyclooxygenase-2 induction and subsequent release of PGs. Differences in the sensitivity of STAT6 in astrocytes (highly sensitive) and microglia (insensitive) to phosphorylation following brief exposure to H2O2 suggest that astrocytes can act as sentinels for certain stimuli, including H2O2 and ROS, refining the canonical notion that microglia are the first line of defense against external stimuli.
Autocrine TNF Is Critical for the Survival of Human Dendritic Cells by Regulating BAK, BCL-2, and FLIPL
Authors: Lehner Manfred , Kellert Beate , Proff Julia , Schmid Martina A. , Diessenbacher Philip , Ensser Armin , Dörrie Jan , Schaft Niels , Leverkus Martin , Kämpgen Eckhart , Holter Wolfgang 
Published: April 2012

Abstract
The life span of dendritic cells (DCs) is determined by the balance of pro- and antiapoptotic proteins. In this study, we report that serum-free cultured human monocyte-derived DCs after TLR stimulation with polyinosinic acid-polycytidylic acid or LPS underwent apoptosis, which was correlated with low TNF production. Apoptosis was prevented by the addition of exogenous TNF or by concomitant stimulation with R-848, which strongly amplified endogenous TNF production. Neutralization of TNF confirmed that DC survival was mediated by autocrine TNF induced either by stimulation with R-848 or by ligation of CD40. DCs stimulated by polyinosinic acid-polycytidylic acid or IFN-β, another known inducer of DC apoptosis, were characterized by high levels and activation of the proapoptotic protein BAK. The ratio of antiapoptotic BCL-2 to BAK correlated best with the survival of activated DCs. Addition of TNF increased this ratio but had little effect on BAX and XIAP. Knockdown experiments using small interfering RNAs confirmed that the survival of activated and also of immature DCs was regulated by BAK and showed that TNF was protective only in the presence of FLIPL. Together, our data demonstrate that the survival of DCs during differentiation and activation depends on autocrine TNF and that the inhibition of BAK plays an important role in this process.
Antigen-Specific IL-2 Secretion Correlates with NK Cell Responses after Immunization of Tanzanian Children with the RTS,S/AS01 Malaria Vaccine
Authors: Horowitz Amir , Hafalla Julius C. R. , King Elizabeth , Lusingu John , Dekker Denise , Leach Amanda , Moris Philippe , Cohen Joe , Vekemans Johan , Villafana Tonya , Corran Patrick H. , Bejon Philip , Drakeley Chris J. , von Seidlein Lorenz , Riley Eleanor M. 
Published: April 2012

Abstract
RTS,S/AS01, a vaccine targeting pre-erythrocytic stages of Plasmodium falciparum, is undergoing clinical trials. We report an analysis of cellular immune response to component Ags of RTS,S—hepatitis B surface Ag (HBs) and P. falciparum circumsporozoite (CS) protein—among Tanzanian children in a phase IIb RTS,S/AS01E trial. RTS,S/AS01 E vaccinees make stronger T cell IFN-γ, CD69, and CD25 responses to HBs peptides than do controls, indicating that RTS,S boosts pre-existing HBs responses. T cell CD69 and CD25 responses to CS and CS-specific secreted IL-2 were augmented by RTS,S vaccination. Importantly, more than 50% of peptide-induced IFN-γ+ lymphocytes were NK cells, and the magnitude of the NK cell CD69 response to HBs peptides correlated with secreted IL-2 concentration. CD69 and CD25 expression and IL-2 secretion may represent sensitive markers of RTS,S-induced, CS-specific T cells. The potential for T cell-derived IL-2 to augment NK cell activation in RTS,S-vaccinated individuals, and the relevance of this for protection, needs to be explored further.
Synchronization of Dendritic Cell Activation and Antigen Exposure Is Required for the Induction of Th1/Th17 Responses
Authors: Kamath Arun T. , Mastelic Béatris , Christensen Dennis , Rochat Anne-Françoise , Agger Else Marie , Pinschewer Daniel D. , Andersen Peter , Lambert Paul-Henri , Siegrist Claire-Anne 
Published: April 2012

Abstract
The dendritic cell (DC) targeting/activation patterns required to elicit Th1/Th17 responses remain undefined. One postulated requirement was that of a physical linkage between Ags and immunomodulators. Accordingly, the separate same-site administration of Ag85B–ESAT-6 (hybrid-1 protein; H1), a mycobacterial fusion Ag, and the CAF01 liposome-based adjuvant induced similar Ab and weak Th2 responses as those of coformulated H1/CAF01 but failed to elicit Th1/Th17 responses. Yet, this separate same-site injection generated the same type and number of activated Ag+/adjuvant+ DCs in the draining lymph nodes (LN) as that of protective H1/CAF01 immunization. Thus, targeting/activating the same DC population by Ag and adjuvant is not sufficient to elicit Th1/Th17 responses. To identify the determinants of Th1/Th17 adjuvanticity, in vivo tracking experiments using fluorescently labeled Ag and adjuvant identified that a separate same-site administration elicits an additional early Ag+/adjuvant− DC population with a nonactivated phenotype, resulting from the earlier targeting of LN DCs by H1 than by CAF01 molecules. This asynchronous targeting pattern was mimicked by the injection of free H1 prior to or with, but not after, H1/CAF01 or H1/CpG/ aluminum hydroxide immunization. The injection of soluble OVA similarly prevented the induction of Th1 responses by OVA/CAF01. Using adoptively transferred OT-2 cells, we show that the Ag targeting of LN DCs prior to their activation generates nonactivated Ag-pulsed DCs that recruit Ag-specific T cells, trigger their initial proliferation, but interfere with Th1 induction in a dose-dependent manner. Thus, the synchronization of DC targeting and activation is a critical determinant for Th1/Th17 adjuvanticity.
Immunoglobulin Fc Fragment Tagging Allows Strong Activation of Endogenous CD4 T Cells To Reshape the Tumor Milieu and Enhance the Antitumor Effect of Lentivector Immunization
Authors: Hong Yuan , Peng Yibing , Xiao Haiyan , Mi Michael , Munn David , He Yukai 
Published: April 2012

Abstract
A major problem with current cancer vaccines is that the induction of CD8 immune responses is rarely associated with antitumor benefits, mainly owing to multiple immune suppressions in established tumor lesions. In this study, we investigated if and how activation of endogenous CD4 T cells could be achieved to influence the suppressive tumor milieu and antitumor effect. We engineered a lentivector (lv) to express a nominal fusion Ag composed of hepatitis B surface protein and IgG2a Fc fragment (HBS-Fc-lv) to increase the magnitude of CD8 response but, more importantly, to induce effective coactivation of CD4 T cells. We found that, remarkably, immunization with HBS-Fc-lv caused significant regression of established tumors. Immunologic analysis revealed that, compared with HBS-lv without Fc fragment, immunization with HBS-Fc-lv markedly increased the number of functional CD8 and CD4 T cells and the level of Th1/Tc1-like cytokines in the tumor while substantially decreasing the regulatory T cell ratio. The favorable immunologic changes in tumor lesions and the improvement of antitumor effects from HBS-Fc-lv immunization were dependent on the CD4 activation, which was Fc receptor mediated. Adoptive transfer of CD4 T cells from the HBS-Fc-lv–immunized mice could activate endogenous CD8 T cells in an IFN-γ–dependent manner. We conclude that endogenous CD4 T cells can be activated by lv expressing Fc-tagged Ag to provide another layer of help—that is, creating a Th1/Tc1-like proinflammatory milieu within the tumor lesion to boost the effector phase of immune responses in enhancing the antitumor effect.
Dissecting Mechanisms of Immunodominance to the Common Tuberculosis Antigens ESAT-6, CFP10, Rv2031c (hspX), Rv2654c (TB7.7), and Rv1038c (EsxJ)
Authors: Lindestam Arlehamn Cecilia S. , Sidney John , Henderson Ryan , Greenbaum Jason A. , James Eddie A. , Moutaftsi Magdalini , Coler Rhea , McKinney Denise M. , Park Daniel , Taplitz Randy , Kwok William W. , Grey Howard , Peters Bjoern , Sette Alessandro 
Published: April 2012

Abstract
Diagnosis of tuberculosis often relies on the ex vivo IFN-γ release assays QuantiFERON-TB Gold In-Tube and T-SPOT.TB. However, understanding of the immunological mechanisms underlying their diagnostic use is still incomplete. Accordingly, we investigated T cell responses for the TB Ags included in the these assays and other commonly studied Ags: early secreted antigenic target 6 kDa, culture filtrate protein 10 kDa, Rv2031c, Rv2654c, and Rv1038c. PBMC from latently infected individuals were tested in ex vivo ELISPOT assays with overlapping peptides spanning the entirety of these Ags. We found striking variations in prevalence and magnitude of ex vivo reactivity, with culture filtrate protein 10 kDa being most dominant, followed by early secreted antigenic target 6 kDa and Rv2654c being virtually inactive. Rv2031c and Rv1038c were associated with intermediate patterns of reactivity. Further studies showed that low reactivity was not due to lack of HLA binding peptides, and high reactivity was associated with recognition of a few discrete dominant antigenic regions. Different donors recognized the same core sequence in a given epitope. In some cases, the identified epitopes were restricted by a single specific common HLA molecule (selective restriction), whereas in other cases, promiscuous restriction of the same epitope by multiple HLA molecules was apparent. Definition of the specific restricting HLA allowed to produce tetrameric reagents and showed that epitope-specific T cells recognizing either selectively or promiscuously restricted epitopes were predominantly T effector memory. In conclusion, these results highlight the feasibility of more clearly defined TB diagnostic reagent.
Mesenchymal Cells Regulate Retinoic Acid Receptor-Dependent Cortical Thymic Epithelial Cell Homeostasis
Authors: Sitnik Katarzyna M. , Kotarsky Knut , White Andrea J. , Jenkinson William E. , Anderson Graham , Agace William W. 
Published: April 2012

Abstract
The vitamin A metabolite and transcriptional modulator retinoic acid (RA) is recognized as an important regulator of epithelial cell homeostasis in several tissues. Despite the known importance of the epithelial compartment of the thymus in T cell development and selection, the potential role of RA in the regulation of thymic cortical and medullary epithelial cell homeostasis has yet to be addressed. In this study, using fetal thymus organ cultures, we demonstrate that endogenous RA signaling promotes thymic epithelial cell (TEC) cell-cycle exit and restricts TEC cellularity preferentially in the cortical TEC compartment. Combined gene expression, biochemical, and functional analyses identified mesenchymal cells as the major source of RA in the embryonic thymus. In reaggregate culture experiments, thymic mesenchyme was required for RA-dependent regulation of TEC expansion, highlighting the importance of mesenchyme-derived RA in modulating TEC turnover. The RA-generating potential of mesenchymal cells was selectively maintained within a discrete Ly51intgp38+ subset of Ly51+ mesenchyme in the adult thymus, suggesting a continual role for mesenchymal cell-derived RA in postnatal TEC homeostasis. These findings identify RA signaling as a novel mechanism by which thymic mesenchyme influences TEC development.
Antigen-Independent Differentiation and Maintenance of Effector-like Resident Memory T Cells in Tissues
Authors: Casey Kerry A. , Fraser Kathryn A. , Schenkel Jason M. , Moran Amy , Abt Michael C. , Beura Lalit K. , Lucas Philip J. , Artis David , Wherry E. John , Hogquist Kristin , Vezys Vaiva , Masopust David 
Published: April 2012

Abstract
Differentiation and maintenance of recirculating effector memory CD8 T cells (TEM) depends on prolonged cognate Ag stimulation. Whether similar pathways of differentiation exist for recently identified tissue-resident effector memory T cells (TRM), which contribute to rapid local protection upon pathogen re-exposure, is unknown. Memory CD8αβ+ T cells within small intestine epithelium are well-characterized examples of TRM, and they maintain a long-lived effector-like phenotype that is highly suggestive of persistent Ag stimulation. This study sought to define the sources and requirements for prolonged Ag stimulation in programming this differentiation state, including local stimulation via cognate or cross-reactive Ags derived from pathogens, microbial flora, or dietary proteins. Contrary to expectations, we found that prolonged cognate Ag stimulation was dispensable for intestinal TRM ontogeny. In fact, chronic antigenic stimulation skewed differentiation away from the canonical intestinal T cell phenotype. Resident memory signatures, CD69 and CD103, were expressed in many nonlymphoid tissues including intestine, stomach, kidney, reproductive tract, pancreas, brain, heart, and salivary gland and could be driven by cytokines. Moreover, TGF-β–driven CD103 expression was required for TRM maintenance within intestinal epithelium in vivo. Thus, induction and maintenance of long-lived effector-like intestinal TRM differed from classic models of TEM ontogeny and were programmed through a novel location-dependent pathway that was required for the persistence of local immunological memory.
Endoscopic therapy for Barrett′s esophagus
Authors: Shaheen Nicholas J. 
Published: April 2012

AbstractBarrett’s esophagus (BE) is the precursor lesion to esophageal adenocarcinoma. This cancer has undergone a rapid increase in incidence in Western societies in the last 30 years. Current practices seek to lower the risk of death from this cancer by performing screening upper endoscopy on those with chronic reflux symptoms, and then surveillance upper endoscopy on those found to have BE at periodic intervals. While this approach is intuitively appealing, no data substantiate a decreased cancer risk with these practices, and substantial issues limit the effectiveness of this approach. This article outlines the current approaches to BE, their shortcomings, and presents data supporting the use of endoscopic therapy for subjects with BE and dysplasia. A significant and growing literature supports the use of endoscopic therapy in BE, and this approach, combined with improved risk stratification, may improve our care of subjects with BE.
Endoscopic management of benign biliary strictures: Possibility or exercise in futility?
Authors: Deprez Pierre H. 
Published: April 2012

AbstractBenign biliary strictures for which endoscopic treatment is proposed are mostly related to liver transplantation or chronic pancreatitis (one third of cases each) and, less frequently, to other causes (e. g., cholecystectomy, sphincterotomy). The question of futility of exercise may therefore be of importance before embarking in these techniques. Endoscopic treatment of iatrogenic (post-operative) benign strictures may be considered as the gold standard since 90% of success is achieved with multiple stent placement. In strictures due to chronic pancreatitis, success rates are lower and surgery may be an appropriate alternative, although it may not be futile to propose an endoscopic try, especially when strictures are related to acute pancreatitis, pseudocyst obstruction or any reversible pancreatic cause of obstruction. In sclerosing cholangitis, endoscopic management is also focused on detection of malignancy. It should therefore not be considered as a futile exercise, but indications and aims of endotherapy should be discussed in a multidisciplinary team involving gastroenterologists, radiologists, and surgical specialists.
DETAILED STRATAL CORRELATION AND STACKING PATTERNS OF THE GREMIASCO AND LOWER CASTAGNOLA TURBIDITE SYSTEMS, TERTIARY PIEDMONT BASIN, NORTHWESTERN ITALY
Authors: BARUFFINI LUCA , CAVALLI CARLO , PAPANI LORENZO 
Published: April 2012

ABSTRACT
The Gremiasco and lower Castagnola turbidite systems, in the syn-collisional Tertiary Piedmont Basin, northwestern Italy, are described and compared. Although belonging to the same basin-fill succession, these two systems show marked differences in terms of facies, stacking patterns, and geometries of sandstone bodies. The Gremiasco turbidite system was deposited by small-volume, sand-rich gravity flows that gave rise to thick sandstone beds showing rapid lateral facies changes. The system can be subdivided into three subunits, each characterized by its own geometry and stacking pattern: the differences observed between the subunits are mainly a function of local synsedimentary deformation. The lower Castagnola turbidite system was laid down by relatively large-volume gravity flows that generated thin to very thick sandstone beds showing no facies nor thickness variations over some kilometres. Based on their unusual thickness and features, most of these beds are intrepreted as seismoturbidites. The impressively isopachous geometry of the lower Castagnola system shows that synsedimentary structural deformation was virtually absent in the basin, whereas it played a major role in the initiation of gravity flows.