Regulation of trophoblast beta1-integrin expression by contact with endothelial cells

BACKGROUND: In human and non-human primates, migratory trophoblasts penetrate the uterine epithelium, invade uterine matrix, and enter the uterine vasculature. Invasive trophoblasts show increased expression of β1 integrin. Since trophoblast migration within the uterine vasculature involves trophoblast attachment to endothelial cells lining the vessel walls, this raises the possibility that cell-cell contact and/or factors released by endothelial cells could regulate trophoblast integrin expression. To test this, we used an in vitro system consisting of early gestation macaque trophoblasts co-cultured on top of uterine microvascular endothelial cells. RESULTS: When cultured alone, trophoblasts expressed low levels of β1 integrin as determined by quantitative immunofluorescence microscopy. When trophoblasts were cultured on top of endothelial cells for 24 h, the expression of trophoblast β1 integrin was significantly increased as determined by image analysis. β1 Integrin expression was not increased when trophoblasts were cultured with endothelial cell-conditioned medium, suggesting that upregulation requires direct contact between trophoblasts and endothelial cells. To identify endothelial cell surface molecules responsible for induction of trophoblast integrin expression, trophoblasts were cultured in dishes coated with recombinant platelet endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), or αVβ3 integrin. Trophoblast β1 integrin expression (assessed by immunofluorescence microscopy and Western blotting) was increased when PECAM-1 or αVβ3 integrin, but not ICAM-1, was used as substrate. CONCLUSIONS: Direct contact between trophoblasts and endothelial cells increases the expression of trophoblast β1 integrin

Metabolomics Fingerprint Induced by the Intranigral Inoculation of Exogenous Human Alpha-Synuclein Oligomers in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is considered a synucleinopathy because of the intraneuronal accumulation of aggregated α-synuclein (αSyn). Recent evidence points to soluble αSyn-oligomers (αSynO) as the main cytotoxic species responsible for cell death. Given the pivotal role of αSyn in PD, αSyn-based models are crucial for the investigation of toxic mechanisms and the identification of new therapeutic targets in PD. By using a metabolomics approach, we evaluated the metabolic profile of brain and serum samples of rats infused unilaterally with preformed human αSynOs (HαSynOs), or vehicle, into the substantia nigra pars compacta (SNpc). Three months postinfusion, the striatum was dissected for striatal dopamine (DA) measurements via High Pressure Liquid Chromatography (HPLC) analysis and mesencephalon and serum samples were collected for the evaluation of metabolite content via gas chromatography mass spectrometry analysis. Multivariate, univariate and correlation statistics were applied. A 40% decrease of DA content was measured in the HαSynO-infused striatum as compared to the contralateral and the vehicle-infused striata. Decreased levels of dehydroascorbic acid, myo-inositol, and glycine, and increased levels of threonine, were found in the mesencephalon, while increased contents of fructose and mannose, and a decrease in glycine and urea, were found in the serum of HαSynO-infused rats. The significant correlation between DA and metabolite content indicated that metabolic variations reflected the nigrostriatal degeneration. Collectively, the metabolomic fingerprint of HαSynO-infused rats points to an increase of oxidative stress markers, in line with PD neuropathology, and provides hints for potential biomarkers of PD

Rat Stem-Cell Factor Induces Splenocytes Capable Of Regenerating The Thymus

Cytokine regulation of prethymic T-lymphoid progenitor-cell proliferation and/or differentiation has not been well-defined, although much is known of cytokine regulation of hemopoietic stem- and progenitor-cell development. Here we use a recently identified hemopoietic growth factor, stem-cell factor (SCF) (a form of the c-kit ligand), and a transplant model of thymocyte regeneration to assess the effect of SCF on the in vivo generation of prethymic, thymocyte progenitor-cell activity. We show that recombinant rat SCF (rrSCF164 administered to weanling rats selectively induces an increase in thymocyte progenitor activity in the spleens of treated rats as compared to rats treated with vehicle, polyethylene glycol (PEG)-conjugated rat albumin, or recombinant human granulocyte colony-stimulating factor (rhG-CSF). These data demonstrate that administration of SCF in vivo affects extrathymic-origin thymocyte regenerating cells and may influence, directly or indirectly, early prethymic stages of T-cell lymphopoiesis in addition to its known effect on early stages of myelopoiesis and erythropoiesis

Building, scaling, and sustaining a learning health system for surgical quality improvement: A toolkit

This article describes how to start, replicate, scale, and sustain a learning health system for quality improvement, based on the experience of the Michigan Surgical Quality Collaborative (MSQC). The key components to operationalize a successful collaborative improvement infrastructure and the features of a learning health system are explained. This information is designed to guide others who desire to implement quality improvement interventions across a regional network of hospitals using a collaborative approach. A toolkit is provided (under Supporting Information) with practical information for implementation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156156/3/lrh210215.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156156/2/lrh210215-sup-0001-supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156156/1/lrh210215_am.pd

"The non-ischemic repair" as a safe alternative method for repair of anterior post-infarction VSD

Patient's myocardium with post-infarction ventricular septum defect (VSD) is characterized by severe dysfunction. The "additive ischemia" caused by the operating process of cross-clamp ischemia and reperfusion injury, has a significant aggravation to the myocardium and overall negative impact to patient's outcome. We present a useful, safe and advantageous methodology in order to abolish "the toxic phase" of ischemia-reperfusion which is adopted by most as the "classic repair method" of myocardial protection. This abolition is in our opinion, particularly beneficial in order to reverse postoperatively the Low Cardiac Output Syndrome (LOS) and achieve better short and long term results. By using this method we avoid the aortic occlusion, the use of systematic hypothermia and any cardioplegic arrest. Furthermore, the total cardio-pulmonary bypass (CPB) time is significantly reduced, tissue debridement and stitching is much easier and safer. We think the method is applicable for every anterior and apical case of post-infarction septum rupture. After application of method in 3 patients with anterior post-myocardial infarction VSD, we are convinced that the patient will have a better postoperative haemodynamic condition and therefore a better outcome

A ventral rotational skin flap to improve cosmesis and avoid chordee recurrence in epispadias repair.

OBJECTIVE: To describe a technical modification that facilitates dorsal skin closure, improves cosmesis and eliminates chordee recurrence secondary to contracture of the dorsal penile skin in the repair of epispadias. PATIENTS AND METHODS: Eleven patients with penopubic epispadias (mean age 1.8 years) had the epispadias repaired using a modified ventral penile skin flap. Four patients had isolated epispadias and seven had had a previous primary closure of bladder exstrophy. Nine patients underwent the Cantwell-Ransley technique, leaving the meatus in a glanular position. Two patients were repaired using the penile disassembly technique of Mitchell and Bägli, because they had a short urethral plate. A ventral island skin flap was fashioned, starting at the base of the penis. Dissection was carried ventrally into the scrotum to allow for adequate dorsal flap transposition. The flap was rotated laterally to shift the suture line from the midline and to cover the dorsal aspect of the penis with untouched penile shaft skin. Redundant ventral foreskin was discarded. RESULTS: All patients had an uneventful course after surgery. Dorsal penile skin was viable in every case and no patient developed recurrence of chordee or a urethrocutaneous fistula. The cosmetic result was excellent in all patients. CONCLUSIONS: Dorsal skin closure using lateral rotation of ventral penile skin flap improves cosmesis after epispadias repair and eliminates the recurrence of chordee secondary to midline dorsal scarring

Bmp7 Functions via a Polarity Mechanism to Promote Cloacal Septation

During normal development in human and other placental mammals, the embryonic cloacal cavity separates along the axial longitudinal plane to give rise to the urethral system, ventrally, and the rectum, dorsally. Defects in cloacal development are very common and present clinically as a rectourethral fistula in about 1 in 5,000 live human births. Yet, the cellular mechanisms of cloacal septation remain poorly understood.We previously detected Bone morphogenetic protein 7 (Bmp7) expression in the urorectal mesenchyme (URM), and have shown that loss of Bmp7 function results in the arrest of cloacal septation. Here, we present evidence that cloacal partitioning is driven by Bmp7 signaling in the cloacal endoderm. We performed TUNEL and immunofluorescent analysis on cloacal sections from Bmp7 null and control littermate embryos. We found that loss of Bmp7 results in a dramatic decrease in the endoderm survival and a delay in differentiation. We used immunological methods to show that Bmp7 functions by activating the c-Jun N-terminal kinase (JNK) pathway. We carried out confocal and 3D imaging analysis of mitotic chromosome bundles to show that during normal septation cells in the cloacal endoderm divide predominantly in the apical-basal direction. Loss of Bmp7/JNK signaling results in randomization of mitotic angles in the cloacal endoderm. We also conducted immunohistochemical analysis of human fetal sections to show that BMP/phospho-SMAD and JNK pathways function in the human cloacal region similar as in the mouse.Our results strongly indicate that Bmp7/JNK signaling regulates remodeling of the cloacal endoderm resulting in a topological separation of the urinary and digestive systems. Our study points to the importance of Bmp and JNK signaling in cloacal development and rectourethral malformations

A Pilot Randomized Controlled Trial of Omega-3 Fatty Acids for Autism Spectrum Disorder

We conducted a pilot randomized controlled trial to determine the feasibility and initial safety and efficacy of omega-3 fatty acids (1.3 g/day) for the treatment of hyperactivity in 27 children ages 3–8 with autism spectrum disorder (ASD). After 12 weeks, hyperactivity, as measured by the Aberrant Behavior Checklist, improved 2.7 (±4.8) points in the omega-3 group compared to 0.3 (±7.2) points in the placebo group (p = 0.40; effect size = 0.38). Correlations were found between decreases in five fatty acid levels and decreases in hyperactivity, and the treatment was well tolerated. Although this pilot study did not find a statistically significant benefit from omega-3 fatty acids, the small sample size does not rule out small to moderate beneficial effects