Folic acid supplementation normalizes the endothelial progenitor cell transcriptome of patients with type 1 diabetes: a case-control pilot study

Background: Endothelial progenitor cells play an important role in vascular wall repair. Patients with type 1 diabetes have reduced levels of endothelial progenitor cells of which their functional capacity is impaired. Reduced nitric oxide bioavailability and increased oxidative stress play a role in endothelial progenitor cell dysfunction in these patients. Folic acid, a B-vitamin with anti-oxidant properties, may be able to improve endothelial progenitor cell function. In this study, we investigated the gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes compared to endothelial progenitor cells from healthy subjects. Furthermore, we studied the effect of folic acid on gene expression profiles of endothelial progenitor cells from patients with type 1 diabetes. Methods: We used microarray analysis to investigate the gene expression profiles of endothelial progenitor cells from type 1 diabetes patients before (n = 11) and after a four week period of folic acid supplementation (n = 10) compared to the gene expression profiles of endothelial progenitor cells from healthy subjects (n = 11). The probability of genes being differentially expressed among the classes was computed using a random-variance t-test. A multivariate permutation test was used to identify genes that were differentially expressed among the two classes. Functional classification of differentially expressed genes was performed using the biological process ontology in the Gene Ontology database. Results: Type 1 diabetes significantly modulated the expression of 1591 genes compared to healthy controls. These genes were found to be involved in processes regulating development, cell communication, cell adhesion and localization. After folic acid treatment, endothelial progenitor cell gene expression profiles from diabetic patients were similar to those from healthy controls. Genes that were normalized by folic acid played a prominent role in development, such as the transcription factors ID1 and MAFF. Few oxidative-stress related genes were affected by folic acid. Conclusion: Folic acid normalizes endothelial progenitor cell gene expression profiles of patients with type 1 diabetes. Signaling pathways modulated by folic acid may be potential therapeutic targets to improve endothelial progenitor cell function

Melanomas prevent endothelial cell death under restrictive culture conditions by signaling through AKT and p38 MAPK/ ERK-1/2 cascades

Although melanoma progression and staging is clinically well characterized, a large variation is observed in pathogenesis, progression, and therapeutic responses. Clearly, intrinsic characteristics of melanoma cells contribute to this variety. An important factor, in both progression of the disease and response to therapy, is the tumor-associated vasculature. We postulate that melanoma cells communicate with endothelial cells (ECs) in order to establish a functional and supportive blood supply. We investigated the angiogenic potential of human melanoma cell lines by monitoring the survival of ECs upon exposure to melanoma conditioned medium (CM), under restrictive conditions. We observed long-term (up to 72 h) EC survival under hypoxic conditions upon treatment with all melanoma CMs. No such survival effect was observed with the CM of melanocytes. The CM of pancreatic and breast tumor cell lines did not show a long-term survival effect, suggesting that the survival factor is specific to melanoma cells. Furthermore, all size fractions (up to < 1 kDa) of the melanoma CM induced long-term survival of ECs. The survival effect observed by the < 1 kDa fraction excludes known pro-angiogenic factors. Heat inactivation and enzymatic digestion of the CM did not inactivate the survival factor. Global gene expression and pathway analysis suggest that this effect is mediated in part via the AKT and p38 MAPK/ ERK-1/2 signaling axis. Taken together, these data indicate the production of (a) survival factor/s (< 1 kDa) by melanoma cell lines, which enables long-term survival of ECs and promotes melanoma-induc

Functionalized carbon nanotubes as immunomodulator systems

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Different Molecular Signatures in Magnetic Resonance Imaging-Staged Facioscapulohumeral Muscular Dystrophy Muscles

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by a non-conventional genetic mechanism activated by pathogenic D4Z4 repeat contractions. By muscle Magnetic Resonance Imaging (MRI) we observed that T2-short tau inversion recovery (T2-STIR) sequences identify two different conditions in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity, takes place. We studied these conditions in order to obtain further information on the molecular mechanisms involved in the selective wasting of single muscles or muscle groups in this disease

Gene Expression Profiling of Embryonic Human Neural Stem Cells and Dopaminergic Neurons from Adult Human Substantia Nigra

Neural stem cells (NSC) with self-renewal and multipotent properties serve as an ideal cell source for transplantation to treat neurodegenerative insults such as Parkinson's disease. We used Agilent's and Illumina Whole Human Genome Oligonucleotide Microarray to compare the genomic profiles of human embryonic NSC at a single time point in culture, and a multicellular tissue from postmortem adult substantia nigra (SN) which are rich in dopaminergic (DA) neurons. We identified 13525 up-regulated genes in both cell types of which 3737 (27.6%) genes were up-regulated in the hENSC, 4116 (30.4%) genes were up-regulated in the human substantia nigra dopaminergic cells, and 5672 (41.93%) were significantly up-regulated in both cell population. Careful analysis of the data that emerged using DAVID has permitted us to distinguish several genes and pathways that are involved in dopaminergic (DA) differentiation, and to identify the crucial signaling pathways that direct the process of differentiation. The set of genes expressed more highly at hENSC is enriched in molecules known or predicted to be involved in the M phase of the mitotic cell cycle. On the other hand, the genes enriched in SN cells include a different set of functional categories, namely synaptic transmission, central nervous system development, structural constituents of the myelin sheath, the internode region of axons, myelination, cell projection, cell somata, ion transport, and the voltage-gated ion channel complex. Our results were also compared with data from various databases, and between different types of arrays, Agilent versus Illumina. This approach has allowed us to confirm the consistency of our obtained results for a large number of genes that delineate the phenotypical differences of embryonic NSCs, and SN cells

Reinterventions after complicated or failed STARR procedure

Background/aims: The stapled transanal rectal resection (STARR) procedure has been suggested as a simple surgical option for patients presenting with evacuatory difficulty in the clinical presence of a rectocele. Most of these patients have a multiplicity of pelvic floor pathology unaddressed by the performance of one procedure. The aim of the study was to assess an unselected group of patients referred to a tertiary coloproctological unit following performance of the STARR procedure for obstructed defecation (OD) where the procedure was complicated or had failed. Materials and methods: Anorectal, urogynecological, and psychological examination with objective constipation/incontinence scoring, anal–vaginal-perineal ultrasound, manometry, and defecography were selectively performed utilizing the Iceberg Diagram to detect occult pelvic floor pathology. Results: Twenty patients were referred with 13 cases (female, 10; median age, 65 years; range, 40–72) operated upon. Post-STARR surgery was performed for three complications and ten failures including recurrent OD, severe proctalgia, and fecal incontinence. Overall, 11 patients underwent biofeedback therapy and psychotherapy. Of the operated group, 11 patients had a median of four associated disorders. Seven patients had a significant psychological overlay with severe depression or anxiety and four heterogeneous anal sphincter defects. Operative procedures were tailored to the clinical findings using enterocele repair, staple removal, fistulectomy, rectosigmoid resection, and levatorplasty where appropriate. Twelve patients were evaluated after a median follow-up of 18 months. Of these, six (all with psychoneurosis remained unchanged. Three patients with no psychological overlay were asymptomatic with a further two improved. Conclusion: The STARR procedure, when complicated or failed, has a poor outcome following surgical reintervention. It requires careful patient selection to determine the associated pelvic floor pathology and pre-existent psychopathology

Imaging atlas of the pelvic floor and anorectal diseases

Exciting technical advances in US, CT, and MRI over the past decade have greatly enhanced the challenging task of investigating intestinal, pelvic floor, and anorectal function and dysfunction. The goal of Imaging Atlas of the Pelvic Floor and Anorectal Diseases, edited and authored by international experts in the field, is to clearly and precisely present indications, techniques, limitations, sources of errors, and pitfalls of these imaging modalities. The concise text describes the abundant, high-quality images that show the normal anorectal anatomy as well as the pathological appearance of the all-too-common large-bowel and pelvic floor functional diseases. The use of radiopaque markers in diagnosing colonic inertia; defecography, 3D US, and MRI in investigating obstructed defecation; 3D US and MRI in differentiating between benign and malignant anorectal neoplasms; CT and MRI in assessing pelviperineal anatomy and identifying pelvic tumors and inflammatory processes; and 2D and 3D US in determining appropriate treatment for fecal incontinence are discussed in depth. One of the atlas’s strongest points is illustrating the use of 3D anorectal US with automatic scan in identifying complex anal fistula tracks, staging benign and malignant tumors, and postradiotherapy follow-up. Of particular importance is the description of novel dynamic techniques, such as dynamic transperineal US, in assessing pelvic floor functional diseases. Also importantly, this atlas demonstrates the value of a "team approach" between colorectal surgeons and radiologists for solving complex clinical disorders of the anorectum and pelvic floor