Local injection of bone marrow progenitor cells for the treatment of anal sphincter injury: in-vitro expanded versus minimally-manipulated cells

Background: Anal incontinence is a disabling condition that adversely affects the quality of life of a large number of patients, mainly with anal sphincter lesions. In a previous experimental work, in-vitro expanded bone marrow (BM)-derived mesenchymal stem cells (MSC) were demonstrated to enhance sphincter healing after injury and primary repair in a rat preclinical model. In the present article we investigated whether unexpanded BM mononuclear cells (MNC) may also be effective. Methods: Thirty-two rats, divided into groups, underwent sphincterotomy and repair (SR) with primary suture of anal sphincters plus intrasphincteric injection of saline (CTR), or of in-vitro expanded MSC, or of minimally manipulated MNC; moreover, the fourth group underwent sham operation. At day 30, histologic, morphometric, in-vitro contractility, and functional analysis were performed. Results: Treatment with both MSC and MNC improved muscle regeneration and increased contractile function of anal sphincters after SR compared with CTR (p < 0.05). No significant difference was observed between the two BM stem cell types used. GFP-positive cells (MSC and MNC) remained in the proximity of the lesion site up to 30 days post injection. Conclusions: In the present study we demonstrated in a preclinical model that minimally manipulated BM-MNC were as effective as in-vitro expanded MSC for the recovery of anal sphincter injury followed by primary sphincter repair. These results may serve as a basis for improving clinical applications of stem cell therapy in human anal incontinence treatment

Systemic Sclerosis Sera Impair Angiogenic Performance of Dermal Microvascular Endothelial Cells: Therapeutic Implications of Cyclophosphamide

In systemic sclerosis (SSc), dermal capillaries are progressively lost with consequent chronic tissue hypoxia insufficiently compensated by angiogenesis. Clinical studies reported that intravenous cyclophosphamide (CYC) may improve SSc-related peripheral microvascular damage. Recently, we showed that CYC treatment may normalize SSc sera-induced abnormalities in endothelial cell-matrix interactions. Our objective was to evaluate in vitro the effects of sera from treatment-naïve or CYC-treated SSc patients on dermal blood microvascular endothelial cell (dMVEC) angiogenesis, migration, proliferation and apoptosis. dMVECs were challenged with sera from 21 SSc patients, treatment-naïve (n = 8) or under CYC treatment (n = 13), and 8 healthy controls. Capillary morphogenesis on Geltrex matrix was significantly reduced upon challenge with sera from naïve SSc patients compared with healthy controls. When dMVECs were challenged with sera from CYC-treated SSc patients, their angiogenic capacity was comparable to that of cells treated with healthy sera. Wound healing capacity and chemotaxis in Boyden chamber were both significantly decreased in the presence either of naïve or CYC-treated SSc sera compared with healthy sera. WST-1 assay revealed that cell proliferation was significantly decreased in dMVECs challenged with sera from naïve SSc patients compared with healthy sera. Conversely, dMVEC proliferation was not impaired in the presence of sera from CYC-treated SSc patients. Accordingly, the percentage of TUNEL-positive apoptotic dMVECs was significantly higher in the presence of sera from naïve SSc patients than healthy controls, while CYC-treated SSc sera did not induce dMVEC apoptosis. Levels of the angiostatic mediators endostatin, pentraxin 3, angiostatin and matrix metalloproteinase-12 were all significantly elevated in sera from naïve SSc patients compared with sera from both healthy controls and CYC-treated SSc patients. In SSc, CYC treatment might boost angiogenesis and consequently improve peripheral microangiopathy through the normalization of the endothelial cell-matrix interactions, reduction of endothelial cell apoptosis and rebalance of dysregulated angiostatic factors

Neuromorphic Circuits for Short-Term Plasticity with Recovery Control

Ramachandran H, Weber S, Aamir SA, Chicca E. Neuromorphic Circuits for Short-Term Plasticity with Recovery Control. In: 2014 IEEE International Symposium on Circuits and Systems (ISCAS). Piscataway, NJ: IEEE; 2014: 858-861.We present real-time neuromorphic VLSI circuits that implement the synaptic dynamics of Short Term Plasticity (STP). STP supports useful signal processing computational primitives such as change detection and gain control. Compact circuits implementing these mechanisms play a key role in providing neuromorphic VLSI systems with autonomous adaptation capabilities. We propose two different, flexible, short-term adaptation CMOS circuits for controlling the efficacy of synapses in response to incoming spikes. These circuits can be configured to either implement short-term depression or facilitation, with independent control over the adaptation and recovery rates. Our results demonstrate the dynamic properties of th

Web 25: histories from the first 25 years of the World Wide Web

If, on the one side, the web offers us a platform where content is searchable and replicable, on the other one, it cannot be forgotten that web content is perishable, unstable and subject to continuous change. This is a challenge for scholarly research about the historical development of web. The research here presented analyzed the historical development of weblogs in Italy investigating their technological, cultural, economic, and institutional dimensions. The approach chosen mixed participant observation, in-depth interviews, and semiotic analysis of blogs and blog posts. Since an important part of the research was about the development of platforms, graphics, layouts, and technology, beside interviews older versions of blogs were retrieved using Internet Wayback Machine. Even if partial versions of the blogs were archived, this part of the research was important to complete data obtained with interviews and blogs’ analysis, since individual memory is not always accurate or some blogs were in the meanwhile closed and original posts were not accessible anymore

Morphometric analysis of lymphatics vessels in fibrotic human lung

In pulmonary fibrosis, the usual interstitial pneumonia (UIP) pattern is characterised by heterogeneous, patchy fibrosis, with areas of normal lung adjacent to areas of complete destruction (honeycombing) and by fibroblastic foci (FF). The NSIP pattern which is characteristic of systemic sclerosis, is characterised by a more homogeneous involvement of the lung without honeycombing and FF. Little is known on lymphatic vessels in lung fibrosis. Defective lymphatic clearance could lead to prolonged exposure to pathogenic antigens and/or pro-inflammatory/pro-fibrotic mediators. We evaluated the distribution and morphology of lymphatic vessels in lung biopsies of 6 patients with UIP, 6 NSIP and 5 controls. Consecutive sections were stained with Movat’s pentachrome and with double immunostaining for von Willebrand factor and podoplanin (D2-40). Area, perimeter and position were recorded for vessels with a diameter &gt; 5µm. We investigated separately in lintralobular, sub-pleural, and interlobular spaces. Lymphatics were consistently larger in subpleural spaces and in interlobular septa than in intralobular tissue. In the latter, the density of lymphatic vessels was significantly reduced in NSIP and in UIP (both 21±1 mm-2) compared to controls (35±4 mm-2) . In controls, 85±6% of the intralobular lymphatics were close (&lt; 100 µm) to a blood vessel, and only 5±4% were in the proximity of bronchoalveolar spaces, while in the disease groups they were less frequently perivascular (NSIP 55 ±3%, UIP 56 ±2%) and more frequently associated with the bronchoalveolar lumen (NSIP 85 ±3%, UIP 69 ±2%). By contrast, in interlobular septa, lymphatic density was significantly increased in NSIP (303±28 mm-2) and in UIP (286±124 mm-2) compared to controls (96±69 mm-2). No differences in lymphatic density was seen in subpleural spaces. Thus, our data show a marked redistribution of lymphatic vessels within the lung in pulmonary fibrosis, without noticeable differences between the NSIP and UIP patterns

Single tube liquid biopsy for advanced non-small cell lung cancer

The need for a liquid biopsy in non-small cell lung cancer (NSCLC) patients is rapidly increasing. We studied the relation between overall survival (OS) and the presence of four cancer biomarkers from a single blood draw in advanced NSCLC patients: EpCAM(high) circulating tumor cells (CTC), EpCAM(low) CTC, tumor-derived extracellular vesicles (tdEV) and cell-free circulating tumor DNA (ctDNA). EpCAM(high) CTC were detected with CellSearch, tdEV in the CellSearch images and EpCAM(low) CTC with filtration after CellSearch. ctDNA was isolated from plasma and mutations present in the primary tumor were tracked with deep sequencing methods. In 97 patients, 21% had >= 2 EpCAM(high) CTC, 15% had >= 2 EpCAM(low) CTC, 27% had >= 18 tdEV and 19% had ctDNA with >= 10% mutant allele frequency. Either one of these four biomarkers could be detected in 45% of the patients and all biomarkers were present in 2%. In 11 out of 16 patients (69%) mutations were detected in the ctDNA. Two or more unfavorable biomarkers were associated with poor OS. The presence of EpCAM(high) CTC and elevated levels of tdEV and ctDNA was associated with a poor OS; however, the presence of EpCAM(low) CTC was not. This single tube approach enables simultaneous analysis of multiple biomarkers to explore their potential as a liquid biopsy

A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Observations versus assessments of personality: A five-method multi-species study reveals numerous biases in ratings and methodological limitations of standardised assessments

Personality assessments and observations were contrasted by applying a philosophy-ofscience paradigm and a study of 49 human raters and 150 capuchin monkeys. Twenty constructs were operationalised with 146 behavioural measurements in 17 situations to study capuchins’ individual-specific behaviours and with assessments on trait-adjective and behaviour-descriptive verb items to study raters’ pertinent mental representations. Analyses of reliability, cross-method coherence, taxonomic structures and socio-demographic associations highlighted substantial biases in assessments. Deviations from observations are located in human impression formation, stereotypical biases and the findings that raters interpret standardised items differently and that assessments cannot generate scientific quantifications or capture behaviour. These issues have important implications for the interpretation of findings from assessments and provide an explanation for their frequent lack of replicability

2024 Recommendations for Validation of Noninvasive Arterial Pulse Wave Velocity Measurement Devices

BACKGROUND: Arterial stiffness, as measured by arterial pulse wave velocity (PWV), is an established biomarker for cardiovascular risk and target-organ damage in individuals with hypertension. With the emergence of new devices for assessing PWV, it has become evident that some of these devices yield results that display significant discrepancies compared with previous devices. This discrepancy underscores the importance of comprehensive validation procedures and the need for international recommendations. METHODS: A stepwise approach utilizing the modified Delphi technique, with the involvement of key scientific societies dedicated to arterial stiffness research worldwide, was adopted to formulate, through a multidisciplinary vision, a shared approach to the validation of noninvasive arterial PWV measurement devices. RESULTS: A set of recommendations has been developed, which aim to provide guidance to clinicians, researchers, and device manufacturers regarding the validation of new PWV measurement devices. The intention behind these recommendations is to ensure that the validation process can be conducted in a rigorous and consistent manner and to promote standardization and harmonization among PWV devices, thereby facilitating their widespread adoption in clinical practice. CONCLUSIONS: It is hoped that these recommendations will encourage both users and developers of PWV measurement devices to critically evaluate and validate their technologies, ultimately leading to improved consistency and comparability of results. This, in turn, will enhance the clinical utility of PWV as a valuable tool for assessing arterial stiffness and informing cardiovascular risk stratification and management in individuals with hypertension

Abrogation of Junctional Adhesion Molecule-A Expression Induces Cell Apoptosis and Reduces Breast Cancer Progression

Intercellular junctions promote homotypic cell to cell adhesion and transfer intracellular signals which control cell growth and apoptosis. Junctional adhesion molecule-A (JAM-A) is a transmembrane immunoglobulin located at tight junctions of normal epithelial cells of mammary ducts and glands. In the present paper we show that JAM-A acts as a survival factor for mammary carcinoma cells. JAM-A null mice expressing Polyoma Middle T under MMTV promoter develop significantly smaller mammary tumors than JAM-A positive mice. Angiogenesis and inflammatory or immune infiltrate were not statistically modified in absence of JAM-A but tumor cell apoptosis was significantly increased. Tumor cells isolated from JAM-A null mice or 4T1 cells incubated with JAM-A blocking antibodies showed reduced growth and increased apoptosis which paralleled altered junctional architecture and adhesive function. In a breast cancer clinical data set, tissue microarray data show that JAM-A expression correlates with poor prognosis. Gene expression analysis of mouse tumor samples showed a correlation between genes enriched in human G3 tumors and genes over expressed in JAM-A +/+ mammary tumors. Conversely, genes enriched in G1 human tumors correlate with genes overexpressed in JAM-A−/− tumors. We conclude that down regulation of JAM-A reduces tumor aggressive behavior by increasing cell susceptibility to apoptosis. JAM-A may be considered a negative prognostic factor and a potential therapeutic target