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Transforming Growth Factor Beta 1 drives a switch in connexin mediated cell-to-cell communication in tubular cells of the diabetic kidney

Aims/Hypothesis: Changes in cell-to-cell communication have been linked to several secondary complications of diabetes, but the mechanism by which connexins affect disease progression in the kidney is poorly understood. This study examines a role for glucose-evoked changes in the beta1 isoform of transforming growth factor (TGFβ1), on connexin expression, gap-junction mediated intercellular communication (GJIC) and hemi-channel ATP release from tubular epithelial cells of the proximal renal nephron. Methods: Biopsy material from patients with and without diabetic nephropathy was stained for connexin-26 (CX26) and connexin-43 (CX43). Changes in expression were corroborated by immunoblot analysis in human primary proximal tubule epithelial cells (hPTECs) and model epithelial cells from human renal proximal tubules (HK2) cultured in either low glucose (5mmol/L) ± TGFβ1 (2-10ng/ml) or high glucose (25mmol/L) for 48h or 7days. Secretion of the cytokine was determined by ELISA. Paired whole cell patch clamp recordings were used to measure junctional conductance in control versus TGFβ1 treated (10ng/ml) HK2 cells, with carboxyfluorescein uptake and ATP-biosensing assessing hemi-channel function. A downstream role for ATP in mediating the effects of TGF-1 on connexin mediated cell communication was assessed by incubating cells with ATPS (1-100M) or TGF-1 +/- apyrase (5 Units/ml). Implications of ATP release were measured through immunoblot analysis of interleukin 6 (IL-6) and fibronectin expression. Results: Biopsy material from patients with diabetic nephropathy exhibited increased tubular expression of CX26 and CX43 (P<0.01, n=10), data corroborated in HK2 and hPTEC cells cultured in TGFβ1 (10ng/ml) for 7days (P<0.001, n=3). High glucose significantly increased TGFβ1 secretion from tubular epithelial cells (P<0.001, n=3). The cytokine (10ng/ml) reduced junctional conductance between HK2 cells from 4.5±1.3nS in control to 1.15±0.9nS following 48h TGFβ1 and to 0.42±0.2nS after 7days TGFβ1 incubation (P<0.05, n=5). Acute (48h) and chronic (7day) challenge with TGFβ1 produced a carbenoxolone (200M)-sensitive increase in carboxyfluorescein loading, matched by an increase in ATP release from 0.29±0.06μM in control to 1.99±0.47μM after 48hr incubation with TGFβ1 (10ng/ml; P<0.05, n=3). TGF-1 (2-10ng/ml) and ATPs (1-100M) increased expression of IL-6 (P<0.001 n=3) and fibronectin (P<0.01 n=3). The effect of TGF-1 on IL-6 and fibronectin expression was partially blunted when preincubated with apyrase (n=3). Conclusion: These data suggest that chronic exposure to glucose-evoked TGFβ1 induce an increase in CX26 and CX43 expression, consistent with changes observed in tubular epithelia from patients with diabetic nephropathy. Despite increased connexin expression, direct GJIC communication decreases, whilst hemichannel expression/function and paracrine release of ATP increases, changes that trigger increased levels of expression of interleukin 6 and fibronectin. Linked to inflammation and fibrosis, local increases in purinergic signals may exacerbate disease progression and highlight connexin mediated cell communication as a future therapeutic target for diabetic nephropath

Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia

Patients with glycogen storage disease type Ia (GSD-Ia) develop renal disease of unknown etiology despite intensive dietary therapies. This renal disease shares many clinical and pathological similarities to diabetic nephropathy. We studied the expression of angiotensinogen, angiotensin type 1 receptor, transforming growth factor-β1, and connective tissue growth factor in mice with GSD-Ia and found them to be elevated compared to controls. While increased renal expression of angiotensinogen was evident in 2-week-old mice with GSD-Ia, the renal expression of transforming growth factor-β and connective tissue growth factor did not increase for another week; consistent with upregulation of these factors by angiotensin II. The expression of fibronectin and collagens I, III, and IV was also elevated in the kidneys of mice with GSD-Ia, compared to controls. Renal fibrosis was characterized by a marked increase in the synthesis and deposition of extracellular matrix proteins in the renal cortex and histological abnormalities including tubular basement membrane thickening, tubular atrophy, tubular dilation, and multifocal interstitial fibrosis. Our results suggest that activation of the angiotensin system has an important role in the pathophysiology of renal disease in patients with GSD-Ia

Genotyping of Sarawak rice cultivars using microsatellite markers

Genetic diversity of 53 Sarawak rice cultivars, originating from Southern Sarawak, was assessed using 54 microsatellite markers. Initial polymorphism detection was conducted using 54 primer pairs distributed on 12 rice chromosomes. Polymorphic markers were chosen from the initial screening results in order to obtain microsatellite marker panels that can differentiate the rice cultivars undertaken in the study. The chosen microsatellite marker panel consisted of RM1, RM240, RM489, RM252, RM413, RM204, RM11, RM404, RM316, RM271, RM206, and RM19, with one representative from each chromosome. A total of 43 alleles were detected with an average of 3.58 alleles per locus. The polymorphism information content (PIC) values obtained from the microsatellite marker panels ranged from 0.306 to 0.730, with an average of 0.622. The Unweighted Pair Group Method with Arithmetic Mean (UPGMA) dendrogram (r = 0.789) revealed 2 major groups with 6 sub-clusters and the wide range of similarity values (0.24-1.0) obtained showed a high degree of diversity among the cultivars. The results suggest microsatellite markers as a useful tool for the estimation of genetic diversity and cultivar differentiation and present invaluable genetic information for future breeding and association mapping efforts

Preliminary results of trial NPC-0501 evaluating the therapeutic gain by changing from concurrent-adjuvant to induction-concurrent chemoradiotherapy, changing from fluorouracil to capecitabine, and changing from conventional to accelerated radiotherapy fractionation in patients with locoregionally advanced nasopharyngeal carcinoma

© 2014 American Cancer Society. BACKGROUND A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.postprin

State Transition Algorithm

In terms of the concepts of state and state transition, a new heuristic random search algorithm named state transition algorithm is proposed. For continuous function optimization problems, four special transformation operators called rotation, translation, expansion and axesion are designed. Adjusting measures of the transformations are mainly studied to keep the balance of exploration and exploitation. Convergence analysis is also discussed about the algorithm based on random search theory. In the meanwhile, to strengthen the search ability in high dimensional space, communication strategy is introduced into the basic algorithm and intermittent exchange is presented to prevent premature convergence. Finally, experiments are carried out for the algorithms. With 10 common benchmark unconstrained continuous functions used to test the performance, the results show that state transition algorithms are promising algorithms due to their good global search capability and convergence property when compared with some popular algorithms.Comment: 18 pages, 28 figure

End-to-End Joint Antenna Selection Strategy and Distributed Compress and Forward Strategy for Relay Channels

Multi-hop relay channels use multiple relay stages, each with multiple relay nodes, to facilitate communication between a source and destination. Previously, distributed space-time codes were proposed to maximize the achievable diversity-multiplexing tradeoff, however, they fail to achieve all the points of the optimal diversity-multiplexing tradeoff. In the presence of a low-rate feedback link from the destination to each relay stage and the source, this paper proposes an end-to-end antenna selection (EEAS) strategy as an alternative to distributed space-time codes. The EEAS strategy uses a subset of antennas of each relay stage for transmission of the source signal to the destination with amplify and forwarding at each relay stage. The subsets are chosen such that they maximize the end-to-end mutual information at the destination. The EEAS strategy achieves the corner points of the optimal diversity-multiplexing tradeoff (corresponding to maximum diversity gain and maximum multiplexing gain) and achieves better diversity gain at intermediate values of multiplexing gain, versus the best known distributed space-time coding strategies. A distributed compress and forward (CF) strategy is also proposed to achieve all points of the optimal diversity-multiplexing tradeoff for a two-hop relay channel with multiple relay nodes.Comment: Accepted for publication in the special issue on cooperative communication in the Eurasip Journal on Wireless Communication and Networkin

Assessing collusion risks in managing construction projects using artificial neural network

Being an insidious risk to construction projects, collusion has attracted extensive attention from numerous researchers around the world. However, little effort has ever been made to assess collusion, which is important and necessary for curbing collusion in construction projects. Specific to the context of China, this paper developed an artificial neural network model to assess collusion risk in construction projects. Based on a comprehensive literature review, a total of 22 specific collusive practices were identified first, and then refined by a two-round Delphi interview with 15 experienced experts. Subsequently, using the consolidated framework of collusive practices, a questionnaire was further developed and disseminated, which received 97 valid replies. The questionnaire data were then utilized to develop and validate the collusion risk assessment model with the facilitation of artificial neural network approach. The developed model was finally applied in a real-life metro project in which its reliability and applicability were both verified. Although the model was developed under the context of Chinese construction projects, its developing strategy can be applied in other countries, especially for those emerging economies that have a significant concern of collusion in their construction sectors, and thus contributing to the global body of knowledge of collusion

The p75 receptor mediates axon growth inhibition through an association with PIR-B

The Nogo receptor and paired immunoglobulin-like receptor B (PIR-B) are receptors for three myelin-derived axon-growth inhibitors, including myelin-associated glycoprotein (MAG). In this study, we report that the p75 receptor is required for the signal transduction of PIR-B, which interacted with p75 upon ligand binding. In addition, p75 was required for activation of Src homology 2-containing protein tyrosine phosphatase (SHP), which is induced by MAG binding to PIR-B. Mice carrying a mutation in the p75 gene showed promotion of axonal regeneration after optic nerve injury. Thus, our results indicate that p75 has a critical role in axon growth inhibition in specific neuronal tracts

Fish bone foreign body presenting with an acute fulminating retropharyngeal abscess in a resource-challenged center: a case report

<p>Abstract</p> <p>Introduction</p> <p>A retropharyngeal abscess is a potentially life-threatening infection in the deep space of the neck, which can compromise the airway. Its management requires highly specialized care, including surgery and intensive care, to reduce mortality. This is the first case of a gas-forming abscess reported from this region, but not the first such report in the literature.</p> <p>Case presentation</p> <p>We present a case of a 16-month-old Yoruba baby girl with a gas-forming retropharyngeal abscess secondary to fish bone foreign body with laryngeal spasm that was managed in the recovery room. We highlight specific problems encountered in the management of this case in a resource-challenged center such as ours.</p> <p>Conclusion</p> <p>We describe an unusual presentation of a gas-forming organism causing a retropharyngeal abscess in a child. The patient's condition was treated despite the challenges of inadequate resources for its management. We recommend early recognition through adequate evaluation of any oropharyngeal injuries or infection and early referral to the specialist with prompt surgical intervention.</p