Macroporous nanowire nanoelectronic scaffolds for synthetic tissues

available in PMC 2013 April 11.The development of three-dimensional (3D) synthetic biomaterials as structural and bioactive scaffolds is central to fields ranging from cellular biophysics to regenerative medicine. As of yet, these scaffolds cannot electrically probe the physicochemical and biological microenvironments throughout their 3D and macroporous interior, although this capability could have a marked impact in both electronics and biomaterials. Here, we address this challenge using macroporous, flexible and free-standing nanowire nanoelectronic scaffolds (nanoES), and their hybrids with synthetic or natural biomaterials. 3D macroporous nanoES mimic the structure of natural tissue scaffolds, and they were formed by self-organization of coplanar reticular networks with built-in strain and by manipulation of 2D mesh matrices. NanoES exhibited robust electronic properties and have been used alone or combined with other biomaterials as biocompatible extracellular scaffolds for 3D culture of neurons, cardiomyocytes and smooth muscle cells. Furthermore, we show the integrated sensory capability of the nanoES by real-time monitoring of the local electrical activity within 3D nanoES/cardiomyocyte constructs, the response of 3D-nanoES-based neural and cardiac tissue models to drugs, and distinct pH changes inside and outside tubular vascular smooth muscle constructs.National Institutes of Health (U.S.) (Director’s Pioneer award)McKnight Foundation (Technological Innovations in Neurosciences Award)Boston Children's Hospital (Biotechnology Research Endowment)National Institutes of Health (U.S.) (DE013023)National Institutes of Health (U.S.) (DE016516

Ethosuximide ameliorates neurodegenerative disease phenotypes by modulating DAF-16/FOXO target gene expression

Background Many neurodegenerative diseases are associated with protein misfolding/aggregation. Treatments mitigating the effects of such common pathological processes, rather than disease-specific symptoms, therefore have general therapeutic potential. Results Here we report that the anti-epileptic drug ethosuximide rescues the short lifespan and chemosensory defects exhibited by C. elegans null mutants of dnj-14, the worm orthologue of the DNAJC5 gene mutated in autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. It also ameliorates the locomotion impairment and short lifespan of worms expressing a human Tau mutant that causes frontotemporal dementia. Transcriptomic analysis revealed a highly significant up-regulation of DAF-16/FOXO target genes in response to ethosuximide; and indeed RNAi knockdown of daf-16 abolished the therapeutic effect of ethosuximide in the worm dnj-14 model. Importantly, ethosuximide also increased the expression of classical FOXO target genes and reduced protein aggregation in mammalian neuronal cells. Conclusions We have revealed a conserved neuroprotective mechanism of action of ethosuximide from worms to mammalian neurons. Future experiments in mouse neurodegeneration models will be important to confirm the repurposing potential of this well-established anti-epileptic drug for treatment of human neurodegenerative diseases

A school-based comprehensive lifestyle intervention among Chinese kids against Obesity (CLICK-Obesity) in Nanjing City, China: The baseline data

Background: urgent development of effective interventions to prevent rapidly rising childhood obesity in China is needed. Methods: Between May 2010 and December 2013, a cluster randomized controlled trial was conducted among 4 graders in eight urban primary schools randomly assigned to intervention or control groups in Nanjing, China. A multi-component intervention program was implemented within the treatment group, while students in the control group followed their usual health education curriculum without additional intervention. Results: At baseline, 638 and 544 students were enrolled in the intervention and control group, respectively. The prevalence of excess body weight was 26.8%, with 27.4% in the intervention group and 26.1% in the control group (p=0.61). The mean (SD) BMI and WC was 18.7 (3.0) and 63.0 (9.2) for participants in intervention schools, and 18.5 (2.9) and 63.6 (8.7) for students in control group, separately (p=0.24 and 0.41, respectively). Compared to those who were not aware of what lifestyle/behavior factors were unhealthy, students who were aware of the unhealthy lifestyle/ behavior factors consumed fewer fried snacks (0.46±0.76 serves/week vs 0.65±0.91 serves/week;

A Randomized Trial of Rofecoxib for the Chemoprevention of Colorectal Adenomas

BACKGROUND & AIMS: In human and animal studies, nonsteroidal anti-inflammatory drugs have been associated with a reduced risk of colorectal neoplasia. Although the underlying mechanisms are unknown, inhibition of cyclooxygenase (COX), particularly COX-2, is thought to play a role. We conducted a randomized, placebo-controlled, double-blind trial to assess whether use of the selective COX-2 inhibitor rofecoxib would reduce the risk of colorectal adenomas. METHODS: We randomized 2587 subjects with a recent history of histologically confirmed adenomas to receive daily placebo or 25 mg rofecoxib. Randomization was stratified by baseline use of cardioprotective aspirin. Colonoscopic follow-up evaluation was planned for 1 and 3 years after randomization. The primary end point was all adenomas diagnosed during 3 years' treatment. In a modified intent-to-treat analysis, we computed the relative risk of any adenoma after randomization, using Mantel-Haenszel statistics stratified by low-dose aspirin use at baseline. RESULTS: Adenoma recurrence was less frequent for rofecoxib subjects than for those randomized to placebo (41% vs 55%; P < .0001; relative risk [RR], 0.76; 95% confidence interval [CI], 0.69-0.83). Rofecoxib also conferred a reduction in risk of advanced adenomas (P < .01). The chemopreventive effect was more pronounced in the first year (RR, 0.65; 95% CI, 0.57-0.73) than in the subsequent 2 years (RR, 0.81; 95% CI, 0.71-0.93). As reported previously, rofecoxib was associated with increased risks of significant upper gastrointestinal events and serious thrombotic cardiovascular events. CONCLUSIONS: In this randomized trial, rofecoxib significantly reduced the risk of colorectal adenomas, but also had serious toxicity

Molecular Signatures of Hemagglutinin Stem-Directed Heterosubtypic Human Neutralizing Antibodies against Influenza A Viruses

Recent studies have shown high usage of the IGHV1-69 germline immunoglobulin gene for influenza hemagglutinin stem-directed broadly-neutralizing antibodies (HV1-69-sBnAbs). Here we show that a major structural solution for these HV1-69-sBnAbs is achieved through a critical triad comprising two CDR-H2 loop anchor residues (a hydrophobic residue at position 53 (Ile or Met) and Phe54), and CDR-H3-Tyr at positions 98±1; together with distinctive V-segment CDR amino acid substitutions that occur in positions sparse in AID/polymerase-η recognition motifs. A semi-synthetic IGHV1-69 phage-display library screen designed to investigate AID/polη restrictions resulted in the isolation of HV1-69-sBnAbs that featured a distinctive Ile52Ser mutation in the CDR-H2 loop, a universal CDR-H3 Tyr at position 98 or 99, and required as little as two additional substitutions for heterosubtypic neutralizing activity. The functional importance of the Ile52Ser mutation was confirmed by mutagenesis and by BCR studies. Structural modeling suggests that substitution of a small amino acid at position 52 (or 52a) facilitates the insertion of CDR-H2 Phe54 and CDR-H3-Tyr into adjacent pockets on the stem. These results support the concept that activation and expansion of a defined subset of IGHV1-69-encoded B cells to produce potent HV1-69-sBnAbs does not necessarily require a heavily diversified V-segment acquired through recycling/reentry into the germinal center; rather, the incorporation of distinctive amino acid substitutions by Phase 2 long-patch error-prone repair of AID-induced mutations or by random non-AID SHM events may be sufficient. We propose that these routes of B cell maturation should be further investigated and exploited as a pathway for HV1-69-sBnAb elicitation by vaccination

Cognitive Information Processing

Contains reports on five research projects.National Science Foundation (Grant SED76-81985)Associated Press (Grant)Providence Gravure, Inc. (Grant)Taylor Publishing Company (Grant)Sony Corporation (Grant

Validation of a case definition to define chronic dialysis using outpatient administrative data

<p>Abstract</p> <p>Background</p> <p>Administrative health care databases offer an efficient and accessible, though as-yet unvalidated, approach to studying outcomes of patients with chronic kidney disease and end-stage renal disease (ESRD). The objective of this study is to determine the validity of outpatient physician billing derived algorithms for defining chronic dialysis compared to a reference standard ESRD registry.</p> <p>Methods</p> <p>A cohort of incident dialysis patients (Jan. 1 - Dec. 31, 2008) and prevalent chronic dialysis patients (Jan 1, 2008) was selected from a geographically inclusive ESRD registry and administrative database. Four administrative data definitions were considered: at least 1 outpatient claim, at least 2 outpatient claims, at least 2 outpatient claims at least 90 days apart, and continuous outpatient claims at least 90 days apart with no gap in claims greater than 21 days. Measures of agreement of the four administrative data definitions were compared to a reference standard (ESRD registry). Basic patient characteristics are compared between all 5 patient groups.</p> <p>Results</p> <p>1,118,097 individuals formed the overall population and 2,227 chronic dialysis patients were included in the ESRD registry. The three definitions requiring at least 2 outpatient claims resulted in kappa statistics between 0.60-0.80 indicating "substantial" agreement. "At least 1 outpatient claim" resulted in "excellent" agreement with a kappa statistic of 0.81.</p> <p>Conclusions</p> <p>Of the four definitions, the simplest (at least 1 outpatient claim) performed comparatively to other definitions. The limitations of this work are the billing codes used are developed in Canada, however, other countries use similar billing practices and thus the codes could easily be mapped to other systems. Our reference standard ESRD registry may not capture all dialysis patients resulting in some misclassification. The registry is linked to on-going care so this is likely to be minimal. The definition utilized will vary with the research objective.</p

Consensus Statement on the Terminology and Classification of Central Neck Dissection for Thyroid Cancer

Background: The primary goals of this interdisciplinary consensus statement are to review the relevant anatomy of the central neck compartment, to identify the nodal subgroups within the central compartment commonly involved in thyroid cancer, and to define a consistent terminology relevant to the central compartment neck dissection. Summary: The most commonly involved central lymph nodes in thyroid carcinoma are the prelaryngeal (Delphian), pretracheal, and the right and left paratracheal nodal basins. A central neck dissection includes comprehensive, compartment-oriented removal of the prelaryngeal and pretracheal nodes and at least one paratracheal lymph node basin. A designation should be made as to whether a unilateral or bilateral dissection is performed and on which side (left or right) in unilateral cases. Lymph node plucking or berry picking implies removal only of the clinically involved nodes rather than a complete nodal group within the compartment and is not recommended. A therapeutic central compartment neck dissection implies that nodal metastasis is apparent clinically (preoperatively or intraoperatively) or by imaging (clinically N1a). A prophylactic/elective central compartment dissection implies nodal metastasis is not detected clinically or by imaging (clinically N0). Conclusion: Central neck dissection at a minimum should consist of removal of the prelaryngeal, pretracheal, and paratracheal lymph nodes. The description of a central neck dissection should include both the indication (therapeutic vs. prophylactic/elective) and the extent of the dissection (unilateral or bilateral).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78103/1/thy.2009.0159.pd