Keratin gene expression profiles after digit amputation in C57BL/6 vs. regenerative MRL mice imply an early regenerative keratinocyte activated-like state

Mouse strains C57BL/6 (B6) and MRL were studied by whole mouse genome chip microarray analyses of RNA isolated from amputation sites at different times pre-and postamputation at the midsecond phalange of the middle digit. Many keratin genes were highly differentially expressed. All keratin genes were placed into three temporal response classes determined by injury/preinjury ratios. One class, containing only Krt6 and Krt16, were uniquely expressed relative to the other two classes and exhibited different temporal responses in MRL vs. B6. Immunohistochemical staining for Krt6 and Krt16 in tissue sections, including normal digit, flank skin, and small intestine, and from normal and injured ear pinna tissue exhibited staining differences in B6 (low) and MRL (high) that were consistent with the microarray results. Krt10 staining showed no injury-induced differences, consistent with microarray expression. We analyzed Krt6 and Krt16 gene association networks and observed in uninjured tissue several genes with higher expression levels in MRL, but not B6, that were associated with the keratinocyte activated state: Krt6, Krt16, S100a8, S100a9, and Il1b; these data suggest that keratinocytes in the MRL strain, but not in B6, are in an activated state prior to wounding. These expression levels decreased in MRL at all times postwounding but rose in the B6, peaking at day 3. Other keratins significantly expressed in the normal basal keratinocyte state showed no significant strain differences. These data suggest that normal MRL skin is in a keratinocyte activated state, which may provide it with superior responses to wounding. © 2013 the American Physiological Society

Demonstration of a microelectromechanical tunable F-P cavity based on graphene-bonded fiber devices

Taking advantage of the high thermal conductivity of graphene, this paper demonstrates a microelectromechanical (MEM) tunable Fabry-Perot (F-P) cavity, based on a graphene-bonded fiber device (GFD) which acts as a microheater. By increasing the electric current from 0 mA to 8 mA in the heater, the temperature of the GFD can rise and approach a value of 760 K theoretically. This high temperature will cause a deformation of the fiber, allowing the graphene-bonded fiber end to forma gap adjustable F-P cavity with a cleaved single mode fiber. The gap in the cavity can be reduced by increasing the current applied, leading the transmittance of the cavity to change. In this work, a highly sensitive current sensor (5.9x10⁵nm/A²) and a tunable modelocked fiber laser (1.2x10⁴nm/A²) are created based on the MEM tunable F-P cavity

The temporal relationship between local school closure and increased incidence of pediatric diabetic ketoacidosis

IMPORTANCE: The incidence of pediatric diabetic ketoacidosis (DKA) increased early in the COVID-19 pandemic, but the relative contribution of behavioral changes and viral-related pathophysiology are unknown. OBJECTIVE: To evaluate the relationship between school closure date and onset of increased DKA to help clarify the etiology of the increased incidence. DESIGN: A multi-center, quality-controlled Pediatric Intensive Care Unit (PICU) database was used to identify the number of admissions to a participating PICU with DKA on each calendar day from 60 days before local school closure to 90 days after, and compared to baseline data from the same periods in 2018-2019. Interrupted time series and multiple linear regression analyses were used to identify admission rates that differed significantly between 2020 and baseline. SETTING: Eighty-one PICUs in the United StatesParticipants: Children ages 29 days to 17 years admitted to a PICU with DKAExposures: Statewide school closureMain outcome/measure: Rate of admission to the PICU for DKA. RESULTS: There were 1936 admissions for children with DKA in 2020 and 1795 admissions/year to those same PICUs in 2018-2019. Demographics and clinical outcomes did not differ before school closure, but pandemic-era patients were less often white and had longer hospital length of stay in the post-school closure period. The difference between 2020 admissions and 2018-2019 admissions was not different than zero before school closure, and significantly higher than zero after school closure, but was significantly increased in 2020 at \u3e30 days after school closure ( CONCLUSIONS/RELEVANCE: An increase in pediatric DKA admissions began one month after school closures. Given that behavioral changes started near school closure dates and viral activity peaked weeks after, this suggests that behavioral factors may not be the primary etiology and it is possible that SARS-CoV-2 infection may have direct effects on pediatric DKA

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors

Background To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin–etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with ‘distant’ disease. The Kaplan–Meier method was used to estimate PFS and OS. Results With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER ‘distant’ cohort between 2000 and 2014, P-value <0.0001. Conclusion The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER ‘distant’ cohort

Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

SummaryAlzheimer's disease (AD) is characterized pathologically by the abundance of senile plaques and neurofibrillary tangles in the brain. We synthesized over 1200 novel gamma-secretase modulator (GSM) compounds that reduced Aβ42 levels without inhibiting epsilon-site cleavage of APP and Notch, the generation of the APP and Notch intracellular domains, respectively. These compounds also reduced Aβ40 levels while concomitantly elevating levels of Aβ38 and Aβ37. Immobilization of a potent GSM onto an agarose matrix quantitatively recovered Pen-2 and to a lesser degree PS-1 NTFs from cellular extracts. Moreover, oral administration (once daily) of another potent GSM to Tg 2576 transgenic AD mice displayed dose-responsive lowering of plasma and brain Aβ42; chronic daily administration led to significant reductions in both diffuse and neuritic plaques. These effects were observed in the absence of Notch-related changes (e.g., intestinal proliferation of goblet cells), which are commonly associated with repeated exposure to functional gamma-secretase inhibitors (GSIs)

BVRI Light Curves for 29 Type Ia Supernovae

BVRI light curves are presented for 27 Type Ia supernovae discovered during the course of the Calan/Tololo Survey and for two other SNe Ia observed during the same period. Estimates of the maximum light magnitudes in the B, V, and I bands and the initial decline rate parameter m15(B) are also given.Comment: 17 pages, figures and tables are not included (contact first author if needed), to appear in the Astronomical Journa

Patience, Persistence and Pragmatism: Experiences and Lessons Learnt from the Implementation of Clinically Integrated Teaching and Learning of Evidence-Based Health Care - A Qualitative Study

Clinically integrated teaching and learning are regarded as the best options for improving evidence-based healthcare (EBHC) knowledge, skills and attitudes. To inform implementation of such strategies, we assessed experiences and opinions on lessons learnt of those involved in such programmes.We conducted semi-structured interviews with 24 EBHC programme coordinators from around the world, selected through purposive sampling. Following data transcription, a multidisciplinary group of investigators carried out analysis and data interpretation, using thematic content analysis. Successful implementation of clinically integrated teaching and learning of EBHC takes much time. Student learning needs to start in pre-clinical years with consolidation, application and assessment following in clinical years. Learning is supported through partnerships between various types of staff including the core EBHC team, clinical lecturers and clinicians working in the clinical setting. While full integration of EBHC learning into all clinical rotations is considered necessary, this was not always achieved. Critical success factors were pragmatism and readiness to use opportunities for engagement and including EBHC learning in the curriculum; patience; and a critical mass of the right teachers who have EBHC knowledge and skills and are confident in facilitating learning. Role modelling of EBHC within the clinical setting emerged as an important facilitator. The institutional context exerts an important influence; with faculty buy-in, endorsement by institutional leaders, and an EBHC-friendly culture, together with a supportive community of practice, all acting as key enablers. The most common challenges identified were lack of teaching time within the clinical curriculum, misconceptions about EBHC, resistance of staff, lack of confidence of tutors, lack of time, and negative role modelling.Implementing clinically integrated EBHC curricula requires institutional support, a critical mass of the right teachers and role models in the clinical setting combined with patience, persistence and pragmatism on the part of teachers

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events