Thrombospondin-1 (TSP-1) Stimulates Expression of Integrin α6 in Human Breast Carcinoma Cells: A Downstream Modulator of TSP-1-Induced Cellular Adhesion

Thrombospondin-1 (TSP-1) is involved in a variety of different cellular processes including cell adhesion, tumor progression, and angiogenesis. This paper reports the novel finding that TSP-1 upregulates integrin α6 subunit in human keratinocytes and human breast cancer cells resulting in increased cell adhesion and tumor cell invasion. The effect of TSP-1 on α6 subunit expression was examined in human keratinocytes and breast adenocarcinoma cell lines (MDA-MB-231) treated with TSP-1 and in TSP-1 stably transfected breast cancer cells. TSP-1 upregulated α6 message and protein in these cells as revealed by differential display, Northern and Western blot analysis and immunohistochemical localization studies. The increased expression of α6 was shown to mediate adhesion and invasion of these cells to laminin, a major component of the basement membrane and extracellular matrix (ECM). These data suggest that TSP-1 plays an integral role in the attachment of cells to the ECM facilitating cell motility and angiogenesis

Age- and Lesion-Related Comorbidity Burden Among US Adults With Congenital Heart Disease: A Population-Based Study.

Background As patients with congenital heart disease (CHD) are living longer, understanding the comorbidities they develop as they age is increasingly important. However, there are no published population-based estimates of the comorbidity burden among the US adult patients with CHD. Methods and Results Using the IBM MarketScan commercial claims database from 2010 to 2016, we identified adults aged ≥18 years with CHD and 2 full years of continuous enrollment. These were frequency matched with adults without CHD within categories jointly defined by age, sex, and dates of enrollment in the database. A total of 40 127 patients with CHD met the inclusion criteria (mean [SD] age, 36.8 [14.6] years; and 48.2% were women). Adults with CHD were nearly twice as likely to have any comorbidity than those without CHD (P<0.001). After adjusting for covariates, patients with CHD had a higher prevalence risk ratio for "previously recognized to be common in CHD" (risk ratio, 9.41; 95% CI, 7.99-11.1), "other cardiovascular" (risk ratio, 1.73; 95% CI, 1.66-1.80), and "noncardiovascular" (risk ratio, 1.47; 95% CI, 1.41-1.52) comorbidities. After adjusting for covariates and considering interaction with age, patients with severe CHD had higher risks of previously recognized to be common in CHD and lower risks of other cardiovascular comorbidities than age-stratified patients with nonsevere CHD. For noncardiovascular comorbidities, the risk was higher among patients with severe than nonsevere CHD before, but not after, the age of 40 years. Conclusions Our data underscore the unique clinical needs of adults with CHD compared with their peers. Clinicians caring for CHD may want to use a multidisciplinary approach, including building close collaborations with internists and specialists, to help provide appropriate care for the highly prevalent noncardiovascular comorbidities

Considerations in Assuring Safety of Increasingly Autonomous Systems

Recent technological advances have accelerated the development and application of increasingly autonomous (IA) systems in civil and military aviation. IA systems can provide automation of complex mission tasks-ranging across reduced crew operations, air-traffic management, and unmanned, autonomous aircraft-with most applications calling for collaboration and teaming among humans and IA agents. IA systems are expected to provide benefits in terms of safety, reliability, efficiency, affordability, and previously unattainable mission capability. There is also a potential for improving safety by removal of human errors. There are, however, several challenges in the safety assurance of these systems due to the highly adaptive and non-deterministic behavior of these systems, and vulnerabilities due to potential divergence of airplane state awareness between the IA system and humans. These systems must deal with external sensors and actuators, and they must respond in time commensurate with the activities of the system in its environment. One of the main challenges is that safety assurance, currently relying upon authority transfer from an autonomous function to a human to mitigate safety concerns, will need to address their mitigation by automation in a collaborative dynamic context. These challenges have a fundamental, multidimensional impact on the safety assurance methods, system architecture, and V&V capabilities to be employed. The goal of this report is to identify relevant issues to be addressed in these areas, the potential gaps in the current safety assurance techniques, and critical questions that would need to be answered to assure safety of IA systems. We focus on a scenario of reduced crew operation when an IA system is employed which reduces, changes or eliminates a human's role in transition from two-pilot operations

PHARMACOGNOSTIC AND HPTLC BASED COMPARATIVE STUDY ON LEAVES OF MERREMIA EMARGINATA BURM. F. AND CENTELLA ASIATICA (L.) URBAN

Objective: In this study, an attempt was made to generate information based on botanical, physicochemical and HPTLC data needed for proper identification and authentication of M. emarginata and C. asiatica belonging to two different families. Methods: Botanical study comprises of macroscopy, microscopy and powder microscopy of leaves of both crude drugs. The physicochemical parameters such as water-soluble extractive, alcohol soluble extractive and loss on drying at 105℃, total ash, acid insoluble ash, and volatile oil were determined according to standard methods. HPTLC studies of chloroform extracts of leaves of both drugs were conducted at 254 nm, 366 nm and 575 nm after derivatisation using vanillin-sulphuric acid and the results were documented. Results: The present study reveals that microscopy and most of the physicochemical parameters of both the plant materials are different. Anatomy of the leaves showed two main characteristic differences. First plenty of trichome with trichome base and calcium oxalate crystal is common in M. emarginata, which is not observed in C. asiatica. Both plants have different venation patterns and leaf constants. The total ash content and the solubility in alcohol and water for leaves of C. asiatica are higher than that of M. emarginata. The HPTLC fingerprinting pattern obtained for both drugs are different. Conclusion: All the results obtained from this study help in determining differences and similarities of leaves of M. emarginata and C. asiatica and thereby preventing adulteration and substitution and emphasizing the importance of standardization

Risk Factors for Scrub Typhus, Murine Typhus, and Spotted Fever Seropositivity in Urban Areas, Rural Plains, and Peri-Forest Hill Villages in South India: A Cross-Sectional Study.

Scrub typhus and spotted fever group rickettsioses are thought to be common causes of febrile illness in India, whereas they rarely test for murine typhus. This cross-sectional study explored the risk factors associated with scrub typhus, tick-borne spotted fever, and murine typhus seropositivity in three different geographical settings, urban, rural, and hill villages in Tamil Nadu, South India. We enrolled 1,353 participants living in 48 clusters. The study included a questionnaire survey and blood sampling. Blood was tested for Orientia tsutsugamushi (scrub typhus), Rickettsia typhi (murine typhus), and spotted fever group Rickettsia IgG using ELISA. The seroprevalence of scrub typhus, spotted fever, and murine typhus were 20.4%, 10.4%, and 5.4%, respectively. Scrub typhus had the highest prevalence in rural areas (28.1%), and spotted fever was most common in peri-forested areas (14.9%). Murine typhus was more common in rural (8.7%) than urban areas (5.4%) and absent in peri-forested hill areas. Agricultural workers had a higher relative risk for scrub typhus, especially in urban areas. For murine typhus, proximity to a waterbody and owning a dog were found to be major risk factors. The main risk factors for spotted fever were agricultural work and living in proximity to a forest. Urban, rural plains, and hill settings display distinct epidemiological pattern of Orientia and rickettsial infections. Although scrub typhus and spotted fever were associated with known risk factors in this study, the findings suggest a different ecology of murine typhus transmission compared with other studies conducted in Asia

Clinical adjudication in acute kidney injury studies: findings from the pivotal TIMP-2*IGFBP7 biomarker study

Background The NEPROCHECK test (Astute Medical, San Diego, CA, USA) combines urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) to identify patients at high risk for acute kidney injury (AKI). In a US Food and Drug Administration registration trial (NCT01573962), AKI was determined by a three-member clinical adjudication committee. The objectives were to examine agreement among adjudicators as well as between adjudicators and consensus criteria for AKI and to determine the relationship of biomarker concentrations and adjudicator agreement. Methods Subjects were classified as AKI 3/3, 2/3, 1/3 or 0/3 according to the proportion of adjudicators classifying the case as AKI. Subjects were classified as Kidney Disease: Improving Global Outcomes (KDIGO) AKI(+) when stage 2 or 3 AKI criteria were met. Results Concordance between adjudicators and between adjudicators and KDIGO criteria were lower for AKI than non-AKI subjects [78.9 versus 97.3% (P \u3c 0.001) and 91.5 versus 97.9% (P = 0.01)]. Subjects who were AKI 3/3 or 2/3 but KDIGO AKI(−) had higher median [TIMP-2]•[IGFBP7] compared with those who were AKI-1/3 or 0/3 but KDIGO AKI(+) {2.78 [interquartile range (IQR) 2.33–3.56] versus 0.52 [IQR 0.26–1.64]; P = 0.008}. [TIMP-2]•[IGFBP7] levels were highest in patients with AKI 3/3 and lowest in AKI 0/3, whereas AKI 2/3 and 1/3 exhibited intermediate values. Conclusions In this analysis, urine [TIMP-2]•[IGFBP7] levels correlated to clinically adjudicated AKI better than to KDIGO criteria. Furthermore, in difficult cases where adjudicators overruled KDIGO criteria, the biomarker test discriminated well. This study highlights the importance of clinical adjudication of AKI for biomarker studies and lends further support for the value of urine [TIMP-2]•[IGFBP7]

From Requirements to Code: Model Based Development of a Medical Cyber Physical System

The advanced use of technology in medical devices has improved the way health care is delivered to patients. Unfortunately, the increased complexity of modern medical devices poses challenges for development, assurance, and regulatory approval. In an e ort to improve the safety of advanced medical devices, organizations such as FDA have supported exploration of techniques to aid in the development and regulatory approval of such systems. In an ongoing research project, our aim is to provide effective development techniques and exemplars of system development artifacts that demonstrate state of the art development techniques. In this paper we present an end-to-end model-based approach to medical device software development along with the artifacts created in the process. While outlining the approach, we also describe our experiences, challenges, and lessons learned in the process of formulating and analyzing the requirements, modeling the system, formally verifying the models, generating code, and executing the generated code in the hardware for generic patient controlled analgesic infusion pump (GPCA). We believe that the development artifacts and techniques presented in this paper could serve as a generic reference to be used by researchers, practitioners, and authorities while developing and evaluating cyber physical medical devices