Influence of TAT-peptide polymerization on properties and transfection activity of TAT/DNA polyplexes.

Use of bioactive cationic peptides as gene carriers is limited by instability of their DNA complexes in vivo and by the loss of their biological activity due to undesired interactions of their bioactive parts with the DNA. To overcome the two major limitations, biodegradable high-molecular-weight form of TAT peptide (POLYTAT) sensitive to cellular redox-potential gradients was synthesized in this study by oxidative polycondensation. Physicochemical and transfection properties of DNA polyplexes based on POLYTAT were investigated and compared with polyplexes based on TAT polymer prepared by in situ template-assisted polymerization. Physicochemical properties of TAT-based polyplexes were affected by the molecular weight and method of polymerization of the TAT peptide. All TAT-based DNA polyplexes exhibited reduced cytotoxicity when compared with control polyethylenimine (PEI) polyplexes. Polyplexes based on both high-molecular-weight TAT polypeptides exhibited increased transfection efficiency compared to control TAT peptide but lower than that of PEI polyplexes. The evidence shows that transfection activity of TAT-based polyplexes is strongly dependent on the presence of chloroquine and therefore suggests that TAT polyplexes are internalized by an endocytosis. Overall, high-molecular-weight reducible polycations based on bioactive peptides has the potential as versatile carriers of nucleic acids that display low cytotoxicity and can prove to be especially beneficial in cases that require surface presentation of membrane-active or cell-specific targeting peptides.     

A Study on Mechanical and Microstructural Characteristics of Concrete Using Recycled Aggregate

The objective of this paper is to provide a comprehensive study about the performance of concrete using mixed coarse recycled aggregate (MCRA) as an alternative for natural aggregate (NA) at replacement levels of 0, 30, 60, and 100%, which can greatly reduce the environmental pollution by incorporating the construction and demolition wastes in the reproduction of concrete. The focus of this study was to use the raw MCRA that was directly obtained from a recycling plant and not further processed. Initially, MCRA was studied to ascertain if its property meets the recommended Indian standards for natural aggregates. Using the slump test, the workability of freshly prepared concrete with a characteristic strength of 30 MPa was assessed. Additionally, the mechanical performance of concrete was assessed on the specimens prepared in the different forms: cubes, cylinders, and beams. Moreover, Scanning Electron Microscopy (SEM) with EDAX, XRD, and FTIR were used to study the microstructural behavior of selected optimum and control mixes at 7 and 28 days of curing. The studies revealed that a higher MCRA content improved the workability of concrete and 30% replacement of MCRA improved the compressive strength by 11.01, 6.98, 6.19, and 14.24% at 7, 28, 56, and 90 days respectively. At the same time, the 30% replacement of the MCRA mix showed an improved split tensile and flexural strength by 2.92 and 6.26%, respectively. The microstructural analysis showed that the optimum mixture had a more condensed microstructure. Therefore, 30% replacement of MCRA can be incorporated in the characteristic strength of concrete of 30 MPa. In particular, MCRA incorporation had a positive influence similar to conventional concrete on the physical, mechanical, and microstructural properties, which can increase the utilization of all kinds of directly obtained construction and demolition wastes to increase the circular economy in the construction sector.     

Quantifying the breadth of antibiotic exposure in sepsis and suspected infection using spectrum scores

A retrospective cohort study. Studies to quantify the breadth of antibiotic exposure across populations remain limited. Therefore, we applied a validated method to describe the breadth of antimicrobial coverage in a multicenter cohort of patients with suspected infection and sepsis. We conducted a retrospective cohort study across 21 hospitals within an integrated healthcare delivery system of patients admitted to the hospital through the ED with suspected infection or sepsis and receiving antibiotics during hospitalization from January 1, 2012, to December 31, 2017. We quantified the breadth of antimicrobial coverage using the Spectrum Score, a numerical score from 0 to 64, in patients with suspected infection and sepsis using electronic health record data. Of 364,506 hospital admissions through the emergency department, we identified 159,004 (43.6%) with suspected infection and 205,502 (56.4%) with sepsis. Inpatient mortality was higher among those with sepsis compared to those with suspected infection (8.4% vs 1.2%; P < .001). Patients with sepsis had higher median global Spectrum Scores (43.8 [interquartile range IQR 32.0–49.5] vs 43.5 [IQR 26.8–47.2]; P < .001) and additive Spectrum Scores (114.0 [IQR 57.0–204.5] vs 87.5 [IQR 45.0–144.8]; P < .001) compared to those with suspected infection. Increased Spectrum Scores were associated with inpatient mortality, even after covariate adjustments (adjusted odds ratio per 10-point increase in Spectrum Score 1.31; 95%CI 1.29–1.33). Spectrum Scores quantify the variability in antibiotic breadth among individual patients, between suspected infection and sepsis populations, over the course of hospitalization, and across infection sources. They may play a key role in quantifying the variation in antibiotic prescribing in patients with suspected infection and sepsis.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Activity of telithromycin against key pathogens associated with community-acquired respiratory tract infections

OBJECTIVES: To investigate the correlation between in vitro susceptibility of isolates and clinical outcomes with telithromycin in respiratory tract infections. METHODS: The activity of telithromycin was determined by in vitro susceptibility testing of key respiratory tract pathogens isolated from patients with community-acquired pneumonia, acute exacerbations of chronic bronchitis or acute maxillary sinusitis enrolled in 14 Phase III/IV clinical trials evaluating the clinical efficacy of telithromycin. RESULTS: In this pooled analysis, telithromycin mode minimum inhibitory concentration (MIC) and MIC90, respectively, were: 0.016 and 0.03 mg/l against Streptococcus pneumoniae (n=626); 0.03 and 0.5 mg/l for penicillin-resistant S. pneumoniae (n=56); 0.03 and 1 mg/l for erythromycin-resistant S. pneumoniae (n=81); 2 and 4 mg/l against Haemophilus influenzae (including beta-lactamase producers; n=627); both 0.12 mg/l for Moraxella catarrhalis (n=159) and both 0.25 mg/l for Staphylococcus aureus (n=124). Telithromycin (5 or 7-10 days) resulted in overall clinical and bacteriologic success rates of 88.1% (1593/1808) and 89% (1593/1789), respectively. CONCLUSIONS: High levels of in vitro susceptibility to telithromycin are paralleled by high rates of clinical cure and bacteriologic eradication.     

Structure–Function Analysis of Liver Flavin Monooxygenase 3 that Drives Trimethylaminuria in Humans

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Mutations in human flavin monooxygenase-3 (hFMO3) enzyme have been implicated in the rare autosomal recessive...     

Fractures of the shaft of humerus

Humeral shaft fractures account for 1–3% of all fractures. Non-surgical management with functional bracing is arguably the standard of care for most humeral shaft fractures.It results in high union rates and in general the outcome is excellent. Surgical management is indicated in some cases, such as open fractures, polytrauma, those with associated vascular injury, pathological fractures, floating elbow injuries and fractures that have failed non-surgical management. Options for surgical fixation include open reduction and internal fixation with plate osteosynthesis, antegrade or retrograde intramedullary nailing and external fixation. Both plate osteosynthesis and intramedullary nailing yield similar results, with a slightly higher rate of complications and re-operations with nailing. A high incidence of radial nerve injury has been associated with humeral shaft fractures and should be actively sought. The management of nerve injuries is still a matter of debate, however; initial expectant treatment with delayed exploration if needed seems to yield similar results to early exploration. Proper patient selection is key to achieving good outcomes with both surgical and non-surgical management of these injuries.     

A report on the Academic Emergency Medicine 2015 consensus conference “Diagnostic imaging in the emergency department: a research agenda to optimize utilization”

In May 2015, the Academic Emergency Medicine consensus conference “Diagnostic imaging in the emergency department: a research agenda to optimize utilization” was held. The goal of the conference was to develop a high-priority research agenda regarding emergency diagnostic imaging on which to base future research. In addition to representatives from the Society of Academic Emergency Medicine, the multidisciplinary conference included members of several radiology organizations: American Society for Emergency Radiology, Radiological Society of North America, the American College of Radiology, and the American Association of Physicists in Medicine. The specific aims of the conference were to (1) understand the current state of evidence regarding emergency department (ED) diagnostic imaging utilization and identify key opportunities, limitations, and gaps in knowledge; (2) develop a consensus-driven research agenda emphasizing priorities and opportunities for research in ED diagnostic imaging; and (3) explore specific funding mechanisms available to facilitate research in ED diagnostic imaging. Through a multistep consensus process, participants developed targeted research questions for future research in six content areas within emergency diagnostic imaging: clinical decision rules; use of administrative data; patient-centered outcomes research; training, education, and competency; knowledge translation and barriers to imaging optimization; and comparative effectiveness research in alternatives to traditional computed tomography use.