Cost of space-based laser ballistic missile defense.
Orbiting platforms carrying infrared lasers have been proposed as weapons forming the first tier of a ballistic missile defense system under the President's Strategic Defense Initiative. As each laser platform can destroy a limited number of missiles, one of several methods of countering such a system is to increase the number of offensive missiles. Hence it is important to know whether the cost-exchange ratio, defined as the ratio of the cost to the defense of destroying a missile to the cost to the offense of deploying an additional missile, is greater or less than 1. Although the technology to be used in a ballistic missile defense system is still extremely uncertain, it is useful to examine methods for calculating the cost-exchange ratio. As an example, the cost of an orbiting infrared laser ballistic missile defense system employed against intercontinental ballistic missiles launched simultaneously from a small area is compared to the cost of additional offensive missiles. If one adopts lower limits to the costs for the defense and upper limits to the costs for the offense, the cost-exchange ratio comes out substantially greater than 1. If these estimates are confirmed, such a ballistic missile defense system would be unable to maintain its effectiveness at less cost than it would take to proliferate the ballistic missiles necessary to overcome it and would therefore not satisfy the President's requirements for an effective strategic defense. Although the method is illustrated by applying it to a space-based infrared laser system, it should be straightforward to apply it to other proposed systems.


Genetic variants of the MRC1 gene and the IFNG gene are associated with leprosy in Han Chinese from Southwest China.
Leprosy is an ancient infectious disease, with over 200,000 affected people (mainly in Asia and Africa) being registered annually. Genetic factors may confer susceptibility to this disease. In the present study, we genotyped 12 genetic variants of the MRC1 gene and the IFNG gene in 527 Han Chinese with leprosy and 583 healthy individuals from Yunnan, China, to discern potential association of these two genes with leprosy. In particular, we aimed to validate the recently reported association of MRC1 variant rs1926736 (p.G396S) and IFNG variant rs2430561 (+874 T>A) with leprosy, which were initially observed in Vietnamese and Brazilian populations, respectively. Our results failed to confirm the reported association between variants rs1926736 and rs2430561 and leprosy in Han Chinese. However, we found that variants rs692527 (P = 0.022) and rs34856358 (P = 0.022) of the MRC1 gene were associated with paucibacillary leprosy, and rs3138557 of the IFNG gene was significantly associated with multibacillary leprosy. The exact role of the MRC1 gene and the IFNG gene in leprosy awaits future study.


Peripheral blood expression levels of inflammasome complex components in two different focal epilepsy syndromes.
Although the role of inflammation in epilepsy pathogenesis has been extensively investigated, the inflammasome complex, a key component of neuroinflammation, has been understudied in epilepsy patients. To better understand the involvement of this system in epilepsy, levels of inflammasome complex components (NLRP1, NLRP3, CASP1, ASC), end-products of inflammasome complex activity [IL-1β, IL-18, nitric oxide synthase (NOS) isoforms] and other inflammatory factors (NFκB, IL-6, TNF-α) were measured in peripheral blood of patients with focal epilepsy of unknown cause (FEoUC) (n = 47), mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (n = 35) and healthy controls using real time qPCR and/or ELISA. Inflammasome complex associated factors were either downregulated or unchanged in epilepsy patients. Likewise, flow cytometry studies failed to show an increase in ratios of NLRP3-expressing CD3+ and CD14+ peripheral blood mononuclear cells (PBMC) in epileptic patients. Anti-neuronal antibody positive epilepsy patients showed increased NLRP1 and neuronal NOS mRNA expression levels, whereas patients under poly-therapy showed reduced serum inflammasome levels. FEoUC patients demonstrated increased PBMC NFκB mRNA expression levels and serum IL-1β and IL-6 levels. Both MTLE-HS and FEoUC patients displayed higher ratios of NFκB-expressing CD14+ PBMC than healthy controls. Although previous clinical studies have implicated increased inflammasome complex expression levels in epilepsy, our results indicate suppressed inflammasome complex activity in the peripheral blood of focal epilepsy patients. Alternatively, the IL-6-NFκB signaling pathway, appears to be activated in focal epilepsy, suggesting that factors of this pathway might be targeted for future theranostic applications.


Autosomal-dominant branchio-otic (BO) syndrome is not allelic to the branchio-oto-renal (BOR) gene at 8q13.
The manifestations of branchio-oto-renal syndrome (BOR), Treacher Collins syndrome, tricho-rhino-phalangeal syndrome, van der Woude syndrome, and Langer-Giedion syndrome are well-defined; these conditions represent clinically and genetically separate syndromes. Autosomal-dominant branchio-oto-renal syndrome comprises preauricular pits, branchial fistulas, hearing loss, and renal anomalies. However, several families have been described without one or more of these clinical findings. In some families, the phenotypic expression is limited to branchial anomalies, preauricular pits, and hearing loss, with no renal dysplasia (branchio-otic or BO syndrome). In other families, branchial and renal anomalies occur without hearing impairment. It is not known whether the variable clinical manifestations are due to the effect of a single gene or whether these represent different syndromes. We investigated BO syndrome in a large family to determine whether BOR and BO syndromes are allelic to each other. The genetic linkage analysis provides evidence that BO syndrome is not allelic to the BOR gene at 8q13.


Treatment patterns, survival and economic outcomes in Medicare-enrolled, older patients with HR+/HER2- metastatic breast cancer.
Background: Endocrine therapy (ET) remains a foundation of systemic therapy for HR+/ HER2- metastatic breast cancer (MBC), although chemotherapy (CT) is used in select patients. In this "real-world" study, we explored treatment patterns, health care resource use (HCRU), costs, adverse events (AEs) and overall survival (OS) in Medicare-enrolled, older patients with HR+/HER2- MBC. Methods: Patients with HR+/HER2- MBC (2007-2011) and aged >66 years were retrospectively analyzed using the SEER-Medicare data. Treatment patterns, HCRU, costs, AEs and OS after MBC diagnosis through end of study period (31 December 2013) were examined using descriptive and multivariable analyses. Results: Among 3622 eligible patients, ET was the most common treatment (77%), followed by CT (50%), radiation (48%) and surgery (19%). The proportion of patients treated with ET monotherapy decreased across therapy lines, from 74% in first line (1 L) to 35% in 4 L. The total number of unique therapy regimens used was 181 in 1 L, 171 in 2 L, 128 in 3 L, and 95 in 4 L. The median OS from MBC diagnosis was 25.3 months (95% CI, 24.0-26.7). In multivariable analyses, receipt of CT and combination CT + ET (versus ET monotherapy) in 1 L, metastatic disease at initial diagnosis, larger tumor size, and presence of visceral and brain metastases at MBC diagnosis significantly predicted receipt of 2 L therapy. Conclusions: ET was the most common first-line treatment for study patients, but its use decreased gradually in the subsequent lines. The heterogeneity in the treatment selection highlights a lack of consensus for the management of HR+/HER2- MBC in routine practice.


[Role of magnetic resonance in the follow-up of surgically treated aortic dissection].
Twenty-one patients were examined with MRI 0.5 to 200 months after surgical aortic dissection. The series included 15 type-I dissections, 1 type-II dissection and 5 complicated type-III dissections. MR images demonstrated the persistence of the intimal flap with patency of both the true and the false lumen in 17 cases, the complete obliteration of the false lumen in 1 case and the partial thrombosis of the false lumen in 3 cases. Coronary artery ostial reimplantation was depicted in all the patients who underwent this kind of surgery; in 1 case, a small hematoma was present at the site of reimplantation. In 3 patients, an organized hematoma was seen between the prosthetic graft and the native aortic wall; in 1 case the aortic lumen was markedly reduced, while in the extant 2 cases, signal intensity features were suggestive of subacute hematoma due to prosthetic graft degeneration. Seven patients underwent two MR exams: the first one immediately after surgery (in most cases) and the second one at 3-11 months. Aortic diameter progressively increased in 4 patients, 3 of them with Marfan syndrome. In conclusion, MRI proved an accurate technique to assess aortic size beyond the prosthetic graft and to demonstrate the residual dissecting process and the postoperative problems in the prosthetic conduit.


Using silver nano-particle ink in electrode fabrication of high frequency copolymer ultrasonic transducers: modeling and experimental investigation.
High frequency polymer-based ultrasonic transducers are produced with electrodes thicknesses typical for printed electrodes obtained from silver (Ag) nano-particle inks. An analytical three-port network is used to study the acoustic effects imposed by a thick electrode in a typical layered transducer configuration. Results from the network model are compared to experimental findings for the implemented transducer configuration, to obtain a better understanding of acoustical effects caused by the additional printed mass loading. The proposed investigation might be supportive of identification of suitable electrode-depositing methods. It is also believed to be useful as a feasibility study for printed Ag-based electrodes in high frequency transducers, which may reduce both the cost and production complexity of these devices.


Genome Features and Secondary Metabolites Biosynthetic Potential of the Class Ktedonobacteria.
The prevalence of antibiotic resistance and the decrease in novel antibiotic discovery in recent years necessitates the identification of potentially novel microbial resources to produce natural products. Ktedonobacteria, a class of deeply branched bacterial lineage in the ancient phylum Chloroflexi, are ubiquitous in terrestrial environments and characterized by their large genome size and complex life cycle. These characteristics indicate Ktedonobacteria as a potential active producer of bioactive compounds. In this study, we observed the existence of a putative "megaplasmid," multiple copies of ribosomal RNA operons, and high ratio of hypothetical proteins with unknown functions in the class Ktedonobacteria. Furthermore, a total of 104 antiSMASH-predicted putative biosynthetic gene clusters (BGCs) for secondary metabolites with high novelty and diversity were identified in nine Ktedonobacteria genomes. Our investigation of domain composition and organization of the non-ribosomal peptide synthetase and polyketide synthase BGCs further supports the concept that class Ktedonobacteria may produce compounds structurally different from known natural products. Furthermore, screening of bioactive compounds from representative Ktedonobacteria strains resulted in the identification of broad antimicrobial activities against both Gram-positive and Gram-negative tested bacterial strains. Based on these findings, we propose the ancient, ubiquitous, and spore-forming Ktedonobacteria as a versatile and promising microbial resource for natural product discovery.


Lightwave nano-converging enhancement by an arrayed optical antenna based on metallic nano-cone-tips for CMOS imaging detection.
A kind of gold-coated glass nano-cone-tips (GGNCTs) is developed as an arrayed optical antenna for highly receiving and converging incident lightwaves. A local light field enhancement factor (LFEF) of ~ 2 × 104 and maximum light absorption of ~ 98% can be achieved. The near-field lightwave measurements at the wavelength of 633 nm show that the surface net charges over a single GGNCT make a typical dipole oscillation and the energy transmits along the wave vector orientation, thus leading to a strong local light field enhancement. An effective detection method by near-field coupling an arrayed GGNCT and complementary metal-oxide-semiconductor (CMOS) sensor for highly efficient imaging detection is proposed. The lightwave detection at several wavelengths, including typical 473 nm, 532 nm, 671 nm, and 980 nm, shows a notable characteristic that a better capability of the net charge distribution adjusting and localized aggregating can be obtained at the absorption peak of the GGNCT developed and a stronger signal detection achieved. The research lays a foundation for further developing a light detector with an ideal optoelectronic sensitivity and broad spectral suitability, which is based on integrating GGNCTs as an arrayed optical antenna with common sensors.


MicroRNA-restricted transgene expression in the retina.
Gene transfer using adeno-associated viral (AAV) vectors has been successfully applied in the retina for the treatment of inherited retinal dystrophies. Recently, microRNAs have been exploited to fine-tune transgene expression improving therapeutic outcomes. Here we evaluated the ability of retinal-expressed microRNAs to restrict AAV-mediated transgene expression to specific retinal cell types that represent the main targets of common inherited blinding conditions. To this end, we generated AAV2/5 vectors expressing EGFP and containing four tandem copies of miR-124 or miR-204 complementary sequences in the 3'UTR of the transgene expression cassette. These vectors were administered subretinally to adult C57BL/6 mice and Large White pigs. Our results demonstrate that miR-124 and miR-204 target sequences can efficiently restrict AAV2/5-mediated transgene expression to retinal pigment epithelium and photoreceptors, respectively, in mice and pigs. Interestingly, transgene restriction was observed at low vector doses relevant to therapy. We conclude that microRNA-mediated regulation of transgene expression can be applied in the retina to either restrict to a specific cell type the robust expression obtained using ubiquitous promoters or to provide an additional layer of gene expression regulation when using cell-specific promoters.


Complications of cerebral angiography: prospective assessment of risk.
A prospective study of 1,517 consecutive cerebral angiographic examinations is reported. The incidence of all complications was 8.5%, and the incidence of all neurologic complications was 2.6%. The overall incidence of permanent neurologic deficit was 0.33%. The incidence of permanent neurologic deficit in patients referred for evaluation of symptomatic cerebrovascular disease was 0.63%. Older age, increased serum creatinine concentration, and the use of more than one catheter all were significantly associated with serious neurologic complications. Although patients with a recent stroke or frequent transient ischemic attacks had a higher incidence of serious neurologic complications, this increase was not statistically significant for this sample.


ED90 of epidural esketamine with 0.075% ropivacaine for labor analgesia in nulliparous parturients: a prospective, randomized and dose-finding study.
Background: Because it has been reported that racemic ketamine had a local anesthetic-sparing effect when used for epidural analgesia this would suggest the likelihood of a potential advantage (less pruritus) over opioid drugs. Esketamine has greater analgesic efficacy than racemic ketamine, but the optimum dosage regimen for epidural use is undetermined. The aim of this study was to determine the ED90 of epidural esketamine when coadministered with 0.075% ropivacaine for labor analgesia. Methods: A total of 65 laboring nulliparous patients were enrolled in this study from 16 March 2022 to 15 October 2022. The patients were randomly assigned to receive 0, 0.25, 0.5, 0.75 or 1.0 mg/mL esketamine with 0.075% ropivacaine epidurally. An effective response to the epidural loading dose was defined as numerical rating scale pain score ≤3 at 30 min after the end of the epidural loading dose (10 mL of the ropivacaine 0.075% solution with the added esketamine). The ED90 of epidural esketamine coadministered with 0.075% ropivacaine with 95% confidence intervals for labor analgesia was determined using probit regression. Secondary outcomes and side effects were recorded. Results: The estimated value of ED90 with 95% CIs for epidural esketamine with 0.075% ropivacaine was 0.983 (0.704-2.468) mg/mL. The characteristics of sensory and motor block, consumption of ropivacaine per hour, duration of first or second stage, Apgar scores did not differ among the five groups. The incidence of mild dizziness in Group esketamine 1.0 mg/mL was significantly higher than that in other groups (p < 0.05). No statistical differences were found in other side effects among groups. Conclusion: The ED90 value of epidural esketamine coadministered with 0.075% ropivacaine for labor analgesia in nulliparous parturients was about 1.0 mg/mL. Furthermore, our results suggested that epidural esketamine would cause dose-dependent mild dizziness especially at doses up to 1.0 mg/mL. As a single epidural additive, esketamine may not be suitable for labor analgesia. Future studies may investigate the appropriate dosage of esketamine at slightly higher concentrations of local anesthetics or larger initial volume of analgesia, or explore other potential advantages of esketamine. Clinical Trial Registration: (https://www.chictr.org.cn/bin/project/edit?pid=159764), identifier (ChiCTR2200057662).


Analysis of the relationships among perceived service encounter quality, service value, satisfaction and behavioral intention for physical therapy patients.
[Purpose] The purpose of this study was to investigate the relationships among perceived service encounter quality, service value, patient satisfaction, and behavioral intention in physical therapy patients. [Subjects and Methods] This study surveyed 335 patients who received physical therapy treatment at five medical institutions in Jeonju-si, Republic of Korea. This study conducted path analysis on the collected data using Smart PLS 2.0 M3. [Results] The analysis of this study showed that service encounter quality had significantly positive relationship with service value, patient satisfaction, and behavioral intention. Service value had significantly positive relationship with patient satisfaction and behavioral intention. Patient satisfaction had significantly positive relationship with behavioral intention. [Conclusion] Improving the perceived quality of service encounters for physical therapy patients increases service value and patient satisfaction, and positively influences behavioral intention.


The influence of immunosuppressive drugs on vascular endothelial growth factor production in relation to VEGF -1154 g and -2578 C genotypes.
The pathogenesis of many diseases is correlated to irregularity in vascular endothelial growth factor (VEGF) expression. RESULTS from several association studies show that variation in the level of VEGF expression is related to polymorphic sequences within the VEGF gene. Additionally, there are many studies showing that some gene polymorphisms significantly influence the pharmacokinetics of immunosuppressive drugs. The aim of this study was to determine the influence of immunosuppressive drugs on VEGF production in individuals with different VEGF genotypes. ARMS-PCR was used to genotype VEGF polymorphisms at positions -1154 and -2578 within the promoter of VEGF gene. A VEGF-specific ELISA was used to determine the influence of immunosuppressive drugs on VEGF production in PBMCs of individuals with different VEGF genotypes. Suppressive effect of mycophenolic acid was observed just in individuals with GG -1154/CC -2578, GG -1154/CA -2578 and GA -1154/CC -2578 haplotypes. Additionally, VEGF was significantly suppressed in all individuals after treatment with rapamycin except those who had AA -1154/CA -2578 and AA -1154/AA -2578 VEGF genotype combinations. RESULTS of a recent study revealed that MMF treatment might be effective in preventing chronic renal rejection only in recipients with IL-10 high producer genotype. Additionally result of another study showed that CYP3A5 genotype markedly influences the pharmacokinetics of rapamycin in kidney transplant recipients. Therefore with regard to our results, different suppressive effect of mycophenolic acid and rapamycin on VEGF production might also be dependent on VEGF genotype.


Filling Gaps and Setting Boundaries: Examining Utilization of Health and Social services at JeffHOPE Student Run Clinics.
The objective of this study was to describe the frequency that healthcare and social support services offered by JeffHOPE, a student run clinic for people experiencing homelessness in Philadelphia, PA, were utilized by patients. This study also aimed to investigate where patients would seek medical care on a given day had they not been able to access JeffHOPE. This study was conducted via mixed methods consisting of retrospective chart review of patient encounter records and a patient survey conducted weekly throughout 2019, both at a single clinic site, and retrospective chart review of January through March 2020 records at 5 clinic sites. This study found that the frequency of services utilized varied between clinic sites, and that Pharmacy and Procedure committees were the most utilized when examining the combined clinic data. Additionally, the survey found that JeffHOPE provided medical care to those that otherwise would not have sought it. Clinics also served as an alternative to accessing care for non-emergent issues in an Emergency Department (ED) for some patients, but for others it replaced seeing their primary care provider (PCP). This study confirmed that the services offered by JeffHOPE are well-utilized by patients experiencing homelessness in Philadelphia. It also revealed that while the organization's medical services filled care gaps and potentially decreased unnecessary ED visits, they were also sometimes accessed in lieu of a PCP visit. A focused effort on linkage to formal primary care services for all JeffHOPE patients and expanding collection of more granular data to all clinics represent important future endeavors for this student run organization.


Anxiety and knowledge of patients before being subjected to orthognathic surgery.
to verify the correlation between anxiety level and degree of knowledge in patients before they are subjected to orthognathic surgery. Descriptive cross-sectional study with 40 patients in the preoperative period before orthognathic surgery of a private clinic in the city of São Paulo. IDATE-trait anxiety levels feature prevalence of medium-level anxiety with 72.5% (n=29), followed by low-level anxiety with 72.5% (n=29) and high-level level anxiety with 10% (n=4). In the pre-operative period, transitory IDATE-state anxiety levels feature medium-level anxiety with 65% (n=26), followed by high-level anxiety with 22.5% (n=9) and low-level anxiety with 10% (n=4). Pearson's correlation coefficient resulted in negative r (-0.2) for anxiety-trait (p 0.197) and in negative r (-0.1) for anxiety-state (p 0.417). The data shows a weak correlation in which greater knowledge about the surgical procedure reduces levels of anxiety that may be related to the absence of appropriate guidance about the surgical procedure.


G.F.R. measuring with 99mTc-DTPA: limits in obstructive acute renal failure.
After a short introduction on the advantages and limits of G.F.R. determination with Ccr, the radioisotopic methods proposed by Schlegel and Gates for this parameter are described, and as well as ERPF and FF, without blood serial samples being necessary. In a severe renal failure case due to obstruction, the Authors have found a great mismatch in the results between the traditional methods and the radioisotopic ones. After the clinical case description, a possible explanation of this discrepancy is proposed: Schlegel and Gates' methods, which well correlate Ccr in chronic renal failure cases, in severe renal failure on obstructive basis, of recent onset, could not indicate the effective glomerular filtrate, but the nephronic mass, functionally blocked by the endocapsular hypertension secondary to the obstruction, but anatomically unaffected and so recoverable by a timely irradication of the obstruction.


Transition analysis: a validation study with known-age modern American skeletons.
Transition Analysis-a recent skeletal age-estimation procedure (Boldsen et al.: Paleodemography: age distributions from skeletal samples (2002) 73-106)-is evaluated using 252 known-age modern American males and females from the Bass Donated Collection and Mercyhurst forensic cases. The pubic symphysis worked best for estimating age, followed by the sacroiliac joint and cranial sutures. Estimates based on all skeletal characteristics are influenced by the choice of prior distribution, although its effect is dwarfed by both the inaccuracy and imprecision of age estimates. Age intervals are narrowest for young adults, but are surprisingly short in old age as well. When using an informative prior distribution, the greatest uncertainty occurs from the late 40s into the 70s. Transition Analysis estimates do not perform as well as experience-based assessments, indicating the existing procedure is too narrowly focused on commonly used pelvic and cranial structures.


MiR-489-3p Reduced Pancreatic Cancer Proliferation and Metastasis By Targeting PKM2 and LDHA Involving Glycolysis.
Malignant proliferation and metastasis are some of the causes of high mortality in pancreatic cancer. MicroRNAs have been a hot spot in cancer research and are involved in tumor formation and metabolic stress responses. However, the biology function and underlying mechanism of miRNA regulating pancreatic cancer progress is remained uncleared. RNA-seq analysis the glycolysis associated miRNAs and verified miRNA-489-3p was involving in glycolysis. We used RNA in situ hybridization (ISH) and qRT-PCR to analyze the differential expression of miR-489-3p in pancreatic cancer tissues and adjacent tissues and cell lines. Then the function assay of in vivo and in vitro were used to evaluated the role of miR-489-3p in the proliferation, metastasis and glucose metabolism of pancreatic cancer. Furthermore, dual luciferase reporter and rescue experiments were performed to explore the mechanism underlying in the role of miRNA-489-3p. We determined that glycolysis associated miRNA miR-489-3p was downregulated in pancreatic cancer tissues and cell lines. The gain and loos of function experiments confirmed that miR-489-3p could inhibit the proliferation, metastasis and glucose metabolism of pancreatic cancer. Further, we found that miR-489-3p could target regulating LDHA and PKM through the luciferase report experiment. Finally, in vivo experiment confirmed that highly expressed miR-489-3p inhibited the growth of pancreatic cancer. In short, this study identified miR-489-3p as a novel therapy target for pancreatic cancer which was involving in the proliferation, metastasis and glycolysis, but its diagnostic value deserves further study.


Exploring Internal Facilitators' Experience With NeoECHO to Foster NEC Prevention and Timely Recognition Through the iPARIHS Lens.
Necrotizing enterocolitis (NEC) remains a major complication in the neonatal population. Standard practices regarding the care of premature infants and attitudes toward NEC prevention strategies vary across neonatal intensive care units (NICUs). Evidence-based best practice dissemination was presented through the NEC-Zero bundle. To close gaps between evidence and practice, a telehealth-delivered intervention (ie, NeoECHO) was provided to NICUs. The purpose of this study was to enable adoption of best practice for NEC prevention using NeoECHO through describing the local volunteer unit leaders', or internal facilitators' (IFs'), experiences in participating in NeoECHO and identifying the extent to which the facilitation activities within the NeoECHO experience were consistent with constructs from the integrated Promoting Action on Research Implementation in Health Services (iPARHIS) framework. The design of this study was qualitative descriptive. Six IFs were recruited in the Southwest. After 6 NeoECHO sessions, individual interviews were conducted and transcribed verbatim. Content analysis was applied. Codes were informed by the iPARIHS framework. Major themes were (1) Innovation: Quality Improvement Projects, Bundles of Care, and Huddle; (2) Recipient: Reluctant Stakeholders and Technical Modalities; (3) Context: Buy-In, Timing, Resources, Leadership, and Blame; (4) Facilitation: Betterment, Buddy System, Passionate Care, and Empowerment; and (5) Adoption: Continuous Quality Improvement, Evidence-Based Practice, and Honest Discussions. NeoECHO fostered a learning community to share current practices, policies, and strategies for NEC prevention, but the IFs were essential to foster local participation. The long-term impacts of NeoECHO are the focus of current research.Video Abstract available athttps://journals.lww.com/advancesinneonatalcare/Pages/videogallery.aspx.


Effect of Nonionic Surfactant on Association/Dissociation Transition of DNA-Functionalized Colloids.
We report the effect of nonionic surfactants (Pluronics F127 and F88) on the melting transition of micron-sized colloids confined in two dimensions, mediated by complementary single-stranded DNA as a function of the surfactant concentration. Micron-sized silica particles were functionalized with single-stranded DNA using cyanuric chloride chemistry. The existence of covalently linked DNA on particles was confirmed by fluorescence spectroscopy. The nonionic surfactant not only plays a significant role in stabilization of particles, with minimization of nonspecific binding, but also impacts the melting temperature, which increases as a function of the nonionic surfactant concentration. These results suggest that the melting transition for DNA-mediated assembly is sensitive to commonly used additives in laboratory buffers, and that these common solution components may be exploited as a facile and independent handle for tuning the melting temperature and, thus, the assembly and possibly crystallization within these systems.


Indolealkylamines and prolactin secretion. A structure-activity study in the central nervous system of the rat.
The present study was performed to examine the central effects of the indolealkylamine hallucinogens, 5-methoxy-N,N-dimethyltryptamine (MDMT), bufotenin and N, N-dimethyltryptamine (DMT), infused intracerebroventricularly (i.c.v.) into the lateral ventricle. They were found to have a stimulatory effect upon the secretion of prolactin. Their order of potency was compared. From a structure-activity point of view, MDMT is the most potent, followed by bufotenin, and then by DMT. Bufotenin, which does not readily cross the blood-brain barrier, caused a prolonged effect on the elevation of prolactin, with a suggestion of a biphasic effect at the maximum dose (0.02 M). N,N-dimethyltryptamine showed a clear dose-response relationship in the stimulation of the release of prolactin. The present results confirm those of previous investigators, who have demonstrated that these drugs cause the release of prolactin, with a possible biphasic effect. The present results suggest that, the response which was obtained was centrally mediated, and probably did not involve stimulation of peripheral receptors and the time course of action of indoles is different when infused centrally, compared to their time course when infused peripherally.


Comparison of Two Ambient Beta Gauge PM10 Samplers.
This paper reports on the performance of the Kimoto 180 sampler and the Wedding ambient PM10 beta gauge sampler. Monodisperse ammonium fluorescein test particles were generated in the laboratory and used to determine the penetration curve of the Kimoto 180 cyclonic inlet. It was found that the actual DpaSOof the Kimoto 180 inlet, 3.5 (xm, is much lower than the designated standard value, 10 um. In the field test, the two beta gauge samplers were collocated with an Andersen SA1200 high-volume sampler to compare their measured daily average PM10 concentrations. The low Dpa50 of the Kimoto 180 inlet serves to explain why its daily average PM10 concentrations were much lower than the actual PM10 concentrations found in the field study. In addition, the PM10 concentrations of the Kimoto 180 beta gauge sampler were found to be seriously affected by the water vapor content of the ambient air. In contrast, the daily average PM10 concentrations of the Wedding beta gauge sampler were found to be more accurate, and influences by ambient conditions were insignificant.


Quality assessment of protein model-structures based on structural and functional similarities.
Experimental determination of protein 3D structures is expensive, time consuming and sometimes impossible. A gap between number of protein structures deposited in the World Wide Protein Data Bank and the number of sequenced proteins constantly broadens. Computational modeling is deemed to be one of the ways to deal with the problem. Although protein 3D structure prediction is a difficult task, many tools are available. These tools can model it from a sequence or partial structural information, e.g. contact maps. Consequently, biologists have the ability to generate automatically a putative 3D structure model of any protein. However, the main issue becomes evaluation of the model quality, which is one of the most important challenges of structural biology. GOBA--Gene Ontology-Based Assessment is a novel Protein Model Quality Assessment Program. It estimates the compatibility between a model-structure and its expected function. GOBA is based on the assumption that a high quality model is expected to be structurally similar to proteins functionally similar to the prediction target. Whereas DALI is used to measure structure similarity, protein functional similarity is quantified using standardized and hierarchical description of proteins provided by Gene Ontology combined with Wang's algorithm for calculating semantic similarity. Two approaches are proposed to express the quality of protein model-structures. One is a single model quality assessment method, the other is its modification, which provides a relative measure of model quality. Exhaustive evaluation is performed on data sets of model-structures submitted to the CASP8 and CASP9 contests. The validation shows that the method is able to discriminate between good and bad model-structures. The best of tested GOBA scores achieved 0.74 and 0.8 as a mean Pearson correlation to the observed quality of models in our CASP8 and CASP9-based validation sets. GOBA also obtained the best result for two targets of CASP8, and one of CASP9, compared to the contest participants. Consequently, GOBA offers a novel single model quality assessment program that addresses the practical needs of biologists. In conjunction with other Model Quality Assessment Programs (MQAPs), it would prove useful for the evaluation of single protein models.


Utilization of formal and informal home care by AIDS patients in Boston: a comparison of intravenous drug users and homosexual males.
The assumption that intravenous (i.v.) drug users have weaker informal support networks than homosexual men has led to opposing policy recommendations: one emphasizes outreach and more formal (paid) home care for i.v. drug users, whereas the other maintains that formal home care programs are less effective for this risk group due to the lack of informal (unpaid) caregivers to coordinate efforts. Data from interviews with a sample of 231 persons with AIDS in the Boston area were used to compare the use of formal and informal home care between the two largest risk groups, homosexual men and i.v. drug users. Multivariate regression analysis was also employed to adjust estimates and to determine the significance of population characteristics in explaining utilization differences. IV drug users received about twice as much formal and informal home care as homosexual men. Controlling for functional status, income and assets, insurance and potential caregiver supply, i.v. drug users obtained significantly fewer formal home care services, but more informal care. Overall, i.v. drug users received a greater number of adjusted home care hours. These findings cast doubt upon the previous assumptions of the literature and suggest that members of both risk groups are appropriate candidates for formal home care services.


Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting.
A 12-year-old boy with Wilson's disease developed exertional dyspnea, cyanosis, and finger clubbing 10 months after diagnosis. The hypoxemia was caused by arteriovenous shunting, demonstrated by radionuclide scanning and pulmonary arteriography. Orthotopic liver transplantation was performed after the development of severe hypoxemia. There was no apparent reversal of the intrapulmonary arteriovenous shunting and he died 10 days posttransplantation of multiple organ failure secondary to hypoxemia. Monitoring arterial oxygen saturation in children with cirrhosis is warranted since the presence of significant arteriovenous shunting may influence prognosis and decisions regarding liver transplantation.


Low-temperature derivatization followed by vortex-assisted liquid-liquid microextraction for the analysis of polyamines in Nicotiana Tabacum.
Polyamines are ubiquitous polycationic molecules that play a key role in many biological processes such as nucleic acid metabolism, protein synthesis, cell growth, and nicotine synthesis precursors. This work describes a rapid, sensitive, convenient, green, and cost-effective method for the determination of polyamines in Nicotiana tabacum by ultra high performance liquid chromatography with photodiode array detection. The analytes were derivatized with 3,5-dinitrobenzoyl chloride at low temperature (about 4°C) and then extracted with vortex-assisted liquid-liquid microextraction. The experimental designs based on quarter-fractional factorial design and Doehlert design were used to screen and optimize the important factors in microextraction process. Under the optimal conditions, the method was linear over 0.05-8.00 μg/mL with an r(2) ≥ 0.992 and exhibited good repeatability and reproducibility less than 6.0 and 6.9%, respectively. The limit of detection ranged between 0.013 and 0.029 μg/g. The newly developed method was successfully employed to analyze different leaf samples of Nicotiana tabacum, among which the polyamines contents were found to be very different. Moreover, tyramine, 1,3-diaminopropane, homospermidine, and canavalmine were tentatively identified with the electrospray ionization quadrupole time-of-flight mass spectrometry. To our knowledge, this is the first report of identification of canavalmine in Nicotiana Tabacum.


Demographics, Management Strategies, and Problems in ST-Elevation Myocardial Infarction from the Standpoint of Emergency Medicine Specialists: A Survey-Based Study from Seven Geographical Regions of Turkey.
This study aimed to explore the ST segment elevation myocardial infarction (STEMI) management practices of emergency medicine specialists working in various healthcare institutions of seven different geographical regions of Turkey, and to examine the characteristics of STEMI presentation and patient admissions in these regions. We included 225 emergency medicine specialists working in all geographical regions of Turkey. We e-mailed them a 20-item questionnaire comprising questions related to their STEMI management practices and characteristics of STEMI presentation and patient admissions. The regions were not significantly different with respect to primary percutaneous coronary intervention (PCI) resources (p = 0.286). Sixty six point two percent (66.2%) of emergency specialists stated that patients presented to emergency within 2 hours of symptom onset. Forty three point six percent (43.6%) of them contacted cardiology department within 10 minutes and 47.1% within 30 minutes. In addition, 68.3% of the participants improved themselves through various educational activities. The Southeastern Anatolian region had the longest time from symptom onset to emergency department admission and the least favorable hospital admission properties, not originating from physicians or 112 emergency healthcare services. Seventy point seven percent (70.7%) of the emergency specialists working in all geographical regions of Turkey comply with the latest guidelines and current knowledge about STEMI care; they also try to improve themselves, and receive adequate support from 112 emergency healthcare services and cardiologists. While inter-regional gaps between the number of primary PCI capable centers and quality of STEMI care progressively narrow, there are still issues to address, such as delayed patient presentation after symptoms onset and difficulties in patient admission.


The epidemiology of bacterial zoonoses in pastoral and dairy cattle in Cameroon, Central Africa.
Previous work identified that bacterial zoonoses (Brucella species, Coxiella burnetii and Leptospira hardjo) were present in Cameroonian pastoral cattle. To assess the characteristics of this zoonotic risk, we analyse seroprevalence of each pathogen and the associated management, herd and environmental factors in Cameroonian pastoral and dairy cattle. Cross-sectional samples included pastoralist herds in the Northwest Region (NWR n = 750) and Vina Division (VD n = 748) and small holder dairy herds in the NWR (n = 60). Exposure to Brucella spp., C. burnetii and L. hardjo were screened for using commercial ELISAs and population adjusted estimates made. In addition, individual, herd and ecological metadata were collected and used to identify risk factors associated with animal-level seropositivity. In the pastoral cattle, seroprevalence to Brucella spp. was relatively low but was higher in the NWR (4.2%, CI: 2.5%-7.0%) than the VD (1.1%: CI 0.5%-2.4%), while L. hardjo seroprevalence was much higher though similar in the NWR (30.7%, CI 26.3%-35.5%) and VD (35.9%, CI 31.3%-40.7%). No differences were noted in C. burnetii seroprevalence between the two study sites (NWR: 14.6%, CI 11.8%-18.0%. VD: 12.4%, 9.6%-15.9%). Compared to pastoral, dairy cattle had lower seroprevalences for L. hardjo (1.7%, CI: 0.0%-4.9%), C. burnetii (0.0%, CI 0.0%-6.0%) but similar for Brucella spp. (5.0%, CI 0.0%-10.6%). Increased odds of Brucella spp. seropositivity were associated with owning sheep or rearing sheep and fencing cattle in at night. Adult cattle had increased odds of being seropositive for both C. burnetii and L. hardjo. Additionally, exposure to C. burnetii was associated with local ecological conditions and L. hardjo was negatively associated with cattle undertaking transhumance. This work highlights that exposure to these 3 important production diseases and occupational zoonoses are widespread in Cameroonian cattle. Further work is required to understand transmission dynamics between humans and livestock to inform implementation of effective control measures.


A special, supplemented 'vegan' diet for nephrotic patients.
High dietary protein intake, in the past recommended for nephrotic syndrome, does not improve hypoproteinemia and may accelerate progressive renal damage. In contrast, low-protein diets reduce proteinuria and preserve renal function in experimental renal models of nephrotic syndrome. In this study, 20 steroid-resistant, nephrotic patients were treated with a pure vegetarian, low-protein diet, supplemented with essential amino acids and ketoanalogues (supplemented vegan diet, SVD) for 4.6 +/- 3.1 months. Before the study, these patients followed an unrestricted protein, low-sodium diet (LSD). Proteinuria, daily urea nitrogen excretion and creatinine clearance decreased significantly on SVD. A similar lowering effect of SVD was observed on serum total cholesterol. Seven of the 20 patients changed from LSD to SVD and vice-versa on 3 occasions, and in all cases, we found an increase of proteinuria during the LSD period. Serum albumin, HDL cholesterol, triglycerides and anthropometric measurements did not change on SVD. Our data suggest that SVD exerts a favorable effect on proteinuria and hypercholesterolemia in nephrotic patients, without inducing clinical or laboratory signs of malnutrition.


Engineered drug resistant γδ T cells kill glioblastoma cell lines during a chemotherapy challenge: a strategy for combining chemo- and immunotherapy.
Classical approaches to immunotherapy that show promise in some malignancies have generally been disappointing when applied to high-grade brain tumors such as glioblastoma multiforme (GBM). We recently showed that ex vivo expanded/activated γδ T cells recognize NKG2D ligands expressed on malignant glioma and are cytotoxic to glioma cell lines and primary GBM explants. In addition, γδ T cells extend survival and slow tumor progression when administered to immunodeficient mice with intracranial human glioma xenografts. We now show that temozolomide (TMZ), a principal chemotherapeutic agent used to treat GBM, increases the expression of stress-associated NKG2D ligands on TMZ-resistant glioma cells, potentially rendering them vulnerable to γδ T cell recognition and lysis. TMZ is also highly toxic to γδ T cells, however, and to overcome this cytotoxic effect γδ T cells were genetically modified using a lentiviral vector encoding the DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) from the O(6)-methylguanine methyltransferase (MGMT) cDNA, which confers resistance to TMZ. Genetic modification of γδ T cells did not alter their phenotype or their cytotoxicity against GBM target cells. Importantly, gene modified γδ T cells showed greater cytotoxicity to two TMZ resistant GBM cell lines, U373(TMZ-R) and SNB-19(TMZ-R) cells, in the presence of TMZ than unmodified cells, suggesting that TMZ exposed more receptors for γδ T cell-targeted lysis. Therefore, TMZ resistant γδ T cells can be generated without impairing their anti-tumor functions in the presence of high concentrations of TMZ. These results provide a mechanistic basis for combining chemotherapy and γδ T cell-based drug resistant cellular immunotherapy to treat GBM.


Culture media-based selection of endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes from the young mouse vestibular system.
The vestibular blood-labyrinth barrier (BLB) is comprised of perivascular-resident macrophage-like melanocytes (PVM/Ms) and pericytes (PCs), in addition to endothelial cells (ECs) and basement membrane (BM), and bears strong resemblance to the cochlear BLB in the stria vascularis. Over the past few decades, in vitro cell-based models have been widely used in blood-brain barrier (BBB) and blood-retina barrier (BRB) research, and have proved to be powerful tools for studying cell-cell interactions in their respective organs. Study of both the vestibular and strial BLB has been limited by the unavailability of primary culture cells from these barriers. To better understand how barrier component cells interact in the vestibular system to control BLB function, we developed a novel culture medium-based method for obtaining EC, PC, and PVM/M primary cells from tiny explants of the semicircular canal, sacculus, utriculus, and ampullae tissue of young mouse ears at post-natal age 8-12 d. Each phenotype is grown in a specific culture medium which selectively supports the phenotype in a mixed population of vestibular cell types. The unwanted phenotypes do not survive passaging. The protocol does not require additional equipment or special enzyme treatment. The harvesting process takes less than 2 h. Primary cell types are generated within 7-10 d. The primary culture ECs, PCs, and PVM/M shave consistent phenotypes more than 90% pure after two passages (∼ 3 weeks). The highly purified primary cell lines can be used for studying cell-cell interactions, barrier permeability, and angiogenesis.


Cognitive and sensory declines in old age: gauging the evidence for a common cause.
Resource accounts of behavioral aging postulate that age-associated impairments within and across intellectual and sensory domains reflect, in part, a common set of senescent alterations in the neurochemistry and neuroanatomy of the aging brain. Hence, these accounts predict sizeable correlations of between-person differences in rates of decline, both within and across intellectual and sensory domains. The authors examined reliability-adjusted variances and covariances in longitudinal change for 8 cognitive measures and for close visual acuity, distant visual acuity, and hearing in 516 participants in the Berlin Aging Study (ages 70 to 103 years at 1st measurement). Up to 6 longitudinal measurements were distributed over up to 13 years. Individual differences in rates of cognitive decline were highly correlated, with a single factor accounting for 60% of the variance in cognitive change. This amount increased to 65% when controlling for age at first measurement, distance to death, and risk of dementia. Contrary to expectations, the correlations between cognitive and sensory declines were only moderate in size, underscoring the need to delineate both domain-general and function-specific mechanisms of behavioral senescence.


Oncogenic K-Ras and basic fibroblast growth factor prevent Fas-mediated apoptosis in fibroblasts through activation of mitogen-activated protein kinase.
By an expression cloning method using Fas-transgenic Balb3T3 cells, we tried to obtain inhibitory genes against Fas-mediated apoptosis and identified proto-oncogene c-K-ras. Transient expression of K-Ras mutants revealed that oncogenic mutant K-Ras (RasV12) strongly inhibited, whereas dominant-inhibitory mutant K-Ras (RasN17) enhanced, Fas-mediated apoptosis by inhibiting Fas-triggered activation of caspases without affecting an expression level of Fas. Among the target molecules of Ras, including Raf (mitogen-activated protein kinase kinase kinase [MAPKKK]), phosphatidylinositol 3 (PI-3) kinase, and Ral guanine nucleotide exchange factor (RalGDS), only the constitutively active form of Raf (Raf-CAAX) could inhibit Fas-mediated apoptosis. In addition, the constitutively active form of MAPKK (SDSE-MAPKK) suppressed Fas-mediated apoptosis, and MKP-1, a phosphatase specific for classical MAPK, canceled the protective activity of oncogenic K-Ras (K-RasV12), Raf-CAAX, and SDSE-MAPKK. Furthermore, physiological activation of Ras by basic fibroblast growth factor (bFGF) protected Fas-transgenic Balb3T3 cells from Fas-mediated apoptosis. bFGF protection was also dependent on the activation of the MAPK pathway through Ras. All the results indicate that the activation of MAPK through Ras inhibits Fas-mediated apoptosis in Balb3T3 cells, which may play a role in oncogenesis.


Polyamine metabolism and tumorigenesis in the Apc(Min/+) mouse.
While polyamine homoeostasis is clearly important in maintenance of normal cell function, the roles of these cations, as well as the enzymes that regulate their metabolism, in the neoplastic process are not clear. In particular, the polyamine catabolic enzyme SSAT (spermidine/spermine N(1)-acetyltransferase) seems to have different roles in tumorigenesis, depending upon the particular system being analysed. In attempts to clarify the function of SSAT in tumour development, we have utilized the Apc(Min/+) mouse, which carries a mutant allele of the Apc (adenomatous polyposis coli) gene, rendering it susceptible to the formation of multiple adenomas in the small intestine and colon. Using genetically engineered animals (i.e. transgenic and knockout mice), we have shown that SSAT acts as a tumour promoter in the Apc(Min/+) model. Modulation of tumorigenesis is not associated with changes in tissue levels of either spermidine or spermine. These findings, along with those made in other animal models of cancer, have prompted us to propose that metabolic flux through the polyamine biosynthetic and catabolic pathways, and the consequent changes in levels of various metabolites within the cell (i.e. the metabolome), is critical to tumour development. The metabolic flux model represents a novel way of thinking about the role of polyamines in cell physiology and the neoplastic process.


Identifying target sites for cooperatively binding factors.
Transcriptional activation in eukaryotic organisms normally requires combinatorial interactions of multiple transcription factors. Though several methods exist for identification of individual protein binding site patterns in DNA sequences, there are few methods for discovery of binding site patterns for cooperatively acting factors. Here we present an algorithm, Co-Bind (for COperative BINDing), for discovering DNA target sites for cooperatively acting transcription factors. The method utilizes a Gibbs sampling strategy to model the cooperativity between two transcription factors and defines position weight matrices for the binding sites. Sequences from both the training set and the entire genome are taken into account, in order to discriminate against commonly occurring patterns in the genome, and produce patterns which are significant only in the training set. We have tested Co-Bind on semi-synthetic and real data sets to show it can efficiently identify DNA target site patterns for cooperatively binding transcription factors. In cases where binding site patterns are weak and cannot be identified by other available methods, Co-Bind, by virtue of modeling the cooperativity between factors, can identify those sites efficiently. Though developed to model protein-DNA interactions, the scope of Co-Bind may be extended to combinatorial, sequence specific, interactions in other macromolecules. The program is available upon request from the authors or may be downloaded from http://ural.wustl.edu.


Endoscopic Ultrasound-guided Pancreatic Pseudocyst Drainage with Lumen-apposing Metal Stents or Plastic Double-pigtail Stents: A Multifactorial Analysis.
To compare the efficiency of plastic and metal stents for symptomatic pancreatic pseudocyst (PP) drainage and analyze other main associated factors that affect the outcome of drainage therapy. Rates of technical and clinical success, procedure-related side effects (hemorrhage, stent migration, and cyst rupture), reinterventions, and duration of hospital stay. There were 52 patients, 40 patients underwent plastic stent placement and 12 patients underwent lumen-apposing metal stent (LAMS) placement. The total rate of technical success was 100%. The total rate of clinical success was 100%. The total rate of adverse events was 7.7% (4/52). On multiple logistic regression analysis, the use of plastic stents (P < 0.05, Exp B = 12.168) and the presence of a large cyst (P < 0.05, Exp B = 1.036) were shown to significantly increase the risk of reintervention. On multivariate linear regression analysis, etiology of pseudocyst (P < 0.05, B = -8.427, -9.785, -5.514) was associated with prolonged hospital stent, while stent type was not shown be a factor (P > 0.05). Both plastic and LAMSs are proven to be highly efficient in PP drainage. The LAMS is superior in preventing complications such as migration and cyst leakage and reducing the rate of reintervention.


Case report: Successful labour epidural analgesia in a patient with spinocerebellar ataxia.
To report the favourable outcome associated with epidural analgesia in a parturient with spinocerebellar ataxia (SCA). A 34-yr-old patient, G2 P0, presented at term with a history of SCA since the age of 22 characterized by slurred speech, balance and gait disturbances, diplopia and nystagmus. A magnetic resonance imaging of the brain at the age of 27 showed cerebellar degeneration. Neurological examination revealed an unsteady, wide-based gait, nystagmus, mild dysarthria, moderate finger to nose ataxia, absent reflexes in all upper and lower limbs, sensory loss to vibration and temperature discrimination up to the level of both knees, and normal motor strength. The patient presented for induction of labour at 40 weeks and requested epidural analgesia, which was performed in the usual manner. Following a negative test dose of 3 mL of 2% lidocaine, a loading dose of 10 mL of 0.125% bupivacaine was administered, and maintenance of analgesia was achieved with a mixture of bupivacaine 0.0625% and fentanyl 2 microg.mL(-1). The patient required standard doses of the epidural mixture, and experienced effective analgesia for labour and delivery. Her recovery was uneventful and no subsequent neurological deficit was detected up to two years after delivery. Neurological disorders may contraindicate regional anesthesia, and the decision to proceed with a regional technique should be based on the pathophysiology and severity of each particular case. Uneventful epidural analgesia was provided to a parturient with SCA, with no long term effects detected up to two years after delivery.


The cell adhesion molecule l1 is required for chain migration of neural crest cells in the developing mouse gut.
During development, the enteric nervous system is derived from neural crest cells that emigrate from the hindbrain, enter the foregut, and colonize the gut. Defects in neural crest migration can result in intestinal aganglionosis. Hirschsprung's disease (congenital aganglionosis) is a human condition in which enteric neurons are absent from the distal bowel. A number of clinical studies have implicated the cell adhesion molecule L1 in Hirschsprung's disease. We examined the role of L1 in the migration of neural crest cells through the developing mouse gut. A variety of in vitro and in vivo assays were used to examine: (1) the effect of L1 blocking antibodies or exogenous soluble L1 protein known to compromise L1 function on the rate of crest cell migration, (2) the effect of blocking L1 activity on the dynamic behavior of crest cells using time-lapse microscopy, and (3) whether the colonization of the gut by crest cells in L1-deficient mice differs from control mice. We show that L1 is expressed by neural crest cells as they colonize the gut. Perturbation studies show that disrupting L1 activity retards neural crest migration and increases the number of solitary neural crest cells. L1-deficient mice show a small but significant reduction in neural crest cell migration at early developmental stages, but the entire gastrointestinal tract is colonized. L1 is important for the migration of neural crest cells through the developing gut and is likely to be involved in the etiology of Hirschsprung's disease.


The rights of a Florida wife: slavery, U.S. expansion, and married women's property law.
Civil law rules were adopted in Florida that granted married women property rights long before legal reforms occurred in northern states. This article analyzes white wives' property and law in Florida between 1820 and 1860. Initially, married women's property rights were inadvertently protected by treaty law and limited to women who married before 1818. Wives' right to own separate property in Florida was subsequently reconfirmed in statute and extended to include later marriages. In contrast, nonwhites generally lost the rights and property they had enjoyed under Spain's civil law in the same period. This contrast reveals that in Florida (and other southern borderlands) it was not concern for women, or simply legal precedent, but the desire to incorporate new territory and expand slavery that influenced the development of marital property law. This challenges previous histories, which have excluded the earlier acts in the Southern borderlands and emphasized those passed in the Northeast beginning in the late 1840s. While those later acts were influenced by the early woman's rights movement and by concern for families reduced to poverty during the rise of market capitalism, this case study indicates that expansion of United States territory and slavery were responsible for the earlier married women's property rights in southern borderland territories such as Florida.


COVID-19 in the Clinic: Trial of an Aerosol Containment Mask for Endoscopic Clinic Procedures.
Create an aerosol containment mask (ACM) for common otolaryngologic endoscopic procedures which also provides nanoparticle-level protection to patients. Prospective feasibility study. In-person testing with a novel ACM. The mask was designed in Solidworks and 3-dimensional printed. Measurements were made on 100 consecutive clinic patients who underwent medically necessarily endoscopy, 50 rigid nasal and 50 flexible, by 9 surgeons. Of the 50 patients who underwent rigid nasal endoscopy with the ACM, 0 of 25 patients with the suction off and 0 of 25 patients with the suction on had evidence of leakage of 0.3 μm particles. Of the 50 patients who underwent flexible endoscopy with the ACM, 0 of 25 patients with the suction off and 0 of 25 patients with the suction on had evidence of leakage of 0.3 μm particles. In terms of comfort, 73% of patients found the ACM somewhat or very comfortable without suction, compared to 86% with the suction on. Surgeons were able to visualize all necessary anatomic areas in 98% of procedures. In 97% of procedures, the masks were able to be placed easily. ACM can accommodate rigid nasal and flexible endoscopes and may prevent leakage of patient-generated aerosols, thus avoiding contamination of the room and protecting health care workers from airborne contagions. The level of evidence is 2.


The Effects of Topographic Micropatterning on Endothelial Colony-Forming Cells.
Artificial small-diameter vascular grafts remain an unmet need in modern medicine, due to the thrombosis and neointimal hyperplasia that plague currently available synthetic devices. Tissue engineering techniques, including in vitro endothelialization, could offer a solution to this problem. A potential minimally invasive source of patient autologous endothelium is endothelial colony-forming cells (ECFCs), endothelial-like outgrowth products of circulating progenitors. While ECFCs respond to shear stress similar to mature endothelial cells (ECs), their response to luminal topographic micropatterning (TMP), a biomaterial modification with the potential to flow-independently, enhance the attachment, migration, gene expression, and function of mature ECs, remains unstudied. In this study, case-matched carotid endothelial cells (CaECs) and blood-derived ECFCs are statically cultured on polyurethane substrates with micropatterned pitches (pitch = peak to peak distance) ranging from 3-to 14 μm. On all pattern pitches tested, both CaECs and ECFCs showed significant and robust alignment to the angle of the micropatterns. Using a novel cell-by-cell image analysis technique, it was found that actin fibers similarly and significantly aligned to the angle of micropatterned features on all pitches tested. Microtubules analyzed through the same novel approach showed significant alignment on most pitches examined, with a greater variation in fiber angle overall. Interestingly, only CaECs showed significant cellular elongation, and notably to a lower degree than previously seen either in vivo due to flow or in vitro due to spatial growth restriction micropatterning, but consistent with earlier studies of TMP. Neither cell type displayed any significant micropattern-driven changes in the expression of KLF-2 or the downstream adhesion molecules it regulates. These results demonstrate that TMP flow-independently affects ECFC morphology, but that alignment alone is insufficient to drive protective changes in EC and ECFC function.


Enteric Virome Sensing-Its Role in Intestinal Homeostasis and Immunity.
Pattern recognition receptors (PRRs) sensing commensal microorganisms in the intestine induce tightly controlled tonic signaling in the intestinal mucosa, which is required to maintain intestinal barrier integrity and immune homeostasis. At the same time, PRR signaling pathways rapidly trigger the innate immune defense against invasive pathogens in the intestine. Intestinal epithelial cells and mononuclear phagocytes in the intestine and the gut-associated lymphoid tissues are critically involved in sensing components of the microbiome and regulating immune responses in the intestine to sustain immune tolerance against harmless antigens and to prevent inflammation. These processes have been mostly investigated in the context of the bacterial components of the microbiome so far. The impact of viruses residing in the intestine and the virus sensors, which are activated by these enteric viruses, on intestinal homeostasis and inflammation is just beginning to be unraveled. In this review, we will summarize recent findings indicating an important role of the enteric virome for intestinal homeostasis as well as pathology when the immune system fails to control the enteric virome. We will provide an overview of the virus sensors and signaling pathways, operative in the intestine and the mononuclear phagocyte subsets, which can sense viruses and shape the intestinal immune response. We will discuss how these might interact with resident enteric viruses directly or in context with the bacterial microbiome to affect intestinal homeostasis.


Activation of MAPKs in human bronchial epithelial cells exposed to metals.
We have previously shown that in vitro exposure to metallic compounds enhances expression of interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha in human bronchial epithelial cells. To characterize signaling pathways involved in metal-induced expression of inflammatory mediators and to identify metals that activate them, we studied the effects of As, Cr, Cu, Fe, Ni, V, and Zn on the mitogen-activated protein kinases (MAPK) extracellular receptor kinase (ERK), c-Jun NH2-terminal kinase (JNK), and P38 in BEAS cells. Noncytotoxic concentrations of As, V, and Zn induced a rapid phosphorylation of MAPK in BEAS cells. Activity assays confirmed marked activation of ERK, JNK, and P38 in BEAS cells exposed to As, V, and Zn. Cr and Cu exposure resulted in a relatively small activation of MAPK, whereas Fe and Ni did not activate MAPK under these conditions. Similarly, the transcription factors c-Jun and ATF-2, substrates of JNK and P38, respectively, were markedly phosphorylated in BEAS cells treated with As, Cr, Cu, V, and Zn. The same acute exposure to As, V, or Zn that activated MAPK was sufficient to induce a subsequent increase in IL-8 protein expression in BEAS cells. These data suggest that MAPK may mediate metal-induced expression of inflammatory proteins in human bronchial epithelial cells.


Post-transcriptional regulation of chloramphenicol acetyl transferase.
The +1 site for initiation of inducible chloramphenicol acetyl transferase (CAT) messenger ribonucleic acid (mRNA) encoded by plasmid pC194 was determined experimentally using gamma-32P-ATP-labeled run-off transcripts partially digested with T1 ribonuclease. By partial digestion of the in vitro transcripts with S1-, T1-, and cobra venom nucleases as probes of mRNA conformation, single- and double-stranded regions, respectively, were also identified. Thus, a prominent inverted complementary repeat sequence was demonstrated spanning the +14 to +50 positions which contain the complementary sequences CCUCC, and GGAGG (the Shine and Dalgarno sequence for synthesis of CAT) symmetrically apposed and paired as part of a perfect 12 bp inverted complementary repeat sequence (-19.5 kcal/mol). The CAT mRNA was stable to digestion by T1 ribonuclease at the 4 guanosine residues in the Shine and Dalgarno sequence GGAGG, even at 60 degrees C, suggesting that nascent CAT mRNA allows ribosomes to initiate protein synthesis inefficiently and that induction involves post-transcriptional unmasking of the Shine and Dalgarno sequence. Consistent with this model of regulation, we found that cells carrying pC194, induced with chloramphenicol (CAM), contain about the same concentration of pulse labeled CAT-specific RNA as do uninduced cells. Induction of CAT synthesis by the nonacetylatable CAM analog fluorothiamphenicol was tested using minicells of Bacillus subtilis carrying pC194 as well as minicells containing the cloned pC194 derivatives in which parts of the CAT structural gene were deleted in vitro using Ba131 exonuclease. Optimal induction of both full-length (active) and deleted (inactive) CAT required similar concentrations of fluorothiamphenicol, whereas induction by CAM required a higher concentration for the wild-type full-length (active) CAT than for the (inactive) deleted CAT. Because synthesis of deleted CAT was inducible, we infer that CAT plays no direct role in regulating its own synthesis.


Prediction and expression analysis of G protein-coupled receptors in the laboratory stick insect, Carausius morosus.
G protein-coupled receptors (GPCRs) are 7-transmembrane proteins that transduce various extracellular signals into intracellular pathways. They are the major target of neuropeptides, which regulate the development, feeding behavior, mating behavior, circadian rhythm, and many other physiological functions of insects. In the present study, we performed RNA sequencing and de novo transcriptome assembly to uncover the GPCRs expressed in the stick insect Carausius morosus. The transcript assemblies were predicted for the presence of 7-transmembrane GPCR domains. As a result, 430 putative GPCR transcripts were obtained and 43 of these revealed full-length sequences with highly significant similarity to known GPCR sequences in the databases. Thirteen different GPCRs were chosen for tissue expression analysis. Some of these receptors, such as calcitonin, inotocin, and tyramine receptors, showed specific expression in some of the tissues. Additionally, GPCR prediction yielded a novel uncharacterized GPCR sequence, which was specifically expressed in the central nervous system and ganglia. Previously, the only information about the anatomy of the stick insect was on its gastrointestinal system. This study provides complete anatomical information about the adult insect.


Nox1 redox signaling mediates oncogenic Ras-induced disruption of stress fibers and focal adhesions by down-regulating Rho.
Generation of reactive oxygen species (ROS) by Ras oncogene-induced NADPH oxidase (Nox) 1 is required for Ras transformation phenotypes including anchorage-independent growth, morphological transformation, and tumorigenesity, but the signaling mechanism downstream of Nox1 remains elusive. Rho is known to be a critical regulator of actin stress fiber formation. Nonetheless, Rho was reported to no longer couple to loss of actin stress fibers in Ras-transformed Swiss3T3 cells despite the elevation of Rho activity. In this study, however, we demonstrate that Rho is inactivated in K-Ras-transformed normal rat kidney cells, and that abrogation of Nox1-generated ROS by Nox1 small interference RNAs or diphenyleneiodonium restores Rho activation, suggesting that Nox1-generated oxidants mediate down-regulation of the Rho activity. This down-regulation involves oxidative inactivation of the low molecular weight protein-tyrosine phosphatase by Nox1-generated ROS and a subsequent elevation in the tyrosine-phosphorylated active form of p190RhoGAP, the direct target of the phosphatase. Furthermore, the decreased Rho activity leads to disruption of both actin stress fibers and focal adhesions in Ras-transformed cells. As for Rac1, Rac1 also appears to participate in the down-regulation of Rho via Nox1. Our discovery defines a mediating role of Nox1-redox signaling for Ras oncogene-induced actin cytoskeletal changes.


Relevance of PD-L1 Non-Coding Polymorphisms on the Prognosis of a Genetically Admixed NSCLC Cohort.
Although non-small cell lung cancer (NSCLC) remains a deadly disease, new predictive biomarkers have emerged to assist in managing the disease, of which one of the most promising is the programmed death-ligand 1 (PD-L1). Each, PD-L1 variant seem to modulate the function of immune checkpoints differently and affect response to adjuvant treatment and outcome in NSCLC patients. We thus investigated the influence of these PD-L1 genetic variations in genetically admixed NSCLC tissue samples, and correlated these values with clinicopathological characteristics, including prognosis. We evaluated PD-L1 non-coding genetic variants and protein expression in lung adenocarcinomas (ADC), squamous cell carcinomas (SqCC), and large cell carcinomas (LCC) in silico. Microarray paraffin blocks from 70 samples of ADC (N=33), SqCC (N=24), and LCC (N=13) were used to create PD-L1 multiplex immunofluorescence assays with a Cell Signaling E1L3N clone. Fifteen polymorphisms of the PD-L1 gene were investigated by targeted sequencing and evaluated in silico using dedicated tools. Although PD-L1 polymorphisms seemed not to interfere with protein expression, PD-L1 expression varied among different histological subtypes, as did clinical outcomes, with the rs4742098A>G, rs4143815G>C, and rs7041009G>A variants being associated with relapse (P=0.01; P=0.05; P=0.02, respectively). The rs7041009 GG genotype showed a significant correlation with younger and alive patients compared to carriers of the A allele (P=0.02 and P<0.01, respectively). The Cox regression model showed that the rs7041009 GG genotype may influence OS (P<0.01) as a co-dependent factor associated with radiotherapy and recurrence in NSCLC patients. Furthermore, the Kaplan-Meier survival curves showed that rs7041009 and rs4742098 might impact PPS in relapsed patients. In silico approaches identified the variants as benign. PD-L1 non-coding variants play an important role in modulating immune checkpoint function and may be explored as immunotherapy biomarkers. We highlight the rs7041009 variant, which impacts OS and PPS in NSCLC patients.


Application of molecular techniques to identification of three plusiine species, Autographa nigrisigna, Macdunnoughia confusa, and Thysanoplusia intermixta (Lepidoptera: Noctuidae), found in integrated pest management lettuce fields in Japan.
Three plusiine species, Autographa nigrisigna, Macdunnoughia confusa, and Thysanoplusia intermixta (Lepidoptera: Noctuidae), are commonly found together in lettuce, Lactuca sativa L., fields in Japan. Given the marked morphological similarities between these species and the difficulty associated with discriminating between them using only visual cues, we used multiplex polymerase chain reaction (PCR) assay to distinguish between the three target species. Multiplex PCR uses four primers to simultaneously amplify a specific region of the mitochondrial DNA and produce species-specific banding patterns. The stringency of the method was tested using specimens of different sex, location, and developmental stage, and consistent results were obtained for all samples. Indeed, our method has the potential to clarify the species structure of plusiine species in lettuce fields.


Contextual incongruency triggers memory reinstatement and the disruption of neural stability.
Schemas, or internal representation models of the environment, are thought to be central in organising our everyday life behaviour by giving stability and predictiveness to the structure of the world. However, when an element from an unfolding event mismatches the schema-derived expectations, the coherent narrative is interrupted and an update to the current event model representation is required. Here, we asked whether the perceived incongruence of an item from an unfolding event and its impact on memory relied on the disruption of neural stability patterns preceded by the neural reactivation of the memory representations of the just-encoded event. Our study includes data from two different experiments whereby human participants (N = 33, 26 females and N = 18, 16 females, respectively) encoded images of objects preceded by trial-unique sequences of events depicting daily routine. We found that neural stability patterns gradually increased throughout the ongoing exposure to a schema-consistent episode, which was corroborated by the re-analysis of data from two other experiments, and that the brain stability pattern was interrupted when the encoding of an object of the event was incongruent with the ongoing schema. We found that the decrease in neural stability for low-congruence items was seen at ∼1000 ms from object encoding onset and that it was preceded by an enhanced N400 ERP and an increased degree of neural reactivation of the just-encoded episode. Current results offer new insights into the neural mechanisms and their temporal orchestration that are engaged during online encoding of schema-consistent episodic narratives and the detection of incongruencies.


Quantitative Comparison of Pyranose Dehydrogenase Action on Diverse Xylooligosaccharides.
Pyranose dehydrogenases (PDHs; EC 184.108.40.206; AA3_2) demonstrate ability to oxidize diverse carbohydrates. Previous studies of these enzymes have also uncovered substrate-dependent regioselectivity, along with potential to introduce more than one carbonyl into carbohydrate substrates. Enzymatic oxidation of carbohydrates facilitates their further derivatization or polymerization into bio-based chemicals and materials with higher value; accordingly, PDHs that show activity on xylooligosaccharides could offer a viable approach to extract higher value from hemicelluloses that are typically fragmented during biomass processing. In this study, AbPDH1 from Agaricus bisporus and AmPDH1 from Leucoagaricus meleagris were tested using linear xylooligosaccharides, along with xylooligosaccharides substituted with either arabinofuranosyl or 4-O-(methyl)glucopyranosyluronic acid residues with degree of polymerization of two to five. Reaction products were characterized by HPAEC-PAD to follow substrate depletion, UPLC-MS-ELSD to quantify the multiple oxidation products, and ESI-MSn to reveal oxidized positions. A versatile method based on product reduction using sodium borodeuteride, and applicable to carbohydrate oxidoreductases in general, was established to facilitate the identification and quantification of oxidized products. AbPDH1 activity toward the tested xylooligosaccharides was generally higher than that measured for AmPDH1. In both cases, activity values decreased with increasing length of the xylooligosaccharide and when using acidic rather than neutral substrates; however, AbPDH1 fully oxidized all linear xylooligosaccharides, and 60-100% of all substituted xylooligosaccharides, after 24 h under the tested reaction conditions. Oxidation of linear xylooligosaccharides mostly led to double oxidized products, whereas single oxidized products dominated in reactions containing substituted xylooligosaccharides. Notably, oxidation of specific secondary hydroxyls vs. the reducing end C-1 depended on both the enzyme and the substrate. For all substrates, however, oxidation by both AbPDH1 and AmPDH1 was clearly restricted to the reducing and non-reducing xylopyranosyl residues, where increasing the length of the xylooligosaccharide did not lead to detectable oxidation of internal xylopyranosyl substituents. This detailed analysis of AbPDH1 and AmPDH1 action on diverse xylooligosaccharides reveals an opportunity to synthesize bifunctional molecules directly from hemicellulose fragments, and to enrich for specific products through appropriate PDH selection.


The reliability of resident self-evaluation of operative performance.
Self-assessment is critical to professional self-regulation yet many trainees may not reliably self-evaluate. We examine the gap between resident and faculty perceptions of trainee operative performance and contributing factors. Surgery resident and faculty evaluations of trainee performance were collected from 14 academic institutions using smartphone-based performance assessments. Differences in resident/faculty ratings evaluating the same procedure were analyzed using descriptive statistics and Bayesian mixed models. Of 7382 evaluations, 46% trainees and faculty performance ratings were discrepant (r = 0.47), with 80% residents rating themselves lower than faculty in those cases. This gap existed regardless of case complexity and widened as trainees gained experience. Trainees who overrated themselves had the lowest mean performance scores from faculty. Half of residents perceived their performance differently from faculty, and this difference widened for senior residents. Future focus should be to provide opportunity for trainees to improve skills to reliably assess themselves before graduation.


Effects of amino acids and energy intake during late gestation of high-performing gilts and sows on litter and reproductive performance under commercial conditions.
The objective of this study was to determine the effects of AA and energy intake during late gestation on piglet birth weight and reproductive performance of high-performing (14.5 total born) gilts and sows housed under commercial conditions. At d 90 of gestation, a total of 1,102 females (PIC 1050) were housed in pens by parity group (gilts or sows) with approximately 63 gilts and 80 sows in each pen, blocked by BW within each pen, and each female was randomly assigned to dietary treatments within BW block. Dietary treatments consisted of combinations of 2 standardized ileal digestible (SID) AA intakes (10.7 or 20.0 g/d SID Lys and other AA met or exceeded the NRC [2012] recommendations) and 2 energy intakes (4.50 or 6.75 Mcal/d intake of NE) in a 2 × 2 factorial arrangement. Data were analyzed using generalized linear mixed models specified to recognize pen as the experimental unit for parity and the individual female as the experimental unit for dietary treatments. Results indicate an overall positive effect of high energy intake on BW gain during late gestation, although this effect was more manifest under conditions of high, as opposed to low, AA intake (interaction, < 0.001). Furthermore, the magnitude of BW gain response to increased energy intake was greater ( < 0.001) for sows compared with gilts. Sows fed high energy intake had a reduced probability of piglets born alive ( < 0.004) compared with those fed low energy, but no evidence for differences was found in gilts. This can be explained by an increased probability ( = 0.002) of stillborns in sows fed high energy intake vs. sows fed low energy intake. There were no evidences for differences among dietary treatments in litter birth weight and individual piglet birth weight of total piglets born. However, individual born alive birth weight was approximately 30 ± 8.2 g heavier ( = 0.011) for females fed high, as opposed to low, energy intake. Furthermore, piglets born alive were approximately 97 ± 9.5 g heavier ( < 0.001) for sows than for gilts. Preweaning mortality was decreased ( = 0.034) for females fed high AA intake compared with females fed low AA intake regardless of energy level. In conclusion, 1) BW gain of gilts and sows depended not only on energy but also on AA intake, 2) sows fed increased amount of energy had an increased stillborn rate, and 3) increased energy intake during late gestation had a positive effect on individual piglet birth weight with no evidence for such an effect for AA intake.


TRP channels as emerging targets for pain therapeutics.
The transient receptor potential (TRP) superfamily of ion channels are a large and diverse group that have received increased attention in recent years. The sub-family of thermo-TRPs which are regulated by temperature, among other physical and chemical stimuli, are of particular interest for the development of potential pain therapeutics. We review the advances in the field in recent years, focusing on a rationale for pain therapy and potential challenges associated with these targets. Vanilloid-type TRP 1 (TRPV1) is the most well studied and advanced member of the family, with selective agonists and antagonists already in clinical use or development, respectively. Among other thermo-TRPs (including TRPV2 - 4, Ankyrin type TRP 1 (TRPA1) and melastatin type TRP 8 (TRPM8)), TRPA1 and TRPM8 are emerging as promising novel pain targets.


Transethmoidal meningoencephalocele in an elderly woman. Case report.
A 69-year-old woman presented with a transethmoidal meningoencephalocele manifesting as gradually developing anosmia. Examinations revealed a mass in the nasal cavity associated with multiple angiomas in her lip and orbit. Neuroimaging showed meningoencephalocele extending via the ethmoid sinus to the nasal cavity. She had no history of craniofacial trauma and intranasal or intracranial operation, and no skull base tumor was detected. Frontal base reconstruction was performed with a two-layer vascularized flap to prevent cerebrospinal fluid leakage. The dural defect was repaired with the pericranial flap, and the bony defect of the cribriform plate was reconstructed using the reversed U-shaped split temporalis musculofascial flap. Transethmoidal meningoencephalocele is a rare congenital malformation and almost half of the cases are identified in the first year of life. We should be aware of this clinical pathology and avoid unexpected rhinorrhea in elderly patients. The most important aspect of the operation is watertight closure of the patent passage to the intracranial compartment. The reversed U-shaped split temporalis musculofascial flap is useful to reconstruct the midline frontal base defect.


A Novel Connectome-Based Electrophysiological Study of Subjective Cognitive Decline Related to Alzheimer's Disease by Using Resting-State High-Density EEG EGI GES 300.
Aim: To investigate for the first time the brain network in the Alzheimer's disease (AD) spectrum by implementing a high-density electroencephalography (HD-EEG - EGI GES 300) study with 256 channels in order to seek if the brain connectome can be effectively used to distinguish cognitive impairment in preclinical stages. Methods: Twenty participants with AD, 30 with mild cognitive impairment (MCI), 20 with subjective cognitive decline (SCD) and 22 healthy controls (HC) were examined with a detailed neuropsychological battery and 10 min resting state HD-EEG. We extracted correlation matrices by using Pearson correlation coefficients for each subject and constructed weighted undirected networks for calculating clustering coefficient (CC), strength (S) and betweenness centrality (BC) at global (256 electrodes) and local levels (29 parietal electrodes). Results: One-way ANOVA presented a statistically significant difference among the four groups at local level in CC [F (3, 88) = 4.76, p = 0.004] and S [F (3, 88) = 4.69, p = 0.004]. However, no statistically significant difference was found at a global level. According to the independent sample t-test, local CC was higher for HC [M (SD) = 0.79 (0.07)] compared with SCD [M (SD) = 0.72 (0.09)]; t (40) = 2.39, p = 0.02, MCI [M (SD) = 0.71 (0.09)]; t (50) = 0.41, p = 0.004 and AD [M (SD) = 0.68 (0.11)]; t (40) = 3.62, p = 0.001 as well, while BC showed an increase at a local level but a decrease at a global level as the disease progresses. These findings provide evidence that disruptions in brain networks in parietal organization may potentially represent a key factor in the ability to distinguish people at early stages of the AD continuum. Conclusions: The above findings reveal a dynamically disrupted network organization of preclinical stages, showing that SCD exhibits network disorganization withintermediate values between MCI and HC. Additionally, these pieces of evidence provide information on the usefulness of the 256 HD-EEG in network construction.


Myocardial Cut-off Sign is a Sensitive and Specific Cardiac Computed Tomography and Magnetic Resonance Imaging Sign to Distinguish Left Ventricular Pseudoaneurysms From True Aneurysms.
The purpose of this study was to describe the myocardial cut-off sign, assess its ability to distinguish left ventricular pseudoaneurysms (LV PSAs) from true aneurysms (LVAs), and compare its performance with other imaging findings and quantitative measurements used to differentiate LV PSAs from LVAs. This retrospective single-center study identified patients with preoperative cardiac computed tomography (CT) or magnetic resonance imaging (MRI) and surgically confirmed LVAs or LV PSAs over a 10-year period. Seventeen LV PSAs (11 MRI, 6 CT) and 18 LVAs (10 MRI, 8 CT) were included. The myocardial cut-off sign was objectively a >50% decrease in aneurysm sac wall thickness measured at 1 cm from the aneurysmal neck (measurements at 2 cm were also assessed) and subjectively an abrupt "cut-off" of myocardium for the aneurysm sac for PSA compared with a gradual tapering of sac wall thickness for LVA. Two radiologists independently evaluated images for the subjective presence of this sign. The myocardial cut-off sign was 91% sensitive and 97% specific when measured 1 cm from the aneurysm neck. When measured at 2 cm from the neck, the sign was 100% sensitive and 69% specific. Subjective analysis of whether the myocardium appeared "cut-off" was 94% to 100% sensitive and 78% to 94% specific with excellent agreement for both PSA (κ=0.94) and LVA (κ=0.83). The myocardial cut-off sign on cardiac CT and MRI is a sensitive and specific finding of LV PSA. Specificity is improved with objective measurements compared with subjective assessment (97% vs. 78% to 94%). This sign may help radiologists distinguish between LV PSAs and LVAs.


Integrative and regularized principal component analysis of multiple sources of data.
Integration of data of disparate types has become increasingly important to enhancing the power for new discoveries by combining complementary strengths of multiple types of data. One application is to uncover tumor subtypes in human cancer research in which multiple types of genomic data are integrated, including gene expression, DNA copy number, and DNA methylation data. In spite of their successes, existing approaches based on joint latent variable models require stringent distributional assumptions and may suffer from unbalanced scales (or units) of different types of data and non-scalability of the corresponding algorithms. In this paper, we propose an alternative based on integrative and regularized principal component analysis, which is distribution-free, computationally efficient, and robust against unbalanced scales. The new method performs dimension reduction simultaneously on multiple types of data, seeking data-adaptive sparsity and scaling. As a result, in addition to feature selection for each type of data, integrative clustering is achieved. Numerically, the proposed method compares favorably against its competitors in terms of accuracy (in identifying hidden clusters), computational efficiency, and robustness against unbalanced scales. In particular, compared with a popular method, the new method was competitive in identifying tumor subtypes associated with distinct patient survival patterns when applied to a combined analysis of DNA copy number, mRNA expression, and DNA methylation data in a glioblastoma multiforme study. Copyright © 2016 John Wiley & Sons, Ltd.


Regularization Methods for High-Dimensional Instrumental Variables Regression With an Application to Genetical Genomics.
In genetical genomics studies, it is important to jointly analyze gene expression data and genetic variants in exploring their associations with complex traits, where the dimensionality of gene expressions and genetic variants can both be much larger than the sample size. Motivated by such modern applications, we consider the problem of variable selection and estimation in high-dimensional sparse instrumental variables models. To overcome the difficulty of high dimensionality and unknown optimal instruments, we propose a two-stage regularization framework for identifying and estimating important covariate effects while selecting and estimating optimal instruments. The methodology extends the classical two-stage least squares estimator to high dimensions by exploiting sparsity using sparsity-inducing penalty functions in both stages. The resulting procedure is efficiently implemented by coordinate descent optimization. For the representative L1 regularization and a class of concave regularization methods, we establish estimation, prediction, and model selection properties of the two-stage regularized estimators in the high-dimensional setting where the dimensionality of co-variates and instruments are both allowed to grow exponentially with the sample size. The practical performance of the proposed method is evaluated by simulation studies and its usefulness is illustrated by an analysis of mouse obesity data. Supplementary materials for this article are available online.


Ex Vivo Plasmodium malariae Culture Method for Antimalarial Drugs Screen in the Field.
In vitro and ex vivo cultivation of Plasmodium (P) falciparum has facilitated active research into the malaria parasite toward the quest for basic knowledge and the discovery of effective drug treatments. Such a drug discovery program is currently difficult for P. malariae simply because of the absence of in vitro and ex vivo cultivation system for its asexual blood stages supporting antimalarial evaluation. Despite availability of artemisinin combination therapies effective on P. falciparum, P. malariae is being increasingly detected in malaria endemic countries. P. malariae is responsible for chronic infections and is associated with a high burden of anemia and morbidity. Here, we optimized and adapted ex vivo conditions under which P. malariae can be cultured and used for screening antimalarial drugs. Subsequently, this enabled us to test compounds such as artemether, chloroquine, lumefantrine, and quinine for ex vivo antimalarial activity against P. malariae.


Investigating the validity of Schrage relationships for water using molecular dynamics simulations.
Recently, molecular dynamics (MD) simulations were utilized to show that Schrage theory predicts evaporation/condensation mass fluxes with good accuracy in the case of monoatomic and non-polar molecular fluids. Here, we examine if they are equally accurate for molecular polar fluids, such as water. In particular, using molecular dynamics (MD) simulations, we study the steady state evaporation/condensation processes of water in a one-dimensional heat-pipe geometry to ascertain the validity of Schrage relationships. Non-equilibrium mass flow is driven by controlling the temperatures of the source/sink. Equilibrium simulations are utilized to evaluate the saturation properties and the mass accommodation coefficients as a function of temperature. Our results indicate that Schrage equations predict the evaporation/condensation rates of water with good accuracy. Moreover, we show that molecular velocity distributions in the vapor phase are indeed Maxwellian distributions shifted by the velocity of the macroscopic vapor flow, as assumed in Schrage's theoretical analysis.


Specific and nonspecific antibody responses in different segments of the respiratory tract in rats infected with Mycoplasma pulmonis.
Murine respiratory mycoplasmosis resulting from Mycoplasma pulmonis infection in rats provides a useful model for the study of immunological and inflammatory mechanisms operative in the respiratory tract. We have previously shown that LEW rats develop more severe disease than do F344 rats. To further study the production of antibody responses in chronic respiratory disease due to M. pulmonis infection, we examined the distribution and development of M. pulmonis-specific antibody-forming cells (AFC) in different segments of the respiratory tracts of infected LEW and F344 rats. In these studies, the upper respiratory nodes were the initial site of antibody production after infection and remained the major site for recovery of AFC. Since infected LEW rats had equal or higher numbers of AFC than did infected F344 rats, these results suggest that the level of local antibody production alone is not responsible for the decreased susceptibility of F344 rats to murine respiratory mycoplasmosis. The differences in total antibody responses appear to be due to the greater numbers of cells recovered from the tissues of infected LEW rats compared with those recovered from F344 rats, suggesting that LEW rats may have greater production of chemotactic factors. Also, we demonstrate that nonspecific activation and/or recruitment of B cells occurs in the respiratory tracts of both LEW and F344 rats after infection with M. pulmonis.


Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2.
Eye development initiates as an evagination of the early neural plate, before the closure of the neural tube. Structural malformations of the eye such as anophthalmia and microphthalmia arise very early in development. It is not surprising therefore that three of the genes currently identified to play a significant role in these developmental eye anomalies are also major players in brain development and regionalization. However, as has been emerging for a high proportion of transcriptional regulators studied, these genes have evolved to play multiple roles throughout development, and perhaps even in adult tissue maintenance. This complex spatiotemporal expression pattern requires elaborate regulatory systems which we are beginning to unravel. A major component of these complex regulatory networks is a series of cis-acting elements, highly conserved through evolution, which spread large distances from the coding region of each gene. We describe how cross regulation for PAX6, SOX2 and perhaps OTX2 has now been uncovered, pointing to the mechanisms that can fine-tune the expression of such essential developmental components. These interactions also help us understand why there is significant phenotypic overlap between mutations at these three loci.