Application of 3D Printed Models of Complex Hypertrophic Scars for Preoperative Evaluation and Surgical Planning.
Complex hypertrophic scar is a condition that causes multiple joint contractures and deformities after trauma or burn injuries. Three-dimensional (3D) printing technology provides a new evaluation method for this condition. The objective of this study was to print individualized 3D models of complex hypertrophic scars and to assess the accuracy of these models. Twelve patients with complex hypertrophic scars were included in this study. Before surgery, each patient underwent a computed tomography (CT) scan to obtain cross-sectional information for 3D printing. Mimics software was used to process the CT data and create 3D printed models. The length, width, height, and volume measurements of the physical scars and 3D printed models were compared. Experienced surgeons used the 3D models to plan the operation and simulate the surgical procedure. The hypertrophic scar was completely removed for each patient and covered with skin autografts. The surgical time, bleeding, complications, and skin autograft take rate were recorded. All patients were followed up at 12 months. The surgeons, young doctors, medical students, and patients involved in the study completed questionnaires to assess the use of the 3D printed models. The 3D models of the hypertrophic scars were printed successfully. The length, width, height, and volume measurements were significantly smaller for the 3D printed models than for the physical hypertrophic scars. Based on preoperative simulations with the 3D printed models, the surgeries were performed successfully and each hypertrophic scar was completely removed. The surgery time was shortened and the bleeding was decreased. On postoperative day 7, there were two cases of subcutaneous hemorrhage, one case of infection and one case of necrosis. On postoperative day 12, the average take rate of the skin autografts was 97.75%. At the 12-month follow-up, all patients were satisfied with the appearance and function. Accurate 3D printed models can help surgeons plan and perform successful operations, help young doctors and medical students learn surgical methods, and enhance patient comprehension and confidence in their surgeons.


IFN-gamma receptor-deficient mice generate antiviral Th1-characteristic cytokine profiles but altered antibody responses.
The lymphokine IFN-gamma is a pleiotropic immunomodulator and possesses intrinsic antiviral activity. We studied its significance in the development of antiviral immune responses by using IFN-gamma receptor-deficient (IFN-gamma R-/-) mice. After inoculation with live attenuated pseudorabies virus (PRV), the mutant mice showed no infectivity titers in various tissues, and transient viral Ag expression only in the spleen, similar as in wild-type mice. However, the absence of the IFN-gamma R resulted in increased proliferative splenocyte responses. The PRV-immune animals showed a normal IFN-gamma and IL-2 production, without detectable IL-4, and with decreased IL-10 secretion in response to viral Ag or Con A. Immunohistochemically, an increased ratio of IFN-gamma:IL-4-producing spleen cells was found. After immunization with either live attenuated or inactivated PRV, IFN-gamma R-/- mice produced significantly less antiviral Ab, and more succumbed to challenge infection than the intact control animals. The reduction in Ab titers in the mutant mice correlated with lower protection by their sera in transfer experiments. Our data demonstrate that ablation of the IFN-gamma receptor surprisingly does not inhibit the generation of antiviral Th1-type and increase Th2-type cytokine responses. However, it profoundly impairs the generation of protective antiviral Ab.


Management of sequelae of Kawasaki disease in adults.
Background: A growing population of young adults is presenting to cardiologists with late manifestations of Kawasaki disease (KD) that include cardiomyopathy, ischemia, and infarction. The management of these conditions differs in important ways from atherosclerotic heart disease, and yet there is little awareness in the adult cardiology community regarding the special challenges posed by the cardiovascular sequelae of KD. Methods: Observations were made on a population of 140 adult KD patients enrolled in the San Diego Adult KD Collaborative Study. Results: Coronary artery aneurysms resulting from KD in childhood are associated with a high risk of thrombosis and stenosis at the inlet or outlet of the aneurysm. These aneurysms are often highly calcified and may contain a large thrombus burden that may obscure the true size of the aneurysm. Pitfalls in the management of these patients stem largely from failure to recognize the nature of the lesions, which leads to attempts to dilate highly calcified stenotic segments and undersizing of stents. Intravascular ultrasound is helpful in appreciating the true dimensions of the aneurysm, which may be filled with thrombus. Thrombolysis and use of anti-platelet agents followed by systemic anti-coagulation are appropriate management strategies for patients presenting with acute infarction. Bypass grafting with the internal thoracic arteries can be a successful strategy, but care must be taken to avoid competitive flow through the native vessel leading to graft failure. In contrast to the individuals who developed coronary artery aneurysms, young adults who had documented normal echocardiograms associated with their acute KD in childhood and who have no evidence of calcium deposition in the arterial wall as assessed by computed tomography (CT) calcium score appear to have no increased cardiovascular risk in the medium term. Long-term outcomes for adults post-KD in childhood are still being defined. Conclusions: KD poses special management challenges for the adult cardiologist who must recognize the unique features of the cardiovascular lesions in this growing population of patients.


High resolution annotation of zebrafish transcriptome using long-read sequencing.
With the emergence of zebrafish as an important model organism, a concerted effort has been made to study its transcriptome. This effort is limited, however, by gaps in zebrafish annotation, which are especially pronounced concerning transcripts dynamically expressed during zygotic genome activation (ZGA). To date, short-read sequencing has been the principal technology for zebrafish transcriptome annotation. In part because these sequence reads are too short for assembly methods to resolve the full complexity of the transcriptome, the current annotation is rudimentary. By providing direct observation of full-length transcripts, recently refined long-read sequencing platforms can dramatically improve annotation coverage and accuracy. Here, we leveraged the SMRT platform to study the transcriptome of zebrafish embryos before and after ZGA. Our analysis revealed additional novelty and complexity in the zebrafish transcriptome, identifying 2539 high-confidence novel transcripts that originated from previously unannotated loci and 1835 high-confidence new isoforms in previously annotated genes. We validated these findings using a suite of computational approaches including structural prediction, sequence homology, and functional conservation analyses, as well as by confirmatory transcript quantification with short-read sequencing data. Our analyses provided insight into new homologs and paralogs of functionally important proteins and noncoding RNAs, isoform switching occurrences, and different classes of novel splicing events. Several novel isoforms representing distinct splicing events were validated through PCR experiments, including the discovery and validation of a novel 8-kb transcript spanning multiple mir-430 elements, an important driver of early development. Our study provides a significantly improved zebrafish transcriptome annotation resource.


Chondroitin sulfate-functionalized polyamidoamine as a tumor-targeted carrier for miR-34a delivery.
Chondroitin sulfate (CS) was modified on a polyamidoamine dendrimer (PAMAM) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The derivative CS-PAMAM was demonstrated to achieve an efficient cellular uptake of miR-34a in a CD44-dependent endocytosis way and further facilitate the endosomal escape of miR-34a after 4h. Through the miR-34a delivery, obvious inhibition of cell proliferation could be detected which was attributed to the enhancement of cell apoptosis and cell cycle arrest, and meanwhile the cell migration and invasion has been observed to be inhibited. Finally, the intravenous injection of CS-PAMAM/miR-34a formulation into mice bearing human lung adenocarcinoma cell A549 xenografts could efficiently inhibit the tumor growth and induce the tumor apoptosis owing to the enhanced accumulation of miR-34a in tumor tissue. Overall, CS-PAMAM is potential to be used as a tumor-targeted oligonucleotide carrier for achieving tumor gene therapy. The cationic dendrimer PAMAM was modified by chondroitin sulfate (CS) through Michael addition to construct a tumor-targeted carrier CS-PAMAM for miR-34a delivery. The introduction of CS could achieve an efficient cellular uptake and intracellular transfection of miR-34a in a CD44-dependent endocytosis manner. The miR-34a delivery could execute the anti-proliferation activity by simultaneously inducing cell apoptosis and cell cycle arrest, and also the anti-migration activity. The CS-PAMAM-mediated systemic delivery of miR-34a showed significant inhibition of tumor growth and induction of tumor apoptosis using a mice model of subcutaneously implanted tumors.


A Case of Live Donor Liver Transplantation in Acute-on-Chronic Liver Failure with Budd-Chiari Syndrome: Donor and Recipient with Antiphospholipid Antibody Syndrome.
BACKGROUND Acute-on-chronic liver failure was first defined within the last 10 years as acute decompensation of chronic liver disease accompanied by multiorgan failure and poor outcome. Budd-Chiari syndrome is a rare and potentially deadly hepatic condition. To the best of our knowledge, this is the first case report of a live liver donor recipient with antiphospholipid antibody syndrome. CASE REPORT A 47-year-old woman from Sudan with acute-on-chronic liver failure and subacute Budd-Chiari syndrome triggered by active pneumonia was evacuated to Amman, Jordan. In Amman, she was transferred to our hospital for liver transplant evaluation. She presented with progressive liver failure, acute kidney failure, acute respiratory failure, and encephalopathy stage IV. Multidisciplinary therapy was initiated with IV anti-infective drugs and optimizing mechanical ventilation. Clinically, we stopped her progressive deterioration after 48 h and she improved slightly in our ICU. Accelerated work-up for donors and recipient was completed and her daughter was selected as a medically appropriate donor despite the fact that she was found to have heterozygote factor V Leiden mutation and antiphospholipid antibody syndrome, similar to her mother. A lifesaving live-donor liver transplantation was carried out after 72 h. Donor and recipient were discharged in good condition with normal liver function and both were discharged on anticoagulant Rivaroxaban 20 mg. CONCLUSIONS We present the first case of a patient with acute-on-chronic liver failure with subacute Budd-Chiari syndrome, which was triggered by bacterial pneumonia and was successfully treated by live-donor liver transplantation from a donor with antiphospholipid antibody syndrome.


Women are underrepresented in fields where success is believed to require brilliance.
Women's underrepresentation in science, technology, engineering, and mathematics (STEM) fields is a prominent concern in our society and many others. Closer inspection of this phenomenon reveals a more nuanced picture, however, with women achieving parity with men at the Ph.D. level in certain STEM fields, while also being underrepresented in some non-STEM fields. It is important to consider and provide an account of this field-by-field variability. The field-specific ability beliefs (FAB) hypothesis aims to provide such an account, proposing that women are likely to be underrepresented in fields thought to require raw intellectual talent-a sort of talent that women are stereotyped to possess less of than men. In two studies, we provide evidence for the FAB hypothesis, demonstrating that the academic fields believed by laypeople to require brilliance are also the fields with lower female representation. We also found that the FABs of participants with college-level exposure to a field were more predictive of its female representation than those of participants without college exposure, presumably because the former beliefs mirror more closely those of the field's practitioners (the direct "gatekeepers"). Moreover, the FABs of participants with college exposure to a field predicted the magnitude of the field's gender gap above and beyond their beliefs about the level of mathematical and verbal skills required. Finally, we found that beliefs about the importance of brilliance to success in a field may predict its female representation in part by fostering the impression that the field demands solitary work and competition with others. These results suggest new solutions for enhancing diversity within STEM and across the academic spectrum.


Type III secretion chaperones of Pseudomonas syringae protect effectors from Lon-associated degradation.
The hrp type III secretion system (TTSS) of Pseudomonas syringae translocates effector proteins into the cytoplasm of host cells. Proteolysis of HrpR by Lon has been shown to negatively regulate the hrp TTSS. The inability to bypass Lon-associated effects on the regulatory system by ectopic expression of the known regulators suggested a second site of action for Lon in TTSS-dependent effector secretion. In this study we report that TTSS-dependent effectors are subject to the proteolytic degradation that appears to be rate-limiting to secretion. The half-lives of the effectors AvrPto, AvrRpt2, HopPsyA, HopPsyB1, HopPtoB2, HopPsyV1, HopPtoG and HopPtoM were substantially higher in bacteria lacking Lon. TTSS-dependent secretion of several effectors was enhanced from Lon mutants. A primary role for chaperones appears to be protection of effectors from Lon-associated degradation prior to secretion. When coexpressed with their cognate chaperone, HopPsyB1, HopPsyV1 and HopPtoM were at least 10 times more stable in strains expressing Lon. Distinct Lon-targeting and chaperone-binding domains were identified in HopPtoM. The results imply that Lon is involved at two distinct levels in the regulation of the P. syringae TTSS: regulation of assembly of the secreton and modulation of effector secretion.


Form and function of dosage-compensated chromosomes--a chicken-and-egg relationship.
Does the three-dimensional (3D) conformation of interphase chromosomes merely reflect their function or does it actively contribute to gene regulation? The analysis of sex chromosomes that are subject to chromosome-wide dosage compensation processes promises new insight into this question. Chromosome conformations are dynamic and largely determined by association of distant chromosomal loci in the nuclear space or by their anchoring to the nuclear envelope, effectively generating chromatin loops. The type and extent of such interactions depend on chromatin-bound transcription regulators and therefore reflects function. Dosage compensation adjusts the overall transcription activity of X chromosomes to assure balanced expression in the two sexes. Initial analyses of mammalian and Drosophila X chromosomes have led to the hypothesis that their conformations may not only reflect their functional state but may in turn contribute to the coordination of chromosome-wide tuning of transcription.


A Journey Undertaken by Families to Access General Surgical Care for their Children at Muhimbili National Hospital, Tanzania; Prospective Observational Cohort Study.
A majority of the 2 billion children lacking access to safe, timely and affordable surgical care reside in low-and middle-income countries. A barrier to tackling this issue is the paucity of information regarding children's journey to surgical care. We aimed to explore children's journeys and its implications on accessing general paediatric surgical care at Muhimbili National Hospital (MNH), a tertiary centre in Tanzania. A prospective observational cohort study was undertaken at MNH, recruiting patients undergoing elective and emergency surgeries. Data on socio-demographic, clinical, symptoms onset and 30-days post-operative were collected. Descriptive statistics and Mann-Whitney, Kruskal-Wallis and Fisher's exact tests were used for data analysis. We recruited 154 children with a median age of 36 months. The majority were referred from regional hospitals due to a lack of paediatric surgery expertise. The time taken to seeking care was significantly greater in those who self-referred (p = 0.0186). Of these participants, 68.4 and 31.1% were able to reach a referring health facility and MNH, respectively, within 2 h of deciding to seek care. Overall insurance coverage was 75.32%. The median out of pocket expenditure for receiving care was $69.00. The incidence of surgical site infection was 10.2%, and only 2 patients died. Although there have been significant efforts to improve access to safe, timely and affordable surgical care, there is still a need to strengthen children's surgical care system. Investing in regional hospitals may be an effective approach to improve access to children surgical care.


Cardiovascular progenitor cells and tissue plasticity are reduced in a myocardium affected by Becker muscular dystrophy.
We describe the association of Becker muscular dystrophy (BMD) derived heart failure with the impairment of tissue homeostasis and remodeling capabilities of the affected heart tissue. We report that BMD heart failure is associated with a significantly decreased number of cardiovascular progenitor cells, reduced cardiac fibroblast migration, and ex vivo survival. Becker muscular dystrophy belongs to a class of genetically inherited dystrophin deficiencies. It affects male patients and results in progressive skeletal muscle degeneration and dilated cardiomyopathy leading to heart failure. It is a relatively mild form of dystrophin deficiency, which allows patients to be on a heart transplant list. In this unique situation, the explanted heart is a rare opportunity to study the degenerative process of dystrophin-deficient cardiac tissue. Heart tissue was excised, dissociated, and analyzed. The fractional content of c-kit+/CD45- cardiovascular progenitor cells (CVPCs) and cardiac fibroblast migration were compared to control samples of atrial tissue. Control tissue was obtained from the hearts of healthy organ donor's during heart transplantation procedures. We report significantly decreased CVPCs (c-kit+/CD45-) throughout the heart tissue of a BMD patient, and reduced numbers of phase-bright cells presenting c-kit positivity in the dystrophin-deficient cultured explants. In addition, ex vivo CVPCs survival and cardiac fibroblasts migration were significantly reduced, suggesting reduced homeostatic support and irreversible tissue remodeling. Our findings associate genetically derived heart failure in a dystrophin-deficient patient with decreased c-kit+/CD45- CVPCs and their resilience, possibly hinting at a lack of cardioprotective capability and/or reduced homeostatic support. This also correlates with reduced plasticity of the explanted cardiac tissue, related to the process of irreversible remodeling in the BMD patient's heart.


Anticoagulation by ancrod for carbon dioxide removal by extracorporeal membrane lung in the dog.
Ten dogs were subjected to defibrinogenation with an intravenous perfusion of ancrod (1 unit/kg) (Arvin, Knoll AG, Ludwigshafen, Federal Republic of Germany) over a 2 1/2 hour period. Six of them were subjected to extracorporeal elimination of carbon dioxide with a polypropylene membrane lung by means of veno-venous bypass. The remaining four dogs did not undergo extracorporeal circulation and served as control subjects. In both groups, ancrod administration itself resulted in a marked drop in alpha 2-antiplasmin (33% and 67%, respectively, of the baseline values) and in slight but significant decreases in factor II and plasminogen activities of 25% and 20%, respectively (p less than 0.05), in the group subjected to carbon dioxide removal. There were no significant changes in platelet number or factor V and antithrombin III activities. During the 6-hour bypass period, platelet count and antithrombin III and factor II and V levels decreased significantly. No bleeding was observed. Histologic examination of lung biopsy tissue showed no pathologic features. Analysis of the membrane of the artificial lungs revealed no fibrin deposits. In the control group, except for a drop in alpha 2-antiplasmin levels (54%), no significant changes in hemostatic parameters occurred during the corresponding 6 hours. We conclude that, despite the drop in coagulation factors and in alpha 2-antiplasmin activity during bypass, ancrod can be considered as a valuable alternative anticoagulant for extracorporeal carbon dioxide removal.


Lunar organic compounds: search and characterization.
The carbon concentration in Apollo 11 lunar fine material is of the order of 200 ppm. By far the largest single amount of this carbon appears to be in carbon monoxide. Some of this seems to be in the form of gas bubbles in the glass spheres, but most of it could be in some complex form other than gas. This result would be consistent with the idea that most of the fines passed through a high temperature and that the carbon was oxidized by mineral oxides at that time.


Patients with the major and minor form of hyperekplexia differ with regards to disynaptic reciprocal inhibition between ankle flexor and extensor muscles.
The aim of the present study was to investigate the contribution of reciprocal inhibition to muscle tone by examining the transmission in the reciprocal inhibitory pathway in patients with a known defect in the glycine receptor. The study was performed in eight patients with hereditary hyperekplexia, six with the major form and two with the minor form of the disease. A mutation in the alpha1-subunit of the glycine receptor had been demonstrated in the patients with the major form, whereas no mutation was seen in the patients with the minor form. Disynaptic reciprocal inhibition, which is presumed to be mediated by glycine, was not seen in the patients with the major form of the disease, while it could be evoked in the patients with the minor form of the disease. Presynaptic inhibition, which is presumed to be mediated by GABA, was seen in both types of patients. It is concluded that the major form of hereditary hyperekplexia is associated with impaired transmission in glycinergic reciprocal inhibitory pathways. The findings demonstrate the importance of reciprocal inhibition for the muscle tone in man, and it is suggested that the impaired reciprocal inhibition seen in patients with a defect in the glycine receptor may contribute to the increased muscle stiffness that is observed in these patients.


Actin in the preprophase band of Allium cepa.
F-actin has been identified in the preprophase band of Allium cepa. Cells attached to subbed slides were obtained from formaldehyde-fixed root tips digested in EGTA and Cellulysin. The air-dried cells were extracted in Triton X-100, treated with rhodamine-phalloidin, rinsed briefly in PBS, and viewed in the fluorescence microscope. Interphase cells contain a network of actin fibers that extends into all areas of the cytoplasm. During preprophase, the network is replaced by a band of fibers aligned in the position of the preprophase band. Colocalization of F-actin with rhodamine-phalloidin and microtubules with tubulin immunocytochemistry confirms that the two bands are coincident. The actin appears to comprise a thin layer of fibers next to the plasmalemma. Like the microtubule preprophase band, the actin band narrows as preprophase progresses and disappears by midprophase. Fluorescent actin bands are not seen in fixed cells pretreated with excess unlabeled phalloidin before staining. They are also absent in roots exposed to cytochalasins B and D before fixation, but preprophase band microtubules at all stages of aggregation are still present. Colchicine treatment leads to the loss of both preprophase band microtubules and actin. The possible function of preprophase band actin is discussed.


The Photosystem II Repair Cycle Requires FtsH Turnover through the EngA GTPase.
Specific degradation of photodamaged D1, the photosystem II (PSII) reaction center protein, is a crucial step in the PSII repair cycle to maintain photosynthesis activity. Processive proteolysis by the FtsH protease is fundamental to cooperative D1 degradation. Here, we attempted to purify the FtsH complex to elucidate its regulation mechanisms and substrate recognition in Arabidopsis (Arabidopsis thaliana). Unlike previously reported prokaryotic and mitochondrial FtsHs, the Arabidopsis chloroplastic FtsH does not appear to form a megacomplex with prohibition-like proteins but instead accumulates as smaller complexes. The copurified fraction was enriched with a partial PSII intermediate presumably undergoing repair, although its precise properties were not fully clarified. In addition, we copurified a bacteria-type GTPase localized in chloroplasts, EngA, and confirmed its interaction with FtsH by subsequent pull-down and bimolecular fluorescence complementation assays. While the engA mutation is embryo lethal, the transgenic lines overexpressing EngA (EngA-OX) showed leaf variegation reminiscent of the variegated mutant lacking FtsH2. EngA-OX was revealed to accumulate more cleaved D1 fragments and reactive oxygen species than the wild type, indicative of compromised PSII repair. Based on these results and the fact that FtsH becomes more stable in EngA-OX, we propose that EngA negatively regulates FtsH stability. We demonstrate that proper FtsH turnover is crucial for PSII repair in the chloroplasts of Arabidopsis. Consistent with the increased turnover of FtsH under high-light conditions in Chlamydomonas reinhardtii, our findings underline the rapid turnover of not only D1 but also FtsH proteases in the PSII repair cycle.


Experience with selective venous sampling in diagnosis of ACTH-dependent Cushing's syndrome.
Twenty-three patients with adrenocorticotrophic hormone-(ACTH)-dependent Cushing's syndrome were subjected to selective venous catheterisation and sampling for ACTH on a total of 26 occasions. Out of 10 patients with pituitary-dependent disease, nine had raised ACTH concentrations in one or both high internal jugular vein samples. Eight patients had 11 proved sites of ectopic hormone production: of these, six were correctly identified by the sampling technique, and in four of them this was the only accurate method of localisation. The results of one catheterisation were misleading, and on 10 occasions they were inconclusive; five patients remained undiagnosed by any method. Overall, 15 of the 26 catheterisations provided diagnostically valuable information. Selective venous catheterisation and sampling for ACTH is effective in confirming a pituitary source of the hormone and may be valuable in locating the source of ectopic ACTH production in some cases.


Mother's education and late-life disparities in memory and dementia risk among US military veterans and non-veterans.
Adverse childhood socioeconomic status (cSES) predicts higher late-life risk of memory loss and dementia. Veterans of U.S. wars are eligible for educational and economic benefits that may offset cSES disadvantage. We test whether cSES disparities in late-life memory and dementia are smaller among veterans than non-veterans. Data came from US-born men in the 1995-2014 biennial surveys of the Health and Retirement Study (n=7916 born 1928-1956, contributing n=38 381 cognitive assessments). Childhood SES was represented by maternal education. Memory and dementia risk were assessed with brief neuropsychological assessments and proxy reports. Military service (veteran/non-veteran) was evaluated as a modifier of the effect of maternal education on memory and dementia risk. We employed linear or logistic regression models to test whether military service modified the effect of maternal education on memory or dementia risk, adjusted for age, race, birthplace and childhood health. Low maternal education was associated with worse memory than high maternal education (β = -0.07 SD, 95% CI -0.08 to -0.05), while veterans had better memory than non-veterans (β = 0.03 SD, 95% CI 0.02 to 0.04). In interaction analyses, maternal education disparities in memory were smaller among veterans than non-veterans (difference in disparities = 0.04 SD, 95% CI 0.01 to 0.08, p = 0.006). Patterns were similar for dementia risk. Disparities in memory by maternal education were smaller among veterans than non-veterans, suggesting military service and benefits partially offset the deleterious effects of low maternal education on late-life cognitive outcomes.


Aberration-corrected STEM imaging of 2D materials: Artifacts and practical applications of threefold astigmatism.
High-resolution scanning transmission electron microscopy (HR-STEM) with spherical aberration correction enables researchers to peer into two-dimensional (2D) materials and correlate the material properties with those of single atoms. The maximum intensity of corrected electron beam is confined in the area having sub-angstrom size. Meanwhile, the residual threefold astigmatism of the electron probe implies a triangular shape distribution of the intensity, whereas its tails overlap and thus interact with several atomic species simultaneously. The result is the resonant modulation of contrast that interferes the determination of phase transition of 2D materials. Here, we theoretically reveal and experimentally determine the origin of resonant modulation of contrast and its unintended impact on violating the power-law dependence of contrast on coordination modes between transition metal and chalcogenide atoms. The finding illuminates the correlation between atomic contrast, spatially inequivalent chalcogenide orientation, and residual threefold astigmatism on determining the atomic structure of emerging 2D materials.


Patient-reported outcomes and visual acuity after 12months of anti-VEGF-treatment for sight-threatening diabetic macular edema in a real world setting.
To examine objective visual acuity measured with ETDRS, retinal thickness (OCT), patient reported outcome and describe levels of glycated hemoglobin and its association with the effects on visual acuity in patients treated with anti-VEGF for visual impairment due to diabetic macular edema (DME) during 12months in a real world setting. In this cross-sectional study, 58 patients (29 females and 29 males; mean age, 68years) with type 1 and type 2 diabetes diagnosed with DME were included. Medical data and two questionnaires were collected; an eye-specific (NEI VFQ-25) and a generic health-related quality of life questionnaire (SF-36) were used. The total patient group had significantly improved visual acuity and reduced retinal thickness at 4months and remains at 12months follow up. Thirty patients had significantly improved visual acuity, and 27 patients had no improved visual acuity at 12months. The patients with improved visual acuity had significantly improved scores for NEI VFQ-25 subscales including general health, general vision, near activities, distance activities, and composite score, but no significant changes in scores were found in the group without improvements in visual acuity. Our study revealed that anti-VEGF treatment improved visual acuity and central retinal thickness as well as patient-reported outcome in real world 12months after treatment start.


Rate of Communicative Gestures and Developmental Outcomes in Toddlers With and Without Autism Spectrum Disorder During a Home Observation.
Purpose Most toddlers with autism spectrum disorder and other developmental delays receive early intervention at home and may not participate in a clinic-based communication evaluation. However, there is limited research that has prospectively examined communication in very young children with and without autism in a home-based setting. This study used granular observational coding to document the communicative acts performed by toddlers with autism, developmental delay, and typical development in the home environment. Method Children were selected from the archival database of the FIRST WORDS Project (N = 211). At approximately 20 months of age, each child participated in everyday activities with a caregiver during an hour-long, video-recorded, naturalistic home observation. Inventories of unique gestures, rates per minute, and proportions of types of communicative acts and communicative functions were coded and compared using a one-way analysis of variance. Concurrent and prospective relationships between rate of communication and measures of social communication, language development, and autism symptoms were examined. Results A total of 40,738 communicative acts were coded. Children with autism, developmental delay, and typical development used eight, nine, and 12 unique gestures on average, respectively. Children with autism used deictic gestures, vocalizations, and communicative acts for behavior regulation at significantly lower rates than the other groups. Statistically significant correlations were observed between rate of communication and several outcome measures. Conclusion Observation of social communication in the natural environment may improve early identification of children with autism and communication delays, complement clinic-based assessments, and provide useful information about a child's social communication profile and the family's preferred activities and intervention priorities. Supplemental Material https://doi.org/10.23641/asha.14204522.


Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models.
The combination of pegylated interferon (PEG-IFN) and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon-stimulated genes (ISGs) in patients treated for hepatitis C virus (HCV) infection. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was studied. Similar to interferon (IFN)-α, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative polymerase chain reaction assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IFN regulatory factors 7 and 9, are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with IFN-α, induction of specific ISGs is synergistic when compared with either drug applied separately. Direct up-regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with IFN signaling and intracellular double-stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and nuclear factor κB pathways in the action of ribavirin. Our study suggests that ribavirin, acting by way of a novel innate mechanism, potentiates the anti-HCV effect of IFN. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals.


Modification and implementation of NCCN guidelines on hepatobiliary cancers in the Middle East and North Africa region.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) on Hepatobiliary Cancers address hepatocellular cancer, cancer of the gallbladder, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma. Hepatocellular cancer incidence is higher in the Middle East and North Africa (MENA) region than in the West, and hepatitis B and C infections are particularly important; the incidence of gallbladder cancer is among the highest in the world. Regional problems include delay in diagnosis, shortage of trained staff, and insufficient liver transplant facilities. Furthermore, costs associated with molecular and targeted therapies are an increasing concern. A committee was formed, consisting of leading specialists and decision-makers from the region, with each member being tasked to suggest modifications to the existing guidelines based on review of the literature and consultations with local colleagues. This committee met as a group, and then continued to discuss and debate the suggested modifications electronically. Several recommendations were finalized after vigorous debate. The final approved recommendations were then presented in April 2009 to the chair of the NCCN Hepatobiliary Cancers Panel for onward transmission and approval. This project represents an effort to modify and implement the NCCN Guidelines on Hepatobiliary Cancers in the MENA region, while taking into consideration local differences in patient and disease characteristics. The hope is that this will form the basis of future local, regional, and international cooperation in guideline development and research.


Contaminant-mobilizing capability of fullerene nanoparticles (nC60): Effect of solvent-exchange process in nC60 formation.
Fullerene nanoparticles (nC(60)) in aqueous environments can significantly enhance the transport of hydrophobic organic contaminants by serving as a contaminant carrier. In the present study, the authors examine the effect of the solvent-exchange process on nC(60) aggregate formation and, subsequently, on nC(60) 's contaminant-mobilizing capability. A series of nC(60) samples were prepared using a modified toluene-water solvent-exchange method through the inclusion of a secondary organic solvent in the phase transfer of molecular C(60) in toluene to nC(60) in water. Two groups of solvents--a water-miscible group and a non-water-miscible group-of varied polarity were selected as secondary solvents. The involvement of a secondary solvent in the phase transfer process had only small effects on the particle size and distribution, ζ potential, and mobility of the nC(60) products but significantly influenced the capability of nC(60) to enhance the transport of 2,2',5,5'-polychlorinated biphenyl (PCB) in a saturated sandy soil column, regardless of whether the secondary solvent was water-miscible or non-water-miscible. The two groups of secondary solvents appear to affect the aggregation properties of nC(60) in water via different mechanisms. In general, nC(60) products made with a secondary water-miscible solvent have stronger capabilities to enhance PCB transport. Taken together, the results indicate that according to formation conditions and solvent constituents, nC(60) will vary significantly in its interactions with organic contaminants, specifically as related to adsorption or desorption as well as transport in porous media.


Corticotropin-(1--24)-tetracosapeptide affects protein phosphorylation and polyphosphoinositide metabolism in rat brain.
1. Effects of corticotropin-(1--24)-tetracosapeptide on the endogenous phosphorylation of proteins and lipids were studied in a membrane/cytosol fraction prepared from a lysed crude mitochondrial/synaptosomal fraction. 2. The labelling of proteins and lipids was monitored by incubation of the subcellular fraction for 10s with [gamma-32P]ATP. 3. The phosphorylation of proteins was dose-dependently inhibited by the peptide (40% of control incubations at 100 microM-corticotropin). 4. Of the membrane phospholipids only phosphatidylinositol phosphate, phosphatidylinositol bisphosphate and phosphatidic acid became labelled. Corticotropin dose-dependently increased the formation of phosphatidylinositol bisphosphate and inhibited the production of phosphatidic acid (470% and 50% respectively of control incubations, at 100 microM of the peptide) and had no effect on phosphatidylinositol phosphate. 5. Phosphatase activity was observed to act on phosphatidylinositol bisphosphate, phosphatidylinositol phosphate and phosphoprotein but not on phosphatidic acid. 6. Corticotropin interacted with the kinases rather than with the phosphatases. 7. The formation of phosphatidylinositol bisphosphate and phosphatidic acid was maximal at 1--10mM-Mg2+ in the absence of Ca2+, and the production of phosphatidylinositol phosphate was maximal at 30mM-Mg2+. 8. The basal value of lipid phosphorylation decreased with increasing Ca2+ concentration. 9. Ca2+ abolished the effect of corticotropin on phosphatidylinositol bisphosphate formation (470%, 190% and 100% of control incubations at respectively 0, 0.1 and 1 mM-Ca2+). 10. The data provide evidence that the effects of corticotropin on protein phosphorylation and on polyphosphoinositide metabolism in brain membranes are related.


Can sarcoidosis and metastatic bone lesions be reliably differentiated on routine MRI?
Sarcoidosis lesions revealed on MRI in the axial skeleton and long bones resemble osseous metastases, which can lead to a potentially significant misdiagnosis. We hypothesized that osseous sarcoidosis lesions could be differentiated from osseous metastases on MRI and sought to propose and evaluate features distinguishing these entities. MR images obtained at 1.5 T of 34 subjects (22 with osseous metastatic disease, 12 with osseous sarcoidosis) with 79 single or multiple bone lesions (40 metastatic, 39 sarcoidal) were reviewed independently by two blinded, experienced musculoskeletal radiologists. Fluid-sensitive and T1-weighted images were viewed separately. Proposed discriminating features were peri- or intralesional fat, specified border characteristics, and the presence of an extraosseous soft-tissue mass. An additional feature for spinal lesions was posterior element involvement. On the basis of these criteria, the readers provided a binary diagnosis and confidence score. The overall sensitivity for both readers was 46.3% and specificity, 97.4%. T1-weighted images were associated with higher sensitivity than T2-weighted images (59.0% vs 34.1%, respectively; p = 0.025) and with comparable specificity (97.6% vs 97.2%, p = 0.91). Diagnostic accuracy was higher using the discriminators of a mass or posterior element involvement for metastasis (83.3%) than border characteristics (68.0%) or lesion fat (65.0%) for sarcoidosis; the latter two features provided near 100% specificity but poor sensitivity (14.3% and 0%, respectively). Readers reported higher confidence diagnosing osseous sarcoidosis lesions than metastatic lesions, with a trend for higher confidence with T1-weighted images (p = 0.088). Osseous sarcoidosis lesions cannot be reliably distinguished from metastatic lesions on routine MRI studies by readers experienced in evaluating these lesions.


Role of ionotropic GABA, glutamate and glycine receptors in the tonic and reflex control of cardiac vagal outflow in the rat.
Cardiac vagal preganglionic neurons (CVPN) are responsible for the tonic, reflex and respiratory modulation of heart rate (HR). Although CVPN receive GABAergic and glutamatergic inputs, likely involved in respiratory and reflex modulation of HR respectively, little else is known regarding the functions controlled by ionotropic inputs. Activation of g-protein coupled receptors (GPCR) alters these inputs, but the functional consequence is largely unknown. The present study aimed to delineate how ionotropic GABAergic, glycinergic and glutamatergic inputs contribute to the tonic and reflex control of HR and in particular determine which receptor subtypes were involved. Furthermore, we wished to establish how activation of the 5-HT1A GPCR affects tonic and reflex control of HR and what ionotropic interactions this might involve. Microinjection of the GABAA antagonist picrotoxin into CVPN decreased HR but did not affect baroreflex bradycardia. The glycine antagonist strychnine did not alter HR or baroreflex bradycardia. Combined microinjection of the NMDA antagonist, MK801, and AMPA antagonist, CNQX, into CVPN evoked a small bradycardia and abolished baroreflex bradycardia. MK801 attenuated whereas CNQX abolished baroreceptor bradycardia. Control intravenous injections of the 5-HT1A agonist 8-OH-DPAT evoked a small bradycardia and potentiated baroreflex bradycardia. These effects were still observed following microinjection of picrotoxin but not strychnine into CVPN. We conclude that activation of GABAA receptors set the level of HR whereas AMPA to a greater extent than NMDA receptors elicit baroreflex changes in HR. Furthermore, activation of 5-HT1A receptors evokes bradycardia and enhances baroreflex changes in HR due to interactions with glycinergic neurons involving strychnine receptors. This study provides reference for future studies investigating how diseases alter neurochemical inputs to CVPN.


A facile approach for the in vitro assembly of multimeric membrane transport proteins.
Membrane proteins such as ion channels and transporters are frequently homomeric. The homomeric nature raises important questions regarding coupling between subunits and complicates the application of techniques such as FRET or DEER spectroscopy. These challenges can be overcome if the subunits of a homomeric protein can be independently modified for functional or spectroscopic studies. Here, we describe a general approach for in vitro assembly that can be used for the generation of heteromeric variants of homomeric membrane proteins. We establish the approach using GltPh, a glutamate transporter homolog that is trimeric in the native state. We use heteromeric GltPh transporters to directly demonstrate the lack of coupling in substrate binding and demonstrate how heteromeric transporters considerably simplify the application of DEER spectroscopy. Further, we demonstrate the general applicability of this approach by carrying out the in vitro assembly of VcINDY, a Na+-coupled succinate transporter and CLC-ec1, a Cl-/H+ antiporter.


DNA nanotechnology for nanophotonic applications.
DNA nanotechnology has touched the epitome of miniaturization by integrating various nanometer size particles with nanometer precision. This enticing bottom-up approach has employed small DNA tiles, large multi-dimensional polymeric structures or more recently DNA origami to organize nanoparticles of different inorganic materials, small organic molecules or macro-biomolecules like proteins, and RNAs into fascinating patterns that are difficult to achieve by other conventional methods. Here, we are especially interested in the self-assembly of nanomaterials that are potentially attractive elements in the burgeoning field of nanophotonics. These materials include plasmonic nanoparticles, quantum dots, fluorescent organic dyes, etc. DNA based self-assembly allows excellent control over distance, orientation and stoichiometry of these nano-elements that helps to engineer intelligent systems that can potentially pave the path for future technology. Many outstanding structures have been fabricated that are capable of fine tuning optical properties, such as fluorescence intensity and lifetime modulation, enhancement of Raman scattering and emergence of circular dichroism responses. Within the limited scope of this review we have tried to give a glimpse of the development of this still nascent but highly promising field to its current status as well as the existing challenges before us.


Telomere length predicts replicative capacity of human fibroblasts.
When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explained by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a striking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublings per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent significantly fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker of somatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age of the donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.


Liquid crystal self-assembly of halloysite nanotubes in ionic liquids: a novel soft nanocomposite ionogel electrolyte with high anisotropic ionic conductivity and thermal stability.
We report a novel class of liquid crystalline (LC) nanohybrid ionogels fabricated via self-assembly of natural halloysite nanotubes (HNTs) in ionic liquids (ILs). The obtained ionogels are very stable and nonvolatile and show LC phases over a wide temperature range. Remarkably, the nanocomposite ionogels exhibit high anisotropic ionic conductivity after shear, and their room temperature ionic conductivity can reach 3.8 × 10(-3) S cm(-1) for aligned nanotubes perpendicular to the electrode even when the HNTs content increases to 40 wt%, which is 380 times higher than that obtained for aligned nanotubes parallel to the electrode, which is 1.0 × 10(-5) S cm(-1). Crucially, the obtained LC nanocomposite ionogels have very high thermal stability, which can sustain 400 °C thermal treatment. The findings will promote the development of novel nanocomposite ionogel electrolytes with faster ion transport and larger anisotropic conductivity.


Mutations in the gene stand still disrupt germ cell differentiation in Drosophila ovaries.
During oogenesis in Drosophila, germ cells appear in sequential clusters of 16 interconnected cells. The events surrounding the differentiation of these cells are not fully understood. Here we present genetic and morphological analysis of mutations in the gene stand still (stil). Through complementation analyses we have refined the location of this gene to cyological region 49B-C. Our analyses of ovaries from ethylmethane sulfonate (EMS)-induced mutant alleles of this gene suggest that mutations in the stil gene produce a wide range of phenotypic abnormalities, from the absence of germ cells in the most severe alleles, to egg chambers with cytoskeletal defects in the less severe alleles. Our results suggest a role for this gene in specifying or maintaining a cytoskeletal component, with consequences during oogenesis and possibly during germ line sex determination.


Robust tactile sensory responses in finger area of primate motor cortex relevant to prosthetic control.
Challenges in improving the performance of dexterous upper-limb brain-machine interfaces (BMIs) have prompted renewed interest in quantifying the amount and type of sensory information naturally encoded in the primary motor cortex (M1). Previous single unit studies in monkeys showed M1 is responsive to tactile stimulation, as well as passive and active movement of the limbs. However, recent work in this area has focused primarily on proprioception. Here we examined instead how tactile somatosensation of the hand and fingers is represented in M1. We recorded multi- and single units and thresholded neural activity from macaque M1 while gently brushing individual finger pads at 2 Hz. We also recorded broadband neural activity from electrocorticogram (ECoG) grids placed on human motor cortex, while applying the same tactile stimulus. Units displaying significant differences in firing rates between individual fingers (p < 0.05) represented up to 76.7% of sorted multiunits across four monkeys. After normalizing by the number of channels with significant motor finger responses, the percentage of electrodes with significant tactile responses was 74.9% ± 24.7%. No somatotopic organization of finger preference was obvious across cortex, but many units exhibited cosine-like tuning across multiple digits. Sufficient sensory information was present in M1 to correctly decode stimulus position from multiunit activity above chance levels in all monkeys, and also from ECoG gamma power in two human subjects. These results provide some explanation for difficulties experienced by motor decoders in clinical trials of cortically controlled prosthetic hands, as well as the general problem of disentangling motor and sensory signals in primate motor cortex during dextrous tasks. Additionally, examination of unit tuning during tactile and proprioceptive inputs indicates cells are often tuned differently in different contexts, reinforcing the need for continued refinement of BMI training and decoding approaches to closed-loop BMI systems for dexterous grasping.


Power pre-emphasis for suppression of FWM in coherent optical OFDM transmission.
Four-wave-mixing (FWM) due to the fiber nonlinearity is a major limiting factor in coherent optical OFDM transmission. We propose to apply power pre-emphasis, i.e. to allocate the transmitted power non-uniformly among subcarriers in order to suppress the FWM impairment. The proposed technique was numerically investigated for both single channel 15.6 Gbs CO-OFDM transmissions and 7-channel WDM transmissions, showing that up to 1 dB improvement in the system's Q-factor can be achieved without considering sophisticated power loading algorithms developed for wireless communications.


A comprehensive evaluation of rodent malaria parasite genomes and gene expression.
Rodent malaria parasites (RMP) are used extensively as models of human malaria. Draft RMP genomes have been published for Plasmodium yoelii, P. berghei ANKA (PbA) and P. chabaudi AS (PcAS). Although availability of these genomes made a significant impact on recent malaria research, these genomes were highly fragmented and were annotated with little manual curation. The fragmented nature of the genomes has hampered genome wide analysis of Plasmodium gene regulation and function. We have greatly improved the genome assemblies of PbA and PcAS, newly sequenced the virulent parasite P. yoelii YM genome, sequenced additional RMP isolates/lines and have characterized genotypic diversity within RMP species. We have produced RNA-seq data and utilised it to improve gene-model prediction and to provide quantitative, genome-wide, data on gene expression. Comparison of the RMP genomes with the genome of the human malaria parasite P. falciparum and RNA-seq mapping permitted gene annotation at base-pair resolution. Full-length chromosomal annotation permitted a comprehensive classification of all subtelomeric multigene families including the 'Plasmodium interspersed repeat genes' (pir). Phylogenetic classification of the pir family, combined with pir expression patterns, indicates functional diversification within this family. Complete RMP genomes, RNA-seq and genotypic diversity data are excellent and important resources for gene-function and post-genomic analyses and to better interrogate Plasmodium biology. Genotypic diversity between P. chabaudi isolates makes this species an excellent parasite to study genotype-phenotype relationships. The improved classification of multigene families will enhance studies on the role of (variant) exported proteins in virulence and immune evasion/modulation.


Oral contraceptive use is associated with prostate cancer: an ecological study.
Background Several recent studies have suggested that oestrogen exposure may increase the risk of prostate cancer (PCa). Objectives To examine associations between PCa incidence and mortality and population-based use of oral contraceptives (OCs). It was hypothesised that OC by-products may cause environmental contamination, leading to an increased low level oestrogen exposure and therefore higher PCa incidence and mortality. Methods The hypothesis was tested in an ecological study. Data from the International Agency for Research on Cancer were used to retrieve age-standardised rates of prostate cancer in 2007, and data from the United Nations World Contraceptive Use 2007 report were used to retrieve data on contraceptive use. A Pearson correlation and multivariable linear regression were used to associate the percentage of women using OCs, intrauterine devices, condoms or vaginal barriers to the age standardised prostate cancer incidence and mortality. These analyses were performed by individual nations and by continents worldwide. Results OC use was significantly associated with prostate cancer incidence and mortality in the individual nations worldwide (r=0.61 and r=0.53, respectively; p<0.05 for all). PCa incidence was also associated with OC use in Europe (r=0.545, p<0.05) and by continent (r=0.522, p<0.05). All other forms of contraceptives (ie, intra-uterine devices, condoms or vaginal barriers) were not correlated with prostate cancer incidence or mortality. On multivariable analysis the correlation with OC was independent of a nation's wealth. Conclusion A significant association between OCs and PCa has been shown. It is hypothesised that the OC effect may be mediated through environmental oestrogen levels; this novel concept is worth further investigation.


Reverse vaccinology and vaccines for serogroup B Neisseria meningitidis.
Whole genome sequence data are increasingly available for a wide range of human pathogens. The use of bioinformatic tools allows the comprehensive in silico screening of genome data for surface-expressed proteins, in order to identify candidate vaccine antigens. In vitro confirmation of surface location and the use of animal models to test immunogenicity further refine the list of proteins likely to be of use as vaccine antigens. This process, first applied to serogroup B Neisseria meningitidis, has been termed as reverse vaccinology. Reverse vaccinology offers the ability to undertake a rapid and comprehensive assessment of a micro-organism's surface protein repertoire, and has advantages over conventional approaches to identifying candidate antigens. Despite the advantages of the approach, development in conventional areas of vaccinology remains important to support the process of producing vaccines from genome-derived antigens.


Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents.
In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for the pathogenesis of NASH. The aim was to dissect the role of hepatocyte Casp8 in a murine model of steatohepatitis. We generated hepatocyte-specific Casp8 knockout (Casp8(Δhep) ) mice. Animals were fed with a methionine-choline-deficient (MCD) diet. Liver injury was assessed by histopathological analysis, apoptotic death, serum alanine aminotransferase (ALT), fluorescent-activated cell sorter (FACS), analysis of liver infiltration and inflammation, reactive oxygen species (ROS), and liver fibrosis. MCD feeding triggered steatosis, hepatic lipid storage, and accumulation of free fatty acid (FFA) in wildtype (WT) livers, which were significantly reduced in Casp8(Δhep) animals. Additionally, lack of Casp8 expression in hepatocytes reduced the MCD-dependent increase in apoptosis and decreased expression of proinflammatory cytokines as well as hepatic infiltration. As a consequence, ROS production was lower, leading to a reduction in the progression of liver fibrosis in Casp8(Δhep) livers. Selective ablation of Casp8 in hepatocytes ameliorates development of NASH by modulating liver injury. Casp8-directed therapy might be a plausible treatment for patients with steatohepatitis. (HEPATOLOGY 2013;57:2189-2201).


Angiogenesis and invasion in gliomas.
Angiogenesis and tumor cell invasion are pathophysiological processes playing a pivotal role in glioma development and growth since the earliest phase. Angiogenesis and tumor invasion both can be considered as an invasive process in which cells are activated, and move away from their initial location, by modyfing the adhesiveness with the extracellular matrix, expressing new adhesion molecules, and degrading the extracellular matrix components by the active secretion of proteases. This process requires a complex cross-talking between endothelial and tumor cells, extracellular matrix components, and cellular elements of the host microenviroment. Both processes are under the tight regulation of a balance between stimulating and inhibiting factors. The existence of common mechanisms of regulation and the presence of naturally occurring factors that inihibit angiogenesis and invasion, makes the inhibition of both processes possible. Tumor cells may develop adapting mechanims that can allow the tumor to partially escape to the treatment, particularly when only one mechanism or one process is inhibited. The ideal treatment should simultaneously affect both angiogenesis and invasion, by the isolation or development of novel therapeutics capable of influencing both processes. As their efficacy seems also be dependent on the mode of delivery, additional studies are also needed to improve these modalities, in order to ultimately improve the extent and the duration of the therapeutic response. The most widely used in vitro and in vivo models to study angiogenesis and invasion are also discussed.


Genetic Correlations Between Diabetes and Glaucoma: An Analysis of Continuous and Dichotomous Phenotypes.
A genetic correlation is the proportion of phenotypic variance between traits that is shared on a genetic basis. Here we explore genetic correlations between diabetes- and glaucoma-related traits. Cross-sectional study. We assembled genome-wide association study summary statistics from European-derived participants regarding diabetes-related traits like fasting blood sugar (FBS) and type 2 diabetes (T2D) and glaucoma-related traits (intraocular pressure [IOP], central corneal thickness [CCT], corneal hysteresis [CH], corneal resistance factor [CRF], cup-to-disc ratio [CDR], and primary open-angle glaucoma [POAG]). We included data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database, the UK Biobank, and the International Glaucoma Genetics Consortium. We calculated genetic correlation (rg) between traits using linkage disequilibrium score regression. We also calculated genetic correlations between IOP, CCT, and select diabetes-related traits based on individual level phenotype data in 2 Northern European population-based samples using pedigree information and Sequential Oligogenic Linkage Analysis Routines. Overall, there was little rg between diabetes- and glaucoma-related traits. Specifically, we found a nonsignificant negative correlation between T2D and POAG (rg = -0.14; P = .16). Using Sequential Oligogenic Linkage Analysis Routines, the genetic correlations between measured IOP, CCT, FBS, fasting insulin, and hemoglobin A1c were null. In contrast, genetic correlations between IOP and POAG (rg ≥ 0.45; P ≤ 3.0 × 10-4) and between CDR and POAG were high (rg = 0.57; P = 2.8 × 10-10). However, genetic correlations between corneal properties (CCT, CRF, and CH) and POAG were low (rg range -0.18 to 0.11) and nonsignificant (P ≥ .07). These analyses suggest that there is limited genetic correlation between diabetes- and glaucoma-related traits.


Failure mechanisms of coiling fibers with sacrificial bonds made by instability-assisted fused deposition modeling.
Instability-assisted 3D printing is a method for producing microstructured fibers with sacrificial bonds and hidden lengths that mimic nature's toughening mechanisms found in spider silk. This hierarchical structure increases the effective toughness of poly(lactic acid) (PLA) fibers by 240-340% in some specimens. Nevertheless, many specimens show worse toughness as low as 25% of that of the benchmark straight fiber due to the incomplete release of hidden lengths caused by premature failures. Here, we report the mechanical tests and simulations of microstructured fibers with coiling loops that identify the material plastic deformation as being crucial to fully release the hidden lengths. Without sufficient material yielding, high local tensile stress results from the bending-torsion-tension coupled deformation of the coiling loop and induces crack initiation at the fiber backbone during the loop unfolding process. On the other hand, the influence of bond-breaking defects is found to be negligible here. Moreover, for a number of broken bonds beyond a critical value, the accumulated elastic energy along the released loops induces a high strain rate (∼1500 mm mm-1 s-1) in a quasi-static tensile test, which fractures the fiber backbone within 0.1 ms after the breaking of a new bond. We also show a size effect in fused deposition modeling (FDM) extruded PLA fibers, which results in a higher effective toughness (∼5 times the performance of the straight fiber benchmark) in small coiling fibers (dia. = 0.37 mm), due to the better ductility in bending and torsion compared to large fibers (dia. = 1.20 mm). The failure mechanisms of single microstructured fibers presented here lay the groundwork for further optimizations of fiber arrays in the next generation of high energy-absorption composites for impact protection and safety-critical applications.


DNA-PKcs-interacting protein KIP binding to TRF2 is required for the maintenance of functional telomeres.
Human telomeres associate with shelterin, a six-protein complex that protects chromosome ends from being recognized as sites of DNA damage. The shelterin subunit TRF2 (telomeric repeat-binding factor 2) protects telomeres by facilitating their organization into the protective capping structure. We have reported previously that the DNA-PKcs (DNA-dependent protein kinase catalytic subunit)-interacting protein KIP associates with telomerase through an interaction with hTERT (human telomerase reverse transcriptase). In the present study, we identify KIP as a novel interacting partner of TRF2. KIP is able to interact with both TRF2 and DNA-PKcs at telomeres. Because KIP is required for the association between TRF2 and DNA-PKcs, the interplay of these three proteins may provide a mechanism for the recruitment of DNA-PKcs to telomeres. We also show that KIP binding to TRF2 enhances the telomere-binding activity of TRF2, suggesting that KIP acts as a positive regulator of TRF2 function. Furthermore, depletion of KIP induces DNA-damage response foci at telomeres, thereby leading to induction of growth arrest, cellular senescence and altered cell cycle distribution. Collectively, our findings suggest that KIP, in addition to its association with catalytically active telomerase, plays important roles in the maintenance of functional telomeres and the regulation of telomere-associated DNA-damage response. Thus KIP represents a new pathway for modulating telomerase and telomere function in cancer.


Proof of concept trial of dronabinol in obstructive sleep apnea.
Animal data suggest that Δ(9)-TetraHydroCannabinol (Δ(9)THC) stabilizes autonomic output during sleep, reduces spontaneous sleep-disordered breathing, and blocks serotonin-induced exacerbation of sleep apnea. On this basis, we examined the safety, tolerability, and efficacy of dronabinol (Δ(9)THC), an exogenous Cannabinoid type 1 and type 2 (CB1 and CB2) receptor agonist in patients with Obstructive Sleep Apnea (OSA). Proof of concept; single-center dose-escalation study of dronabinol. Seventeen adults with a baseline Apnea Hypopnea Index (AHI) ≥15/h. Baseline polysomnography (PSG) was performed after a 7-day washout of Continuous Positive Airway Pressure treatment. Dronabinol was administered after baseline PSG, starting at 2.5 mg once daily. The dose was increased weekly, as tolerated, to 5 mg and finally to 10 mg once daily. Repeat PSG assessments were performed on nights 7, 14, and 21 of dronabinol treatment. Change in AHI (ΔAHI, mean ± SD) was significant from baseline to night 21 (-14.1 ± 17.5; p = 0.007). No degradation of sleep architecture or serious adverse events was noted. Dronabinol treatment is safe and well-tolerated in OSA patients at doses of 2.5-10 mg daily and significantly reduces AHI in the short-term. These findings should be confirmed in a larger study in order to identify sub-populations with OSA that may benefit from cannabimimetic pharmacologic therapy.


Surveillance of avian influenza virus type A in semi-scavenging ducks in Bangladesh.
Ducks are the natural reservoir of influenza A virus and the central host for highly pathogenic avian influenza (H5N1), while domestic ducks rearing in semi-scavenging system could serve as re-assortment vessels for re-emerging new subtypes of influenza viruses between birds to human. Avian influenza virus (AIV) surveillance in Bangladesh has been passive, relying on poultry farmers to report suspected outbreaks of highly pathogenic H5N1 influenza. Here, the results of an active surveillance effort focusing on the semi-scavenging ducks are presented. A total of 2100 cloacal swabs and 2100 sera were collected from semi-scavenging ducks from three wintering-sites of Bangladesh during three successive winter seasons, December through February in the years between 2009 and 2012. Virus isolation and identification were carried out from the cloacal swabs by virus propagation in embryonated hen eggs followed by amplification of viral RNA using Avian influenza virus (AIV) specific RT-PCR. The overall prevalence of avian influenza type A was 22.05% for swab samples and 39.76% ducks were sero-positive for avian influenza type A antibody. Extremely low sero-prevalence (0.09%) of AIV H5N1 was detected. Based on our surveillance results, we conclude that semi-scavenging ducks in Bangladesh might play important role in transmitting Avian Influenza virus (AIV) type A. However, the current risk of infection for humans from domestic ducks in Bangladesh is negligible. We believe that this relatively large dataset over three winters in Bangladesh might create a strong foundation for future studies of AIV prevalence, evolution, and ecology in wintering sites around the globe.


Robotic ultrasound-guided SBRT of the prostate: feasibility with respect to plan quality.
Advances in radiation therapy delivery systems have enabled motion compensated SBRT of the prostate. A remaining challenge is the integration of fast, non-ionizing volumetric imaging. Recently, robotic ultrasound has been proposed as an intra-fraction image modality. We study the impact of integrating a light-weight robotic arm carrying an ultrasound probe with the CyberKnife system. Particularly, we analyze the effect of different robot poses on the plan quality. A method to detect the collision of beams with the robot or the transducer was developed and integrated into our treatment planning system. A safety margin accounts for beam motion and uncertainties. Using strict dose bounds and the objective to maximize target coverage, we generated a total of 7650 treatment plans for five different prostate cases. For each case, ten different poses of the ultrasound robot and transducer were considered. The effect of different sets of beam source positions and different motion margins ranging from 5 to 50 mm was analyzed. Compared to reference plans without the ultrasound robot, the coverage typically drops for all poses. Depending on the patient, the robot pose, and the motion margin, the reduction in coverage may be up to 50 % points. However, for all patient cases, there exist poses for which the loss in coverage was below 1 % point for motion margins of up to 20 mm. In general, there is a positive correlation between the number of treatment beams and the coverage. While the blocking of beam directions has a negative effect on the plan quality, the results indicate that a careful choice of the ultrasound robot's pose and a large solid angle covered by beam starting positions can offset this effect. Identifying robot poses that yield acceptable plan quality and allow for intra-fraction ultrasound image guidance, therefore, appears feasible.


Altered Heart Rate Variability During Gameplay in Internet Gaming Disorder: The Impact of Situations During the Game.
Internet gaming disorder (IGD) is characterized by a loss of control over gaming and a decline in psychosocial functioning derived from excessive gameplay. We hypothesized that individuals with IGD would show different autonomic nervous system (ANS) responses to the games than those without IGD. In this study, heart rate variability (HRV) was assessed in 21 young males with IGD and 27 healthy controls while playing their favorite Internet game. The subjects could examine the game logs to identify the most and least concentrated periods of the game. The changes in HRV during specific 5-min periods of the game (first, last, and high- and low-attention) were compared between groups via a repeated measures analysis of variance. Significant predictors of HRV patterns during gameplay were determined from stepwise multiple linear regression analyses. Subjects with IGD showed a significant difference from controls in the patterns of vagally mediated HRV, such that they showed significant reductions in high-frequency HRV, particularly during the periods of high attention and the last 5 min, compared with baseline values. A regression analysis showed that the IGD symptom scale score was a significant predictor of this reduction. These results suggest that an altered HRV response to specific gaming situations is related to addictive patterns of gaming and may reflect the diminished executive control of individuals with IGD while playing Internet games.


Antiviral effects of ferric ammonium citrate.
Iron is an essential nutrient for cell survival and is crucial for DNA replication, mitochondrial function and erythropoiesis. However, the immunological role of iron in viral infections has not been well defined. Here we found the iron salt ferric ammonium citrate (FAC) inhibited Influenza A virus, HIV virus, Zika virus, and Enterovirus 71 (EV71) infections. Of note, both iron ion and citrate ion were required for the antiviral capability of FAC, as other iron salts and citrates did not exhibit viral inhibition. Mechanistically, FAC inhibited viral infection through inducing viral fusion and blocking endosomal viral release. These were further evidenced by the fact that FAC induced liposome aggregation and intracellular vesicle fusion, which was associated with a unique iron-dependent cell death. Our results demonstrate a novel antiviral function of FAC and suggest a therapeutic potential for iron in the control of viral infections.


Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the "Advanced Dissolution, Absorption, Metabolism (ADAM)" model.
Bioavailability of orally administered drugs can be influenced by a number of factors including release from the formulation, dissolution, stability in the gastrointestinal (GI) environment, permeability through the gut wall and first-pass gut wall and hepatic metabolism. Although there are various enzymes in the gut wall which may contribute to gut first pass metabolism, Cytochrome P450 (CYP) 3A has been shown to play a major role. The efflux transporter P-glycoprotein (P-gp; MDR1/ABCB1) is the most extensively studied drug efflux transporter in the gut and might have a significant role in the regulation of GI absorption. Although not every CYP3A substrate will have a high extent of gut wall first-pass extraction, being a substrate for the enzyme increases the likelihood of a higher first-pass extraction. Similarly, being a P-gp substrate does not necessarily pose a problem with the gut wall absorption however it may reduce bioavailability in some cases (e.g. when drug has low passive permeability). An on-going debate has focused on the issue of the interplay between CYP3A and P-gp such that high affinity to P-gp increases the exposure of drug to CYP3A through repeated cycling via passive diffusion and active efflux, decreasing the fraction of drug that escapes first pass gut metabolism (F(G)). The presence of P-gp in the gut wall and the high affinity of some CYP3A substrates to this transporter are postulated to reduce the potential for saturating the enzymes, thus increasing gut wall first-pass metabolism for compounds which otherwise would have saturated CYP3A. Such inferences are based on assumptions in the modelling of oral drug absorption. These models should be as mechanistic as possible and tractable using available in vitro and in vivo information. We review, through simulation, this subject and examine the interplay between gut wall metabolism and efflux transporters by studying the fraction of dose absorbed into enterocytes (F(a)) and F(G) via systematic variation of drug characteristics, in accordance with the Biopharmaceutics Classification System (BCS) within one of the most physiological models of oral drug absorption currently available, respectively ADAM. Variables studied included the intrinsic clearance (CLint) and the Michaelis-Menten Constant (Km) for CYP3A4 and P-gp (C(Lint-CYP3A4) and K(m-CYP3A4), CL(int-P-gp) and K(m-P-gp)). The impact of CYP3A4 and P-gp intracellular topography were not investigated since a well-stirred enterocyte is assumed within ADAM. An increased CLint-CYP3A4 resulted in a reduced F(G) whereas an increase in C(Lint-P-gp) resulted in a reduced F(a), but interestingly decreased F(G) too. The reduction in FG was limited to certain conditions and was modest. Non-linear relationships between various parameters determining the permeability (e.g. P(app), C(Lint-P-gp,) and K(m-P-gp)) and gut wall metabolism (e.g. C(Lint-CYP3A4,) K(m-CYP3A4)) resulted in disproportionate changes in F(G) compared to the magnitude of singular effects. The results suggest that P-gp efflux decreases enterocytic drug concentration for drugs given at reasonably high dose which possess adequate passive permeability (high P(app)), by de-saturating CYP3A4 in the gut resulting in a lower F(G). However, these findings were observed only in a very limited area of the parameters space matching very few therapeutic drugs (a group with very high metabolism, high turn-over by efflux transporters and low F(a)). The systematic approach in this study enabled us to recognise the combination of parameters values where the potential interplay between metabolising enzymes and efflux transporters is expected to be highest, using a realistic range of parameter values taken from an intensive literature search.


Health care reform and social movements in the United States.
Because of the importance of grassroots social movements, or "change from below," in the history of US reform, the relationship between social movements and demands for universal health care is a critical one. National health reform campaigns in the 20th century were initiated and run by elites more concerned with defending against attacks from interest groups than with popular mobilization, and grassroots reformers in the labor, civil rights, feminist, and AIDS activist movements have concentrated more on immediate and incremental changes than on transforming the health care system itself. However, grassroots health care demands have also contained the seeds of a wider critique of the American health care system, leading some movements to adopt calls for universal coverage.


Immunization of primates with a Newcastle disease virus-vectored vaccine via the respiratory tract induces a high titer of serum neutralizing antibodies against highly pathogenic avian influenza virus.
The ongoing outbreak of highly pathogenic avian influenza virus (HPAIV) in birds, the incidence of transmission to humans with a resulting high mortality rate, and the possibility of a human pandemic warrant the development of effective human vaccines against HPAIV. We developed an experimental live-attenuated vaccine for direct inoculation of the respiratory tract based on recombinant avian Newcastle disease virus (NDV) expressing the hemagglutinin (HA) glycoprotein of H5N1 HPAIV (NDV-HA). Expression of the HPAIV HA gene slightly reduced NDV virulence, as evidenced by the increased mean embryo death time and reduced replication in chickens. NDV-HA was administered to African green monkeys in two doses of 2 x 10(7) infectious units each with a 28-day interval to evaluate the systemic and local antibody responses specific to H5N1 HPAIV. The virus was shed only at low titers from the monkeys, indicative of safety. Two doses of NDV-HA induced a high titer of H5N1 HPAIV-neutralizing serum antibodies in all of the immunized monkeys. Moreover, a substantial mucosal immunoglobulin A response was induced in the respiratory tract after one and two doses. The titers of neutralizing antibodies achieved in this study suggest that the vaccine would be likely to prevent mortality and reduce morbidity caused by the H5N1 HPAIV. In addition, induction of a local immune response in the respiratory tract is an important advantage that is likely to reduce or prevent transmission of the virus during an outbreak or a pandemic. This vaccine is a candidate for clinical evaluation in humans.


Characterization of the nonenzymatic chloramphenicol resistance (cmlA) gene of the In4 integron of Tn1696: similarity of the product to transmembrane transport proteins.
Integrons constitute a novel family of DNA elements which evolved by site-specific integration of discrete units between two conserved segments. On the In4 integron of Tn1696, a precisely inserted gene cassette of 1,549 bp conferring nonenzymatic chloramphenicol resistance (cmlA) is present between the streptomycin-spectinomycin resistance (aadA2) gene cassette and the 3'-conserved segment of the integron. In this study, we present the nucleotide sequence of the cmlA gene cassette of Tn1696, show its similarity to bacterial efflux systems and other transport proteins, and present evidence for alterations that its expression exerts on bacterial membranes. The cmlA gene cassette apparently carries its own promoter(s), a situation that has not heretofore been observed in the integrons of multiresistance plasmids and transposons of gram-negative bacteria. One or more of these promoters were shown to be functionally active in expressing a cat marker gene from promoter-probe vectors. The putative CmlA polypeptide appears to provoke a reduction of the content of the major porins OmpA and OmpC.


Hypoxia increases ROS signaling and cytosolic Ca(2+) in pulmonary artery smooth muscle cells of mouse lungs slices.
Precapillary arteries constrict during alveolar hypoxia in a response known as hypoxic pulmonary vasoconstriction (HPV). The mechanism by which pulmonary arterial smooth muscle cells (PASMCs) detect a decrease in Po(2) and trigger contraction is not fully understood. Previous studies in cultured PASMCs show that hypoxia induces an increase in reactive oxygen species (ROS) production, but these results may not reflect responses of PASMCs in their native tissue environment. We therefore assessed hypoxia-induced changes in cytosolic ROS in PASMCs of precision-cut mouse lung slices expressing the redox-sensitive protein, RoGFP. Superfusion of lung slices with hypoxic media (1.5% O(2)) resulted in a significant oxidation of RoGFP from normoxic baseline that was attenuated by overexpression of cytosolic catalase. Hypoxic superfusion also increased [Ca(2+)](i) above normoxic baseline; this response was significantly attenuated by cytosolic catalase overexpression or by the administration of EUK134, a synthetic SOD-catalase mimetic. The hypoxia-induced increase in [Ca(2+)](i) was abolished in the absence of extracellular Ca(2+), indicating that ROS signals trigger entry of extracellular calcium. Collectively, these results indicate that an increase in cytosolic ROS signaling is required for the increase in [Ca(2+)](i) in PASMCs in precision-cut mouse lung slices during the acute HPV response.


Initial Development of the Mental Health Assessment and Dynamic Referral for Oncology (MHADRO).
The Mental Health Assessment and Dynamic Referral for Oncology (MHADRO) is a program that conducts a computerized assessment of physical, psychological, and social functioning related to oncology treatment, prints personalized summary reports for both the patient and the provider, and for those who provide consent, faxes a referral and assessment summary report to a matched mental health treatment provider (i.e., dynamic referral). The functionality, feasibility, and end user satisfaction of the MHADRO were tested in a comprehensive care center. Of the 101 participants enrolled, 61 (60%) exhibited elevated distress on at least one of the mental health indices, and, of these, 12 (20%) chose a dynamic referral for mental health services. Patients and health care providers exhibited high levels of satisfaction with the program. The MHADRO has potential for assisting in meeting the psychosocial needs faced by individuals with cancer and should be tested further for its facilitation of mental health treatment initiation.


The High Cost of Prescription Drugs in the United States: Origins and Prospects for Reform.
The increasing cost of prescription drugs in the United States has become a source of concern for patients, prescribers, payers, and policy makers. To review the origins and effects of high drug prices in the US market and to consider policy options that could contain the cost of prescription drugs. We reviewed the peer-reviewed medical and health policy literature from January 2005 to July 2016 for articles addressing the sources of drug prices in the United States, the justifications and consequences of high prices, and possible solutions. Per capita prescription drug spending in the United States exceeds that in all other countries, largely driven by brand-name drug prices that have been increasing in recent years at rates far beyond the consumer price index. In 2013, per capita spending on prescription drugs was $858 compared with an average of $400 for 19 other industrialized nations. In the United States, prescription medications now comprise an estimated 17% of overall personal health care services. The most important factor that allows manufacturers to set high drug prices is market exclusivity, protected by monopoly rights awarded upon Food and Drug Administration approval and by patents. The availability of generic drugs after this exclusivity period is the main means of reducing prices in the United States, but access to them may be delayed by numerous business and legal strategies. The primary counterweight against excessive pricing during market exclusivity is the negotiating power of the payer, which is currently constrained by several factors, including the requirement that most government drug payment plans cover nearly all products. Another key contributor to drug spending is physician prescribing choices when comparable alternatives are available at different costs. Although prices are often justified by the high cost of drug development, there is no evidence of an association between research and development costs and prices; rather, prescription drugs are priced in the United States primarily on the basis of what the market will bear. High drug prices are the result of the approach the United States has taken to granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits. The most realistic short-term strategies to address high prices include enforcing more stringent requirements for the award and extension of exclusivity rights; enhancing competition by ensuring timely generic drug availability; providing greater opportunities for meaningful price negotiation by governmental payers; generating more evidence about comparative cost-effectiveness of therapeutic alternatives; and more effectively educating patients, prescribers, payers, and policy makers about these choices.


Azadirachta indica (Sapindales: Meliaceae) Neem Oil as a Repellent Against Aedes albopictus (Diptera: Culicidae) Mosquitoes.
Increased concerns regarding the safety of many chemicals used as insecticides or repellents, together with the development of resistance by insects to various insecticides, have led to the search for new active natural ingredients. For what we believe is the first time, that is monitored the efficiency of neem oil (Azadirachta indica) as a repellent against adult Aedes albopictus directly in the field. To test the efficacy of repellency against adults, treatments were performed (5 ml/l) in six different locations. For each location, two closed gardens distance between them 200 m were chosen (one where the treatment was performed, consisting in spraying a mixture of water and Neem oil 5 g/l and one which was used as a control where only water with emulsifier was used). To monitor the treatment efficacy, six ovitraps were used (for each location three for the treated garden and three for the control garden). Data (n° mosquito eggs trapped in each ovitrap) were collected weekly for 6 mo (from May to October) for a total of 900 samplings. Daily temperature and daily rainfall were monitored throughout the trial. The treatment was most effective in June and July. Very high temperatures and high rainfall reduced the efficacy of neem oil over time.


Optimal integration of intraneural somatosensory feedback with visual information: a single-case study.
Providing somatosensory feedback to amputees is a long-standing objective in prosthesis research. Recently, implantable neural interfaces have yielded promising results in this direction. There is now considerable evidence that the nervous system integrates redundant signals optimally, weighting each signal according to its reliability. One question of interest is whether artificial sensory feedback is combined with other sensory information in a natural manner. In this single-case study, we show that an amputee with a bidirectional prosthesis integrated artificial somatosensory feedback and blurred visual information in a statistically optimal fashion when estimating the size of a hand-held object. The patient controlled the opening and closing of the prosthetic hand through surface electromyography, and received intraneural stimulation proportional to the object's size in the ulnar nerve when closing the robotic hand on the object. The intraneural stimulation elicited a vibration sensation in the phantom hand that substituted the missing haptic feedback. This result indicates that sensory substitution based on intraneural feedback can be integrated with visual feedback and make way for a promising method to investigate multimodal integration processes.


Catheter Ablation of Atrial Fibrillation in U.S. Community Practice--Results From Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).
The characteristics of patients undergoing atrial fibrillation (AF) ablation and subsequent outcomes in community practice are not well described. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we investigated the prevalence and impact of catheter ablation of AF. Among 9935 patients enrolled, 5.3% had previous AF ablation. Patients with AF ablation were significantly younger, more frequently male, and had less anemia, chronic obstructive pulmonary disease, and previous myocardial infarction (P<0.05 for all analyses) than those without previous catheter ablation of AF. Ablated patients were more likely to have a family history of AF, obstructive sleep apnea, paroxysmal AF, and moderate-to-severe symptoms (P<0.0001 for all analyses). Patients with previous ablation were more often in sinus rhythm on entry into the registry (52% vs. 32%; P<0.0001). Despite previous ablation, 46% in the ablation group were still on antiarrhythmic therapy. Oral anticoagulation was prescribed in 75% of those with previous ablation versus 76% in those without previous ablation (P=0.5). The adjusted risk of death (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.52 to 1.18; P=0.2) and cardiovascular (CV) hospitalization (HR, 1.06; 95% CI, 0.90 to 1.26; P=0.5) were similar in both groups. Patients with incident AF ablation had higher risk of subsequent CV hospitalization than matched patients without incident ablation (HR, 1.67; 95% CI, 1.24 to 2.26; P=0.0008). In U.S. clinical practice, a minority of patients with AF are managed with catheter ablation. Subsequent to ablation, there were no significant differences in oral anticoagulation use or outcomes, including stroke/non-central nervous system embolism/transient ischemic attack or death. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01165710.


Synthesis of porous PEG microgels using CaCO3 microspheres as hard templates.
Porous poly(ethylene glycol) (PEG) microgels of both 17.6 and 8.3 μm in diameter are synthesized via hard templating with calcium carbonate (CaCO(3)) microparticles. The synthesis is performed in three steps: loading of PEG macromonomers into CaCO(3) microparticles, crosslinking via photopolymerization, and removal of the CaCO(3) template under acidic conditions. The resulting porous PEG microgels are inverse replicates of their templates as indicated by light microscopy, cryo-scanning electron microscopy (cryo-SEM), and permeability studies. Thus this process allows for the straightforward and highly reproducible synthesis of porous hydrogel particles of two different diameters and porosities that show great potential as carriers for drugs or nanomaterials.


Global analysis of the ground-state wrapping conformation of a charged polymer on an oppositely charged nano-sphere.
We investigate the wrapping conformations of a single, strongly adsorbed polymer chain on an oppositely charged nano-sphere by employing a reduced (dimensionless) representation of a primitive chain-sphere model. This enables us to determine the global behavior of the chain conformation in a wide range of values for the system parameters including the chain contour length, its linear charge density and persistence length as well as the nano-sphere charge and radius, and also the salt concentration in the bathing solution. The structural behavior of a charged chain-sphere complex can be described in terms of a few distinct conformational symmetry classes separated by continuous or discontinuous transition lines which are determined by means of appropriately defined (order) parameters. Our results can be applied to a wide class of strongly coupled polymer-sphere complexes including, for instance, complexes that comprise a mechanically flexible or semiflexible polymer chain or an extremely short or long chain and, as a special case, include the biologically relevant example of DNA-histone complexes.


Lung inflammation and genotoxicity in mice lungs after pulmonary exposure to candle light combustion particles.
Candle burning produces a large amount of particles that contribute substantially to the exposure to indoor particulate matter. The exposures to various types of combustion particles, such as diesel exhaust particles, have been associated with increased risk of lung cancer by mechanisms that involve oxidative stress, inflammation and genotoxicity. The aim of this study was to compare pulmonary effects of candle light combustion particles (CP) with two benchmark diesel exhaust particles (A-DEP and SRM2975). Intratracheal (i.t.) instillation of CP (5mg/kg bodyweight) in C57BL/6n mice produced a significant influx of alveolar macrophages and polymorphonuclear leukocytes and increased concentrations of proteins and lactate dehydrogenase activity in bronchoalveolar fluid. Lower levels of these markers of inflammation and cytotoxicity were observed after i.t. instillation of the same dose of A-DEP or SRM2975. The i.t. instillation of CP did not generate oxidative damage to DNA in lung tissue, measured as DNA strand breaks and human 8-oxoguanine glycosylase-sensitive sites by the comet assay. The lack of genotoxic response was confirmed in lung epithelial (A549) cells, although the exposure to CP increased intracellular levels of reactive oxygen species. In conclusion, pulmonary exposure to particles from burning candles is associated with inflammation and cytotoxicity in the lungs.


Safety and effectiveness of vibration massage by deep oscillations: a prospective observational study.
The objective of this study is to assess the safety of treatment with vibration massage using a deep oscillation device and the effects on symptom severity and quality of life in patients with primary fibromyalgia syndrome (FMS). Outpatients with FMS performed an observational prospective study with visits 2-4 weeks after the last treatment (control) and after further 2 months (follow-up). Patients were treated with 10 sessions of 45 min deep oscillation massage, 2/week. Primary outcome parameters were safety and tolerability (5-level Likert scale (1 = very good)) (after each treatment session and at control visit). Secondary outcome parameters were symptom severity (Fibromyalgia Impact Questionnaire (FIQ), pain) and quality of life (SF-36). Seventy patients (97.1% females) were included. At control visit, 41 patients (58.6%) reported 63 mild and short-lasting adverse events, mainly worsening of prevalent symptoms such as pain and fatigue. Tolerability was rated as 1.8 (95% confidence interval: 1.53; 2.07). Symptoms and quality of life were significantly improved at both control and follow-up visits (at least P < 0.01). In conclusion, deep oscillation massage is safe and well tolerated in patients with FMS and might improve symptoms and quality of life rather sustained.