A cognitive-behavioral skills building program improves mental health and enhances healthy lifestyle behaviors in nurses and other hospital employees.
Mental health outcomes in nurses have historically indicated a greater prevalence of anxiety, depression, and suicide than the general population. It is vital to provide programming for healthcare workers to gain the necessary skills to reduce burnout and improve their mental and physical health. The aims of this study were to evaluate mental health outcomes and healthy lifestyle beliefs and behaviors among nurses and other hospital employees who completed MINDBODYSTRONG, a cognitive-behavioral skill building program. A pre-experimental, pre- and poststudy design was used to examine mental health and well-being outcomes among 100 hospital personnel who participated in MINDBODYSTRONG, a program designed to improve coping and resiliency and decrease stress, anxiety, and depressive symptoms. Outcomes measured included healthy lifestyle behaviors, healthy lifestyle beliefs, anxiety, depression, stress, and burnout. One hundred hospital personnel, including 93 nurses, completed the pre- and post-survey. Among all participants, post- MINDBODYSTRONG scores for healthy lifestyle beliefs (p = .00; Cohen's d = 0.52) and healthy lifestyle behaviors (p = .00; Cohen's d = -0.74) increased significantly with medium effects, while depression (p = .00; Cohen's d = -0.51), anxiety (p = .00; Cohen's d = -0.54), stress (p = .00; Cohen's d = -0.33), and burnout (p = .00; Cohen's d = -0.37) decreased significantly with small and medium effects. The program produced even stronger positive effects on mental health outcomes for participants who started the study with higher levels of depression and anxiety. Anxiety, depression, stress, and burnout decreased significantly postintervention. Participants also significantly improved their healthy lifestyle beliefs and behaviors with the MINDBODYSTRONG program. MINDBODYSTRONG is an effective program that reduces anxiety, depression, burnout, and stress and improves healthy lifestyle beliefs and behaviors in hospital-based clinicians. It is of utmost importance to provide evidence-based programs to improve mental resiliency and decrease stress, anxiety, burnout, and depressive symptoms, which will ultimately improve the safety and quality of health care.


Accuracy and borehole influences in pulsed neutron gamma density logging while drilling.
A new pulsed neutron gamma density (NGD) logging has been developed to replace radioactive chemical sources in oil logging tools. The present paper describes studies of near and far density measurement accuracy of NGD logging at two spacings and the borehole influences using Monte-Carlo simulation. The results show that the accuracy of near density is not as good as far density. It is difficult to correct this for borehole effects by using conventional methods because both near and far density measurement is significantly sensitive to standoffs and mud properties.


Manipulating the growth environment through co-culture to enhance stress tolerance and viability of probiotic strains in the gastrointestinal tract.
The viability of probiotics in the human gastrointestinal tract is important, as some reports indicate that the health benefits of live bacteria are greater than those of dead ones. Therefore, the higher the viability of the probiotic strain, the better it may be. However, probiotic strains lose their viability due to gastrointestinal stress such as gastric acid and bile. This study provides an example of the use of co-culture or pH-controlled monoculture, which uses more stringent conditions (lower pH) than normal monoculture to produce probiotic strains that are more resistant to gastrointestinal stress. In addition, co-cultured beverages showed higher viability of the probiotic strain in the human gastrointestinal tract than monocultured beverages in our human study.


Clinical experience with gamma knife stereotactic radiosurgery in the management of vestibular schwannomas secondary to type 2 neurofibromatosis.
To evaluate the results of stereotactic radiosurgery treating vestibular schwannomas secondary to type 2 neurofibromatosis. A retrospective review of 122 type 2 neurofibromatosis vestibular schwannomas consecutively treated in 96 patients. Tumour control was assessed by recourse to surgical intervention, by serial radiological imaging, and by the calculation of relative growth ratios in patients (n=29) habouring untreated contralateral tumours to act as internal controls. Hearing function was assessed with Gardner-Robertson grades and with averaged pure tone audiogram thresholds. Other complications are detailed. Applying current techniques, eight years after radiosurgery it was estimated that 20% of patients will have undergone surgery for their tumour, 50% will have radiologically controlled tumours, and in 30% there will be some variable concern about tumour control, but up to that time they will have been managed conservatively. Relative growth ratios one and two years after treatment indicate that radiosurgery confers a significant (p=0.01) advantage over the natural history of the disease. Analysis of these ratios beyond two years was precluded by the need to intervene and radiosurgically treat the contralateral control tumours in more than 50% of the cases. This growth control was achieved with 40% of patients retaining their Gardner-Robertson hearing grades three years after treatment, (40% having some deterioration in grade, 20% becoming deaf). Pure tone audiogram results suggest some progressive long term hearing loss, although interpretation of this is difficult. Facial and trigeminal neuropathy occurred in 5% and 2%. Radiosurgery is a valuable minimally invasive alternative treatment for these tumours. For most patients, it controls growth or defers the need for surgery, or both. There is a price in terms of hearing function, although this may compare favourably with the deafness associated with the natural history of the disease, and with surgery. In deciding on therapy, patients should be aware of this treatment option.


Volumetric descriptions of objects from multiple views.
Occluding contours from an image sequence with view-point specifications determine a bounding volume approximating the object generating the contours. The initial creation and continual refinement of the approximation requires a volumetric representation that facilitates modification yet is descriptive of surface detail. The ``volume segment'' representation presented in this paper is one such representation.


Effect of aspirin on aqueous protein values in the dog.
Aqueous protein concentration, degree of miosis, and intraocular pressure were evaluated in dogs given aspirin, then subjected to aqueous paracentesis and reverse cyclodialysis. Compared with control dogs, the dogs given aspirin had less aqueous protein, but there was no difference in miosis or in intraocular pressure. The practical application of this finding is that aspirin given prior to intraocular surgery may be of value in minimizing the postoperative increase in aqueous protein content.


Systemic adjuvant therapy for adult patients at high risk for recurrent melanoma: A systematic review.
Cutaneous melanoma is typically treated with wide local excision and, when appropriate, a sentinel node biopsy. Many patients are cured with this approach but for patients who have cancers with high risk features there is a significant risk of local and distant relapse and death. Interferon-based adjuvant therapy was recommended in the past but had modest results with significant toxicity. Recently, new therapies (immune checkpoint inhibitors and targeted therapies) have been found to be effective in the treatment of patients with metastatic melanoma and many of these therapies have been evaluated and found to be effective in the adjuvant treatment of high risk patients with melanoma. This systematic review of adjuvant therapies for cutaneous and mucosal melanoma was conducted for Ontario Health (Cancer Care Ontario) as the basis of a clinical practice guideline to address the question of whether patients with completely resected melanoma should be considered for adjuvant systemic therapy and which adjuvant therapy should be used.


Comparison of 3 different anesthetic approaches for intravitreal injections: a prospective randomized trial.
To compare the anesthetic effectiveness of topical proparacaine drops, subconjunctival lidocaine, and 2% lidocaine gel. Ninety-two patients undergoing intravitreal injections were randomized to 1 of 3 groups: proparacaine 0.5% drops (Group Drops), proparacaine 0.5% drops plus subconjunctival lidocaine (Group SC), or 2% lidocaine gel (Group Gel). Patients were asked to score their pain experience using a visual analog scale of 0 to 10 immediately following the injections and 10 min, 1 h, 6 h, and 24 h after the injections. Patients also graded the overall injection experience as Excellent, Very Good, Fair, Poor, or Awful. The physician evaluated the patients' eye movement during intravitreal injection on 3 levels: (0) none or minimal, (1) not compromising the injection, and (2) compromising the injection. The patients in Group Drops had the worst mean pain scores during the injection and 10 min after, with the highest occurrence of movements compromising the procedure (Grade 2; 38.7%). The patients in Group SC had a higher percentage of good experiences (37.9%) but a higher incidence of chemosis (16.7%). The patients in Group Gel had similar overall pain scores to Group Drops patients but a higher incidence of keratitis (19.4%). There was no statistically significant correlation between the use of aspirin or anticoagulants and the occurrence of hyperemia or hyposphagma. Subconjunctival lidocaine was most effective in preventing pain and eye movements during intravitreal injections. Although 2% lidocaine gel produced a good overall experience for the patients, the incidence of keratitis was very high (19.4%). Therefore, we do not recommend 2% lidocaine gel as the first anesthetic choice for intravitreal injections. There is no evidence to suspend the use of aspirin or other anticoagulants drugs prior to intravitreal injections.


[Perception of students of a public university on the Education Program for Work in Health].
This study sought to analyze the Education Program for Work in Health from the perspective of students at a public university in Belo Horizonte, State of Minas Gerais, in their first year and its impact on the students' qualification. It is a prospective cohort study with students who participated on this program, and the data was collected by a structured and self-applied questionnaire, during the sixth and tenth months of the program, with sociodemographic questions, methodology, aims and impact of the program. The majority reported that the program's proposed aims were attained, especially interdisciplinary work and academic research focused on the Unified Health System's needs. The program also contributed to training in research, teaching and extension work, and in the second evaluation, the students reported greater interaction with social equipment. It is considered that the program is an important strategy for human resources training in accordance with the Unified Health System's needs, by enabling the exercise of teamwork, communication, agility and creativity to deal with adverse situations, as well as the practice of the primary health care principles integrated in the community.


Use of an extraretinal signal by monkey superior colliculus neurons to distinguish real from self-induced stimulus movement.
1. In order to see whether cells in the superficial layers of the monkey superior colliculus can differentiate between real stimulus movement and self-induced stimulus movement we compared the discharge of these cells to stimulus movement in front of the stationary eye with stimulus movement generated by eye movements across a stationary stimulus. 2. Most of the cells recorded (65% of 231 cells) responded to stimulus velocities in front of the stationary eye as fast as those occurring during the peak velocity of a saccadic eye movement. Those cells that do respond usually have weak inhibitory regions and tend to have receptive fields further from fovea. 3. Move (61% of 105 cells) of the cells that did respond to rapid stimulus movement did not respond when an eye movement swept the receptive field over a stationary stimulus. 4. About half of these cells differentiated between these stimulus conditions when we used stimuli at least 1 log unit above background illumination; the remaining cells differentiated for stimuli 2 and 3 log units above background. Many cells differentiated between the two stimulus conditions over a wide range of directions of movement and the effect appears with about equal frequency in receptive fields at all distances from the fovea. 5. The differentiation is present for most cells even when the background illumination is reduced, indicating that visual factors are not the cause of the effect on these cells but may modify the response of other cells. 6. The suppression of background activity accompanying eye movements in the light is present following eye movements made in total darkness; the suppression, therefore, must result from an extraretinal signal. 4. The failure of these cells to respond to visual stimulation during eye movements is due to the same extraretinal signal that produces the suppression since a) the cells that show this suppression tend to be those that fail to respond to stimuli during eye movements, b) the time course of the suppression matches the time at which the effects of visual stimulation during an eye movement would reach the colliculus, and c) the cells which differentiate also show a decreased responsiveness to visual stimulation during the time of background suppression. While this extraretinal signal has the characteristics one would expect of a corollary discharge, proprioception as a source of the signal cannot be excluded. 8. Cells which differentiate between the two stimulus conditions usually also show an enhanced response to a visual stimulus in their receptive field when it is to be the target for a saccadic eye movement. These cells in the superior colliculus receive an extraretinal input which permits them to differentiate betweent real stimulus movements and stimulus movements resulting from the monkey's own eye movements. This differentiation would provide an uncontaminated visual movement signal and facilitate the detection of real movement in the environment...


Non-parametric treatment time-lag effect estimation.
In general, the change point problem considers inference of a change in distribution for a set of time-ordered observations. This has applications in a large variety of fields, and can also apply to survival data. In survival analysis, most existing methods compare two treatment groups for the entirety of the study period. Some treatments may take a length of time to show effects in subjects. This has been called the time-lag effect in the literature, and in cases where time-lag effect is considerable, such methods may not be appropriate to detect significant differences between two groups. In this paper, we propose a novel non-parametric approach for estimating the point of treatment time-lag effect by using an empirical divergence measure. Theoretical properties of the estimator are studied. The results from the simulated data and the applications to real data examples support our proposed method.


Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells.
Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro. t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs.


Recommendations for reporting C cell pathology of the thyroid.
Calcitonin screening programs have proved to be effective in early detection of medullary thyroid carcinoma, not only in patients with known risk factors for the development of hereditary tumors. Thus, more thyroidectomies, based on an abnormal pentagastrin test, can be expected. Here we give summarizing recommendations for reporting C cell pathology. All patients underwent total thyroidectomy and were tested for germ-line mutations in the RET-Protooncogene. The entire surgical specimens were blocked and C-cell disorders were assessed using conventional histology and immunohistochemistry. Among 110 patients with an abnormal pentagastrin test, 60 (55%) had medullary thyroid carcinoma (T1 34% [n = 37], T2 14% [n = 16], T4 6% [n = 7]), and 50 (45%) had C cell hyperplasia only. C cell hyperplasia accompanying medullary thyroid carcinoma was found in 13 of 15 familial and in 28 of 45 sporadic patients. All C cell changes were found in the upper two thirds of the thyroid lobes and 83% of the medullary thyroid carcinomas could be identified with frozen sections. 1. Abnormal pentagastrin stimulation is always associated with either medullary thyroid carcinoma or C cell hyperplasia. 2. Blocking of the entire upper two thirds of the thyroid lobes is essential for reliable detection of C cell hyperplasia and small medullary thyroid carcinomas. 3. Most medullary thyroid carcinomas can be detected with intraoperative frozen sections. 4. The presence of C cell hyperplasia should always be reported; however its usefulness for indicating familial risk is limited and its role as a preneoplastic condition in patients without RET-protooncogene mutations remains to be elucidated.


Pulmonary Involvement in Acute Rheumatic Fever: A Case Report and Literature Review.
Rheumatic pneumonia is a pulmonary complication of rheumatic fever, often with grave outcomes. It has been described sporadically in literature, most recently a decade ago. Here, we describe a case of a 12-year-old Native American girl presenting with chest pain, gastrointestinal complaints, and frequent nosebleeds. After the initial diagnosis with acute pericarditis, she was found to meet diagnostic criteria for rheumatic fever. Revised Jones criteria met included significantly elevated streptolysin O antibody and anti-DNase B, carditis, arthralgia, fever, and elevated inflammatory markers. Findings complicating the diagnosis were an elevated antinuclear antigen with a family history of systemic lupus erythematosus (SLE), hemoptysis, and a chest CT finding of right lower lobe alveolar hemorrhage as well as right-sided mediastinal adenopathy. The patient was discharged on day nine of admission after a course of high-dose methylprednisolone with prednisone taper, furosemide, enalapril, naproxen, monthly penicillin G injections, and multidisciplinary outpatient follow-up. A repeat chest CT scan three months later showed significant improvement. The pulmonary findings described in our patient are consistent with prior reports of rheumatic pneumonia, however, most prior cases described did not include high-resolution imaging. Our patient recovered well aside from complications secondary to mitral regurgitation, unlike many patients seen in our literature search who died due to early or later complications of pulmonary disease. Although acute rheumatic fever, and its pulmonary complications, is significantly less common than it once was, it remains a disease entity that should remain on the differential for multisystem rheumatic complaints.


Epithelial respiratory cells from cystic fibrosis patients do not possess specific Pseudomonas aeruginosa-adhesive properties.
Nasal polyp cells in primary culture from cystic fibrosis (CF) and non-CF patients were compared for the ability to bind Pseudomonas aeruginosa cells and for the presence of sulphated glycoconjugates at the epithelial cell surface. Quantitation of bacterial adhesion, by scanning electronmicroscopy, showed no significant difference between the cells cultured from CF and non-CF patients. Micro-organisms associated with ciliated cells were mainly aggregated, in contrast with those from non-ciliated cells. Sulphated glycoconjugates were identified on cells cultured from both CF and non-CF patients, regardless of whether or not these cells had attached bacteria. A matrix-like material that surrounded the aggregated bacteria was more prominent on cells cultured from CF patients than on those from non-CF patients. The interaction of aggregated P aeruginosa cells with polyp cells cultured from both CF and non-CF patients appeared to occur by means of this matrix material. Our findings suggest that chronic colonisation of the airways of CF patients cannot be explained by an increased affinity between the P. aeruginosa cells and the respiratory cell surface receptors in the CF patient. Nevertheless, the in-vitro observation that the matrix surrounding the bacteria reacted with a monoclonal antibody against respiratory mucins allows us to speculate that increased mucin secretion by cells from CF patients might, in vivo, play a decisive role in the interaction between P. aeruginosa and the respiratory epithelium.


Use of rivaroxaban in Germany: a database drug utilization study of a drug started in hospital.
The purpose of this drug utilization study was to describe the use of rivaroxaban in Germany during a time period in which approval was limited to the prevention of venous thromboembolism following hip or knee replacement. Additionally, we explored the feasibility of reconstructing inpatient drug use of rivaroxaban in a database where with a few exceptions inpatient prescribing information is not available. Source of data was one statutory health insurance providing data on about seven million insurants throughout Germany. Analyses were based on a cohort of rivaroxaban users from launch (October 2008) to December 2009 and encompassed potential indications for rivaroxaban use, treatment duration, and co-prescribing of potentially interacting drugs. Start of rivaroxaban treatment was defined by the date of surgery. During the study period, 425 rivaroxaban users were identified contributing 440 treatment periods. For more than 82% of these episodes labelled indications could be determined. Treatment durations exceeded recommendations in 95% of the episodes following knee replacement whereas rivaroxaban use after elective hip surgery was found to be longer than recommended in 56%. Prescribing of potentially interacting medication was rare except for non-steroidal anti-inflammatory drugs. Overall, no important off-label use of rivaroxaban was identified. Based on several assumptions that have to be considered in the interpretation of the results our study describes a database approach to reconstruct inpatient drug use for a drug started after a coded hospital procedure, when treatment continues after hospital discharge and no change in drug use is expected in the outpatient setting.


Evidence that the major hemolymph protein of the Pacific oyster, Crassostrea gigas, has antiviral activity against herpesviruses.
Viruses belonging to the family Malacoherpesviridae currently pose a serious threat to global production of the Pacific oyster, Crassostrea gigas. Hemolymph extracts from C. gigas are known to have potent antiviral activity. The compound(s) responsible for this broad-spectrum antiviral activity in oyster hemolymph have not been identified. The objective of this study was to identify these antiviral compound(s) and establish whether hemolymph antiviral activity is under genetic control in the Australian C. gigas population. Hemolymph antiviral activity of 18 family lines of C. gigas were assayed using a herpes simplex virus type 1 (HSV-1) and Vero cell plaque reduction assay. Differences in anti-HSV-1 activity between the family lines were observed (p<0.001) with heritability estimated to be low (h(2)=0.21). A glycoprotein that inhibits HSV-1 replication was identified by resolving oyster hemolymph by native-polyacrylamide gel electrophoresis (PAGE) and assaying extracted protein fractions using the HSV-1 and Vero cell plaque assay. Highest anti-HSV-1 activity corresponded with an N-linked glycoprotein with an estimated molecular mass of 21kDa under non-reducing SDS-PAGE conditions. Amino acid sequencing by tandem mass spectrometry revealed this protein matched the major hemolymph protein, termed cavortin. Our results provide further evidence that cavortin is a multifunctional protein involved in immunity and that assays associated with its activity might be useful for marker-assisted selection of disease resistant oysters.


Lipid profile and glycosylated hemoglobin status of gestational diabetic patients and healthy pregnant women.
Lipid profile and glycosylated hemoglobin level changes in gestational diabetes. The extent to which this alteration takes place is still not clearly documented. To add a clear answer to this question, lipid profile parameters, and glycosylated hemoglobin status were determined in patients with gestational diabetes mellitus and compared to healthy pregnant women (controls). Fasting plasma glucose levels, plasma glucose levels 1 hour, and plasma glucose levels 2 hours after 75 gm oral glucose administration (oral glucose tolerance test) were significantly higher in patients with gestational diabetes as compared to controls. Glycosylated hemoglobin was significantly higher in gestational diabetes than in controls. It was observed that there was a significant increase in serum cholesterol and serum triglyceride level in cases with gestational diabetes when compared to healthy pregnant women. The results of our study suggest that abnormal glucose levels, glycosylated hemoglobin, serum cholesterol, and serum triglycerides play an important role in pathophysiology of gestational diabetes, and therefore, extensive studies are required. Early diagnosis of gestational diabetes will decrease adverse neonatal and maternal outcomes.


The effects of safinamide according to gender in Chinese parkinsonian patients.
The incidence and prevalence of Parkinson's disease (PD) is expected to raise dramatically over the next decades. Gender-related differences are not yet widely recognized, particularly regarding the response to dopaminergic medications. To analyse gender differences in the clinical effects of safinamide, compared to placebo, in Chinese PD patients of the pivotal XINDI trial. The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Patients were followed for 16 weeks receiving safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 items. A post-hoc analysis was performed to describe the efficacy of safinamide in both genders on motor symptoms, motor fluctuations and quality of life. 128 (42%) out of 305 patients enrolled were women and 177 (58%) men. Our additional analyses of the XINDI study have shown that safinamide, compared to placebo, was associated with improvements in motor symptoms, motor fluctuations and quality of life in both genders, with some differences in the response that did not reach statistical significance, possibly due to sample size limitation and post-hoc design of the study. The changes from baseline at week 16 were > 50% higher in the females compared to males for the total daily OFF time (- 1.149 h vs - 0.764 h in males), the total daily ON time (1.283 h vs 0.441 h in males), the UPDRS total score (- 8.300 points vs - 5.253 points in males) and the UPDRS part II score (- 2.574 points vs - 1.016 points in males). The changes from baseline at week 16 were higher in the females compared to males in the "ADL" domain (- 6.965 points vs - 5.772 points in males), the "Emotional well-being" domain (- 6.243 points vs - 4.203 in males), the "Stigma" domain (- 6.185 points vs - 4.913 points in males) and the "Bodily discomfort" domain (- 5.196 points vs 1.099 points in males), while were higher in males in the "Mobility" score (- 6.523 points vs - 4.961 points in females) and the "Communication" score (- 3.863 points vs - 1.564 points in females). Safinamide was shown to improve PD symptoms and quality of life in both male and female Chinese patients. Possible differences in the response between genders need to be further studied in larger and different ethnic populations.


The prevalence of Behçet's disease in Korea: data from Health Insurance Review and Assessment Service from 2011 to 2015.
The aim of this study is to identify the prevalence of Behçet's disease (BD) from data in the Healthcare Bigdata Hub of the Health Insurance Review & Assessment (HIRA) Service from 2011 to 2015 in Korea. This study collected information on primary and auxiliary diagnoses of BD (M352) by physicians according to the Korean Standard Classification of Diseases (KCD) codes. The prevalence of BD was assessed on the basis of age, sex, and geographical distribution. We used time series analysis, using the ARIMA model for the expected prevalence of BD from 2016 to 2025. The overall prevalence of BD was gradually increased, ranging from 32.8 to 35.7 per 100,000 population over the study period. The male to female ratio of BD ranged from 0.54:1 to 0.56:1, revealing a female predominance from 2011 to 2015. Among five districts in Korea, the prevalence in the Seoul Metropolitan district was the highest, with a slowly increasing trend for the study period, accounting for about 60.3% of total BD patients. The expected prevalence of BD patients was estimated to range from 36.9 (95% CI 35.0 - 39.0) to 44.7 (95% CI 40.2 - 49.6) between 2016 and 2025. This study found that the overall prevalence of BD is estimated to be approximately 35.0 per 100,000 population, with female predominance, and predicts gradually increased prevalence of BD in Korea.


Efficient high-resolution refinement in cryo-EM with stochastic gradient descent.
Electron cryomicroscopy (cryo-EM) is an imaging technique widely used in structural biology to determine the three-dimensional structure of biological molecules from noisy two-dimensional projections with unknown orientations. As the typical pipeline involves processing large amounts of data, efficient algorithms are crucial for fast and reliable results. The stochastic gradient descent (SGD) algorithm has been used to improve the speed of ab initio reconstruction, which results in a first, low-resolution estimation of the volume representing the molecule of interest, but has yet to be applied successfully in the high-resolution regime, where expectation-maximization algorithms achieve state-of-the-art results, at a high computational cost. In this article, we investigate the conditioning of the optimization problem and show that the large condition number prevents the successful application of gradient descent-based methods at high resolution. Our results include a theoretical analysis of the condition number of the optimization problem in a simplified setting where the individual projection directions are known, an algorithm based on computing a diagonal preconditioner using Hutchinson's diagonal estimator, and numerical experiments showing the improvement in the convergence speed when using the estimated preconditioner with SGD. The preconditioned SGD approach can potentially enable a simple and unified approach to ab initio reconstruction and high-resolution refinement with faster convergence speed and higher flexibility, and our results are a promising step in this direction.


Sleep quality and nocturnal pain in patients with femoroacetabular impingement and acetabular dysplasia.
Femoroacetabular impingement (FAI) syndrome and acetabular dysplasia (AD) are common pathologies that lead to pain in the young adult hip. Nocturnal pain in these patients is often reported, yet little is known regarding the effect of these hip pathologies on overall sleep quality. The purpose of this study was to evaluate sleep quality in patients with AD and FAI syndrome. This cross-sectional study consisted of 115 patients who complained of hip pain secondary to either FAI syndrome or AD. One hundred fifteen patients with hip pain secondary to FAI syndrome and AD were assessed using the Hip Outcome Score (HOS), Modified Harris Hip Score (mHHS), and then Hip disability and Osteoarthritis Outcome Score (HOOS). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Multiple linear regression, with adaptive LASSO variable selection, was used to assess factors associated with sleep quality. Of the 115 patients, 62 had a diagnosis of FAI syndrome and 53 with AD. The mean age was 34.55 ± 11.66 (age range: 14 to 58 years), 76.52% had an ASA classification of 1 (ASA range: 1 to 3), and all Tonnis grades were either 0 or 1. The mean PSQI global score for all patients was 8.46 ± 4.35 (PSQI range: 0 to 21), indicating poor sleep quality. The adaptive LASSO-penalized least squares multiple linear regression revealed that HOOS Pain, SF-12 Role Emotional, and SF-12 Mental Health significantly predicted Sleep Quality (Adjusted R2 = 0.4041). Sleep quality improved as pain, emotional problems, and mental health improved. Patients with symptomatic FAI syndrome and AD have poor sleep quality. Worsening pain from a patient's hip pathology is associated with poor sleep, even prior to the onset of osteoarthrosis of the hip. Patients presenting with hip pain from FAI syndrome and AD should be screened for sleep disturbance and may benefit from a multidisciplinary treatment approach.


Understanding charged vesicle suspensions as Wigner glasses: dynamical aspects.
Suspensions of charged vesicles in water with added salt are widespread in nature and industrial production. Here we investigate, via Brownian dynamics simulations, a model that grasps the key features of these systems, with bidisperse colloidal beads interacting via a hard-core and an electrostatic double layer potential. Our goal is to focus on a set of interaction parameters that is not generic but measured in recent experiments, and relevant for a class of consumer products, such as liquid fabric softeners. On increasing the volume fraction in a range relevant to real formulation, we show that the dynamics become progressively slower and heterogeneous, displaying the typical signatures of an approaching glass transition. On lowering the salt concentration, which corresponds to increasing the strength and range of the electrostatic repulsion, the emergence of glassy dynamics becomes significantly steeper, and, remarkably, occurs at volume fractions well below the hard-sphere glass transition. The volume fraction dependence of the structural relaxation time at different salt concentration is well described through a functional law inspired by a recently proposed model (Krausser et al 2015 Proc. Natl Acad. Sci. USA 112 13762). According to our results, the investigated system may be thought of as a Wigner glass, i.e. a low-density glassy state stabilized by long-range repulsive interactions. Overall, our study suggests that glassy dynamics plays an important role in controlling the stability of these suspensions.


Identification of 2-anilino-9-methoxy-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation.
To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9-position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines.


Using non-vitamin K oral anticoagulants in specific patient populations: a study of Korean cases.
Non-vitamin K oral anticoagulants (NOACs) are increasingly used as alternatives to conventional therapies and have considerable accumulated real-world clinical data in patients with non-valvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). However, it is not easy to make a complete changeover to NOACs in real-world clinical practice because NOACs still have challenges in specific patient populations (eg, Asian patients, NVAF patients presenting with acute coronary syndrome [ACS], dialysis patients with NVAF, patients with cancer-associated VTE, etc.). Clinical data on the optimal dose of NOACs in Asian patients with NVAF are not sufficient. The intensity of NOAC and antiplatelet treatment and the duration of antiplatelet treatment should be adjusted according to the bleeding and thrombotic risk profiles of the individual NVAF patient presenting with ACS. Increased bleeding risk and unclear efficacy of NOACs in dialysis patients with NVAF should be considered when making decisions on whether to give NOACs for these patients. If dialysis patients with NVAF require anticoagulant for stroke prevention, then apixaban could be considered while awaiting more clinical efficacy and safety data. Additional studies are needed to determine the utility of continuing treatment with reduced-dose NOACs for long-term therapy after VTE. We have enough experiences in using NOACs in cancer patients showing the benefit of antithrombotic treatment counterbalanced the bleeding risk; however, some challenges of cancer-associated VTE management exist due to differences in cancer types or chemotherapy regimens and comorbidities. Different dosing regimens among NOACs may impact on medication adherence; thus, individual patient preference should be considered in choosing a particular NOAC. A significant proportion of patients remain on warfarin because of the high price of NOACs and variability in reimbursement coverage. To compensate clinical-evidence and achieve optimal use of NOACs, we should pay attention to the outcomes of ongoing studies and evaluate more real-world data.


Descemet Membrane Endothelial Transfer: Ultimate Outcome.
To evaluate the clinical outcome of 16 eyes undergoing Descemet membrane endothelial transfer (DMET). In this retrospective cohort study, a consecutive series of 16 eyes from 16 patients was evaluated after subtotal detachment of the Descemet graft after a Descemet membrane endothelial keratoplasty procedure (n = 8) or intended DMET (n = 8) for either Fuchs endothelial dystrophy (n = 10) or bullous keratopathy (BK; n = 6). All 8 Descemet membrane endothelial keratoplasty procedures were complicated by subtotal detachment of the donor graft. The remaining 8 eyes that underwent a DMET procedure were uneventful and no postoperative complications occurred, except 1 eye with BK that experienced a postoperative wound leak. Throughout all postoperative time points, the partially attached status of all Descemet grafts was maintained. Although all eyes operated on for Fuchs endothelial dystrophy showed initial central corneal clearance, no eye operated for BK demonstrated any degree of corneal deturgescence. Ultimately, all 16 corneas decompensated and 15 of the 16 patients elected retransplantation, while 1 patient declined further surgery for health reasons. Retransplantation was performed on average 10.3 (±7.4) months (range, 3-31 mo) postoperatively. Ultimately, regardless of the etiology of endothelial dysfunction, DMET fails to provide satisfactory results in the long term; durable corneal clearance may therefore require the presence of a nearly completely attached Descemet graft.


Association of tumor-infiltrating T-cell density with molecular subtype, racial ancestry and clinical outcomes in prostate cancer.
The inflammatory microenvironment plays an important role in the pathogenesis and progression of tumors and may be associated with somatic genomic alterations. We examined the association of tumor-infiltrating T-cell density with clinical-pathologic variables, tumor molecular subtype, and oncologic outcomes in surgically treated primary prostate cancer occurring in patients of European-American or African-American ancestry. We evaluated 312 primary prostate tumors, enriched for patients with African-American ancestry and high grade disease. Tissue microarrays were immunostained for CD3, CD8, and FOXP3 and were previously immunostained for ERG and PTEN using genetically validated protocols. Image analysis for quantification of T-cell density in tissue microarray tumor spots was performed. Automated quantification of T-cell densities in tumor-containing regions of tissue microarray spots and standard histologic sections were correlated (r = 0.73, p < 0.00001) and there was good agreement between visual and automated T-cell density counts on tissue microarray spots (r = 0.93, p < 0.00001). There was a significant correlation between CD3+, CD8+, and FOXP3+ T-cell densities (p < 0.00001), but these were not associated with most clinical or pathologic variables. Increased T-cell density was significantly associated with ERG positivity (median 309 vs. 188 CD3+ T cells/mm2; p = 0.0004) and also with PTEN loss (median 317 vs. 192 CD3+ T cells/mm2; p = 0.001) in the combined cohort of matched European-American and African-American ancestry patients. The same association or a similar trend was present in patients of both ancestries when analyzed separately. When the African-American patients from the matched race set were combined with a separate high grade set of African-American cases, there was a weak association of increased FOXP3+ T-cell densities with increased risk of metastasis in multivariable analysis. Though high T-cell density is associated with specific molecular subclasses of prostate cancer, we did not find an association of T-cell density with racial ancestry.


Induction of endogenous genes following infection of human endothelial cells with an E1(-) E4(+) adenovirus gene transfer vector.
Recombinant adenovirus (Ad) gene transfer vectors are effective at transferring exogenous genes to a variety of cells and tissue types both in vitro and in vivo. However, in the process of gene transfer, the Ad vectors induce the expression of target cell genes, some of which may modify the function of the target cell and/or alter the local milieu. To develop a broader understanding of Ad vector-mediated induction of endogenous gene expression, genes induced by first-generation E1(-) E4(+) Ad vectors in primary human umbilical vein endothelial cells were identified by cDNA subtraction cloning. The identified cDNAs included signaling molecules (lymphoid blast crisis [LBC], guanine nucleotide binding protein alpha type S [Galpha-S], and mitogen kinase [MEK5]), calcium-regulated/cytoskeletal proteins (calpactin p11 and p36 subunits, vinculin, and spinocerebellar ataxia [SCA1]), growth factors (insulin-like growth factor binding protein 4 and transforming growth factor beta2), glyceraldehyde-6-phosphate dehydrogenase, an expressed sequence tag, and a novel cDNA showing homology to a LIM domain sequence. Two- to sevenfold induction of the endogenous gene expression was observed at 24 h postinfection, and induction continued up to 72 h, although the timing of gene expression varied among the identified genes. In contrast to that observed in endothelial cells, the Ad vector-mediated induction of gene expression was not found following Ad vector infection of primary human dermal fibroblasts or human alveolar macrophages. Empty Ad capsids did not induce endogenous gene expression in endothelial cells. Interestingly, additional deletion of the E4 gene obviated the upregulation of genes in endothelial cells by the E1(-) E3(-) Ad vector, suggesting that genes carried by the E4 region play a central role in modifying target cell gene expression. These findings are consistent with the notion that efficient transfer of exogenous genes to endothelial cells by first-generation Ad vectors comes with the price that these vectors also induce the expression of a variety of cellular genes.


Detection of Real-World Trips in At-Fall Risk Community Dwelling Older Adults Using Wearable Sensors.
Background: Near-falls such as a trip, slip, stumble, or misstep involve a loss of balance (LOB) that does not result in a fall, occur more frequently than actual falls, and are associated with an increased fall risk. To date, studies have largely involved detection of simulated laboratory LOBs using wearable devices in young adults. Data on the detection of and kinematics of naturally occurring LOBs in people at high risk of falling are lacking. This may provide a new way to identify older adults at high risk for falls. We aimed to explore key body kinematics underlying real-world trips in at-fall risk community dwelling older adults wearing inertial measurement units (IMU). Methods: Five community-dwelling older adults with a history of falls who reported trips during the study period participated. They wore a voice recorder and 4 IMUs mounted on feet, lower back and wrist for two consecutive weeks to provide a record of the context and timing of LOB events. Sensor data prior to time-stamped voice recording of a trip were processed in order to visually identify unusual foot trajectories and lower back and arm orientations. Then, data of feet, lower back and wrist position and orientation were combined to create a three-dimensional animation representing the estimated body motion during the noted time segments in order to corroborate the occurrence of a trip. Events reported as a trip by the participant and identified as a trip by a researcher, blinded to voice recordings description, were included in the final analysis. Results: A total of 18 trips obtained from five participants were analyzed. Twelve trips occurred at home, three outside and for three the location was not reported. Trips were identified in the sensor data by observing (1) additional peaks to the typical foot velocity signal during swing phase; (2) increased velocity of the contralateral foot and (3) sharp changes in lower back pitch angles. Conclusions: Our approach demonstrates the feasibility of identifying and studying the mechanisms and context underlying trip-related LOBs in at-fall risk older adults during real world activities.


An expanding bacterial colony forms a depletion zone with growing droplets.
Many species of bacteria have developed effective means to spread on solid surfaces. This study focuses on the expansion of Pseudomonas aeruginosa on an agar gel surface under conditions of minimal evaporation. We report the occurrence and spread of a depletion zone within an expanded colony, where the bacteria laden film becomes thinner. The depletion zone is colocalized with a higher concentration of rhamnolipids, the biosurfactants that are produced by the bacteria and accumulate in the older region of the colony. With continued growth in population, dense bacterial droplets occur and coalesce in the depletion zone, displaying remarkable fluid dynamic behavior. Whereas expansion of a central depletion zone requires activities of live bacteria, new zones can be seeded elsewhere by adding rhamnolipids. These depletion zones due to the added surfactants expand quickly, even on plates covered by bacteria that have been killed by ultraviolet light. We explain the observed properties based on considerations of bacterial growth and secretion, osmotic swelling, fluid volume expansion, interfacial fluid dynamics involving Marangoni and capillary flows, and cell-cell cohesion.


Dynamic, Time-Resolved CT Angiography After EVAR: A Quantitative Approach to Accurately Characterize Aortic Endoleak Type and Identify Inflow Vessels.
Our purpose was to study the accuracy of dynamic computed tomography angiography (d-CTA) in characterizing endoleak type, inflow vessels as compared with digital subtraction angiography (DSA) using qualitative and quantitative analysis. Between March 2019 and January 2021, all patients who underwent d-CTA imaging after EVAR were retrospectively reviewed. Two blinded independent reviewers qualitatively reviewed d-CTA and DSA images. Quantitative region of interest (ROI) analysis was performed by measuring time-resolved contrast enhancement within the aorta and endoleak lesion(s) in the aneurysm sac. Differences between time-to-peak enhancement (Δ TTP) across different ROIs were quantified. A total of 48 patients underwent d-CTA during the study period, of whom 24 patients had abdominal EVAR and DSA imaging for comparison. Qualitative review of DSA imaging showed type I (n=4), type II (n=16), and type III (n=2) and no endoleak (n=2). In 23 of 24 patients (95.8%), d-CTA findings correlated with DSA findings for endoleak type. One patient had a type III endoleak that was demonstrated only in d-CTA (arising from defect in polymer sealing ring of Ovation stent graft) imaging. In type II endoleak cases, d-CTA identified more inflow vessels than DSA imaging (33 vs 21 vessels, p=0.010). Quantitative analysis showed mean (±SD) Δ TTP values for type I endoleak as 1.8 (±1.8) seconds, type II as 9.6 (±3.5) seconds, and for type III endoleak as 5.6 (±1.3) seconds. Dynamic CTA can accurately characterize aortic endoleak type, inflow vessels as compared with DSA imaging. Quantitative parameters such as Δ TTP enhancement can help better differentiate endoleak types and provide an objective approach to endoleak diagnosis.


Antidepressant Use in Late Gestation and Breastfeeding Rates at Discharge from Hospital.
Few studies have investigated breastfeeding outcomes among women exposed to antidepressants. Research aim: This study aimed to evaluate the association between antidepressant use in late gestation and maternal psychiatric illness on breastfeeding rates at discharge from hospital. The authors conducted a retrospective cohort study of 32,662 women delivering live-born singletons between January 2001 and December 2008. Electronic hospital records were used to obtain data on antidepressant exposure during late gestation and whether mothers were breastfeeding at discharge from hospital following delivery. Five hundred seventy-five women received a dispensing for an antidepressant in late gestation (exposed), 1,552 did not receive a dispensing for an antidepressant but had a reported psychiatric illness (disease comparison), and 30,535 served as nonexposed controls. Exposed women were significantly less likely to be breastfeeding their infants at discharge from hospital compared with nonexposed women, adjusted odds ratio ( AOR) = 0.63, 95% confidence interval (CI) [0.50-0.80], but no statistically significant difference was observed when compared with women in the disease comparison group, AOR = 0.83, 95% CI [0.65-1.07]. In stratified analyses, compared with women in the disease comparison group, exposed women were significantly less likely to be breastfeeding their infants at discharge from hospital if their neonate was delivered at term, AOR = 0.73, 95% CI [0.55-0.98], but not preterm, AOR = 1.24, 95% CI [0.66-2.32]. While antidepressant use is associated with a reduction in breastfeeding rates, this association appears to be strongly influenced by factors such as underlying maternal psychiatric illness. Overall, these results highlight that these women may benefit from additional education and support to improve breastfeeding rates.


Seizures and encephalopathy.
There is a complex relationship between seizures and encephalopathy. Seizures alone without any underlying neurologic or medical illness can be the sole cause of encephalopathy. Often these patients have a history of epilepsy, in which case accurate diagnosis is straightforward. Acute neurologic conditions often contribute to encephalopathy, but also increase the risk of seizures--many of which are subclinical. In these scenarios, it can be difficult to determine whether the encephalopathy is caused by seizures, the underlying neurologic disorder, or both. In addition, systemic diseases are commonly associated with encephalopathy; they may also increase the risk of seizures, although less commonly than acute neurologic conditions, and therefore may go unrecognized. This review will examine common and uncommon causes of seizures in encephalopathic patients, typical clinical presentations as well as diagnosis and treatment.


Enhancement of carbon and nitrogen removal by helophytes along subsurface water flowpaths receiving treated wastewater.
Wastewater treatment plant (WWTP) effluents are sources of dissolved organic carbon (DOC) and inorganic nitrogen (DIN) to receiving streams, which can eventually become saturated by excess of DIN. Aquatic plants (i.e., helophytes) can modify subsurface water flowpaths as well as assimilate nutrients and enhance microbial activity in the rhizosphere, yet their ability to increase DIN transformation and removal in WWTP-influenced streams is poorly understood. We examined the influence of helophytes on DIN removal along subsurface water flowpaths and how this was associated with DOC removal and labile C availability. To do so, we used a set of 12 flow-through flumes fed with water from a WWTP effluent. The flumes contained solely sediments or sediments with helophytes. Presence of helophytes in the flumes enhanced both DIN and DOC removal. Experimental addition of a labile C source into the flumes resulted in a high removal of the added C within the first meter of the flumes. Yet, no concomitant increases in DIN removal were observed. Moreover, results from laboratory assays showed significant increases in the potential denitrifying enzyme activity of sediment biofilms from the flumes when labile C was added; suggesting denitrification was limited by C quality. Together these results suggest that lack of DIN removal response to the labile C addition in flumes was likely because potential increases in denitrification by biofilms from sediments were counterbalanced by high rates of mineralization of dissolved organic matter. Our results highlight that helophytes can enhance DIN removal in streams receiving inputs from WWTP effluents; and thus, they can become a relevant bioremediation tool in WWTP-influenced streams. However, results also suggest that the quality of DOC from the WWTP effluent can influence the N removal capacity of these systems.


Characterization of a recombinant outer surface protein A (OspA) vaccine against Lyme disease.
Lyme disease, the most prevalent tick-borne disease in the United States, results from infection with Borrelia burgdorferi sensu stricto. Early studies of Borrelia burgdorferi sensu stricto identified outer surface protein A (OspA), a lipoprotein on the surface of spirochetes that could be the target of protective antibodies to this agent. Pasteur Mérieux Connaught has developed a Lyme vaccine, ImuLyme, using recombinant OspA protein (rOspA). Methods were developed to routinely assess the identity, quantity, structure, purity, biological activity, heterogeneity, stability, and potency of rOspA. In addition, several methods were performed on a series of lots to support the routine testing methods and further our understanding of the physicochemical characteristics of rOspA. These tests were electrospray mass spectrometry, circular dichroism, two-dimensional gel electrophoresis, amino acid analysis, peptide mapping with peptide sequencing, and the application of proteomic methodology to identify trace contaminant host cell proteins. The results of these methods indicate that the rOspA lots are composed of highly purified and properly processed and folded rOspA with trace amounts of E. coli host cell proteins.


The role of NF-kappaB in hepatocellular carcinoma cell.
To evaluate the role of nuclear factor-kappa B (NF-kappaB) and inhibitory kappaB alpha (IkappaBalpha) in hepatocellular cacinoma (HCC) SMMC7721 cells, the consequence of NF-kappaB inhibition in SMMC7721 cells transfected with mutated IkappaBalpha (mIkappaBalpha) plasmid and the effect of stable inhibition of NF-kappaB activity in combination with Doxorubicin. Western blot was used to determine the expression of NF-kappaB and IkappaBalpha in SMMC7721 cells and normal liver cells. Nuclear protein was used to evaluate the binding of the (32)P-labeled tandem kappaB sequence using electrophoretic mobility shift assay and the expression of NF-kappaB using Western blot between SMMC7721 cells transfected with mIkappaBalpha plasmid (SMMC7721-MT) and control cells. Furthermore, cell viability was plotted between SMMC7721-MT and control cells. The binding of kappaB sequence and cell viability between SMMC7721-MT and control cells at different concentrations of Doxorubicin were also investigated. Western blot analysis for nuclear extract showed more P50 (NF-kappaB1) and P65 (RelA) expression in SMMC7721 cells compared with normal liver cells. The expression of cytosolic IkappaBalpha protein in SMMC7721 cells was less than that in normal cells. SMMC7721-MT cells inhibited NF-kappaB nuclear translocation at 0, 24, 48 and 96 hours. Furthermore, NF-kappaB cannot be detected in the nuclear protein of SMMC7721-MT cells by Western blot. By calculating cell viability, the proliferation of SMMC7721-MT cells was shown to be suppressed more significantly than that of control cells. NF-kappaB in untransfected cells was activated by Doxorubicin in a dose-dependent manner, but that in SMMC7721-MT cells was not induced at low concentrations of Doxorubicin. Compared with untransfected cells, the viability of SMMC7721-MT cells was significantly suppressed at the same concentration of Doxorubicin (P < 0.01). The present study demonstrates that upregulation of NF-kappaB and downregulation of inhibitory kappa B (IkappaBalpha) in SMMC7721 cells are related with the growth of hepatocellular cacinoma cells. Stable expression of mIkappaBalpha in SMMC7721-MT cells can inhibit NF-kappaB nuclear translocation and suppress cell growth. Furthermore, stable inhibition of NF-kappaB activity in combination with Doxorubicin can significantly inhibit cell proliferation in SMMC7721-MT cells. Thus, modulation of NF-kappaB may represent an improvement in the efficacy of HCC therapies and be worthy of further research and investigation.


Demographic estimates from the Palaeolithic-Mesolithic boundary in Scandinavia: comparative benchmarks and novel insights.
Prehistoric demography has recently risen to prominence as a potentially explanatory variable for episodes of cultural change as documented in the archaeological and ethnographic record. While this has resulted in a veritable boom in methodological developments seeking to address temporal changes in the relative size of prehistoric populations, little work has focused on the manner in which population dynamics manifests across a spatial dimension. Most recently, the so-called Cologne Protocol has led the way in this endeavour. However, strict requirements of raw-material exchange data as analytical inputs have prevented further applications of the protocol to regions outside of continental Europe. We apply an adjusted approach of the protocol that makes it transferable to cases in other parts of the world, while demonstrating its use by providing comparative benchmarks of previous research on the Late Glacial Final Palaeolithic of southern Scandinavia, and novel insights from the early Holocene pioneer colonization of coastal Norway. We demonstrate again that population size and densities remained fairly low throughout the Late Glacial, and well into the early Holocene. We suggest that such low population densities have played a significant role in shaping what may have been episodes of cultural loss, as well as potentially longer periods of only relatively minor degrees of cultural change. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.


Predicting the vibroacoustic response of satellite equipment panels.
Modern satellites are constructed of large, lightweight equipment panels that are strongly excited by acoustic pressures during launch. During design, performing vibroacoustic analyses to evaluate and ensure the integrity of the complex electronics mounted on the panels is critical. In this study the attached equipment is explicitly addressed and how its properties affect the panel responses is characterized. FEA and BEA methods are used to derive realistic parameters to input to a SEA hybrid model of a panel with multiple attachments. Specifically, conductance/modal density and radiation efficiency for nonhomogeneous panel structures with and without mass loading are computed. The validity of using the spatially averaged conductance of panels with irregular features for deriving the structure modal density is demonstrated. Maidanik's proposed method of modifying the traditional SEA input power is implemented, illustrating the importance of accounting for system internal couplings when calculating the external input power. The predictions using the SEA hybrid model agree with the measured data trends, and are found to be most sensitive to the assumed dynamic mass ratio (attachments/structure) and the attachment internal loss factor. Additional experimental and analytical investigations are recommended to better characterize dynamic masses, modal densities and loss factors.


Prevalence and severity of carpal tunnel syndrome (CTS) during pregnancy.
Carpal Tunnel Syndrome (CTS) is the entrapment of Median nerve at wrist. Pregnancy can affect prevalence and severity of CTS. In this study frequency and severity of CTS in pregnancy was evaluated. In this study 100 pregnant women were evaluated by Hand symptoms, CTS provocation tests (Tinel and Phalen) and for definite diagnosis of CTS standard EDX studies were used. For this purpose sensory and motor distal latency of Median were measured and compared with ulnar nerve. 17% of pregnant women had CTS with 23.5% bilateral involvement and 17.5% severe CTS. Prevalence of hand symptom and clinical sign of CTS (phalen and tinel sign) were 36% and 26% respectively. Results indicated that prevalence of CTS in pregnant women was significant. Although hand signs and symptoms are useful, EDX study is more reliable.


Evaluation of Vision-Related Quality of Life After Unilateral Implantation of a New Trifocal Intraocular Lens.
The objective of the study was to evaluate visual performance and subjective quality of life after unilateral implantation of a new trifocal intraocular lens (IOL) in young and middle-aged patients. Patients that underwent unilateral cataract surgery with implantation of trifocal TFNT00 IOL with an emmetropic fellow eye were included in the study. Vision related daily activity performance was evaluated in postoperative 6th month. Patients were divided in two groups according to the uncorrected near visual acuity of their fellow eyes: İn Group I if worse than the operated eye and in Group II if equal or better than the operated eye. The visual function-14 (VF-14) questionnaire was used with scores of 4 with no difficulty, 3 points with mild difficulty, 2 points with moderate difficulty, 1 point with severe difficulty, and 0 point if unable to perform. Twenty-one patients were enrolled in this study. Patients had good visual performance, showing VF-14 scores above 3 in all categories. Reading small print (3.67±0.48) and driving at night (3.67±0.48) were found to be the most difficult tasks to perform. No significant difference was found between two groups in any category that was investigated by the VF-14 questionnaire. Unilateral implantation of TFNT00 trifocal IOL is well tolerated with good patient satisfaction assessed by VF-14 questionnaire in subjects that have cataract in one eye, encouraging single-eye surgical procedure in this particular group of patients.


Induced regeneration of calvaria by bone morphogenetic protein (BMP) in dogs.
In the adult dog, a 14-mm skull trephine defect regenerates only incompletely in the lifetime of the individual. Only about half of the defect is repaired; the regenerated part develops by extension of growth from the bony rim. Correlated roentgenographic and histomorphometric methods demonstrate that new bone develops by proliferation of preexisting osteoprogenitor cells lining the diploë and perivascular cells of the bone marrow stroma. An autogeneic bone graft, including bone marrow, provides a supplementary supply of cells in a homostructural framework and generally completes the repair process. Transplants of bone marrow alone fail to repair the defect. Implants of bovine bone morphogenetic protein (bBMP) and a carrier consisting of matrix gamma-carboxyglutamic acid rich protein (without any additional bone or bone marrow) induce repair almost as completely as an autograft. BMP-induced bone regeneration is incomplete in the thin lateral temporal marrow-deficient part of the cranium. Implants of BMP plus bone marrow induce complete repair, suggesting that calvarial bone regeneration is bone marrow stroma-dependent for a supply of target cells. The target for BMP in cranial bone regeneration is the perivascular connective tissue cells (pericyte) of the host bed marrow stroma and endosteum. The molecular mechanism of differentiation of pericytes into osteoprogenitor cells is not known, but the process is irreversible, heritable, and presents a solvable problem.


Guanidino N-substituted and N,N-disubstituted derivatives of the kappa-opioid antagonist GNTI.
Derivatives of the highly selective kappa-opioid receptor antagonist GNTI (2a) have been prepared. Binding and functional studies conducted on cloned human opioid receptors expressed in Chinese hamster ovarian (CHO) cells suggested that adding a benzyl or a substituted benzyl group to the guanidino moiety led, in general, to a retention of high kappa-affinity and antagonist potency. Disubstitution of the guanidino moiety led to reduced kappa-selectivity.


Laminar and columnar organization of ascending excitatory projections to layer 2/3 pyramidal neurons in rat barrel cortex.
Excitatory synaptic projections to layer 2/3 (L2/3) pyramidal neurons in brain slices from the rat barrel cortex were measured using quantitative laser-scanning photostimulation (LSPS) mapping. In the barrel cortex, cytoarchitectonic "barrels" and "septa" in L4 define a stereotypical array of landmarks, allowing alignment and averaging of LSPS maps from multiple cells in different slices. We distinguished inputs to L2 and L3 neurons above barrels and septa. Average input maps revealed that barrel-related ascending projections (L4-->2/3barrel) interdigitated with a novel septum-related projection (L5A-->2septum). We also explored the functional organization of these projections by comparing the input maps of multiple cells in individual slices. L2/3 cells sharing the same barrel-related column showed strong correlations in their input maps, independent of their precise locations within the column; otherwise, correlations fell rapidly as a function of intersomatic separation. Our data indicate that barrel-related and septum-related columns are associated with distinct functional circuits. These projections are likely to mediate parallel processing of somatosensory signals within the barrel cortex, with L4-->2/3barrel and L5A-->2septum representing the intracortical continuations of, respectively, the subcortical lemniscal and paralemniscal systems conveying somatosensory information to the barrel cortex.


[Age-related structural asymmetry of human adrenal glands].
This investigation was aimed at the comparative evaluation of mass and some morphometric parameters of the right and left adrenal glands obtained from 161 men of different ages (15-19 to 60-69 years). It is established that age-dependent increase of adrenal mass is accompanied by the changes in cortex-to-medulla mass ratio. The increase of adrenal mass was predominantly caused by the growth of the cortex in the left adrenal and by the growth of medulla in both adrenal glands. Domination of the mass of left adrenal and of its cortex over the similar parameters of the right adrenal gland is discussed from the standpoint of neuroendocrine system asymmetry and is found in all the age groups.


Rapid Nuclear Exclusion of Hcm1 in Aging Saccharomyces cerevisiae Leads to Vacuolar Alkalization and Replicative Senescence.
The yeast, Saccharomyces cerevisiae, like other higher eukaryotes, undergo a finite number of cell divisions before exiting the cell cycle due to the effects of aging. Here, we show that yeast aging begins with the nuclear exclusion of Hcm1 in young cells, resulting in loss of acidic vacuoles. Autophagy is required for healthy aging in yeast, with proteins targeted for turnover by autophagy directed to the vacuole. Consistent with this, vacuolar acidity is necessary for vacuolar function and yeast longevity. Using yeast genetics and immunofluorescence microscopy, we confirm that vacuolar acidity plays a critical role in cell health and lifespan, and is potentially maintained by a series of Forkhead Box (Fox) transcription factors. An interconnected transcriptional network involving the Fox proteins (Fkh1, Fkh2 and Hcm1) are required for transcription of v-ATPase subunits and vacuolar acidity. As cells age, Hcm1 is rapidly excluded from the nucleus in young cells, blocking the expression of Hcm1 targets (Fkh1 and Fkh2), leading to loss of v-ATPase gene expression, reduced vacuolar acidification, increased α-syn-GFP vacuolar accumulation, and finally, diminished replicative lifespan (RLS). Loss of vacuolar acidity occurs about the same time as Hcm1 nuclear exclusion and is conserved; we have recently demonstrated that lysosomal alkalization similarly contributes to aging in C. elegans following a transition from progeny producing to post-reproductive life. Our data points to a molecular mechanism regulating vacuolar acidity that signals the end of RLS when acidification is lost.


Longer sleep is associated with lower BMI and favorable metabolic profiles in UK adults: Findings from the National Diet and Nutrition Survey.
Ever more evidence associates short sleep with increased risk of metabolic diseases such as obesity, which may be related to a predisposition to non-homeostatic eating. Few studies have concurrently determined associations between sleep duration and objective measures of metabolic health as well as sleep duration and diet, however. We therefore analyzed associations between sleep duration, diet and metabolic health markers in UK adults, assessing associations between sleep duration and 1) adiposity, 2) selected metabolic health markers and 3) diet, using National Diet and Nutrition Survey data. Adults (n = 1,615, age 19-65 years, 57.1% female) completed questions about sleep duration and 3 to 4 days of food diaries. Blood pressure and waist circumference were recorded. Fasting blood lipids, glucose, glycated haemoglobin (HbA1c), thyroid hormones, and high-sensitivity C-reactive protein (CRP) were measured in a subset of participants. We used regression analyses to explore associations between sleep duration and outcomes. After adjustment for age, ethnicity, sex, smoking, and socioeconomic status, sleep duration was negatively associated with body mass index (-0.46 kg/m2 per hour, 95% CI -0.69 to -0.24 kg/m2, p < 0.001) and waist circumference (-0.9 cm per hour, 95% CI -1.5 to -0.3cm, p = 0.004), and positively associated with high-density lipoprotein cholesterol (0.03 mmol/L per hour, 95% CI 0.00 to 0.05, p = 0.03). Sleep duration tended to be positively associated with free thyroxine levels and negatively associated with HbA1c and CRP (p = 0.09 to 0.10). Contrary to our hypothesis, sleep duration was not associated with any dietary measures (p ≥ 0.14). Together, our findings show that short-sleeping UK adults are more likely to have obesity, a disease with many comorbidities.


Nutraceuticals Synergistically Promote Osteogenesis in Cultured 7F2 Osteoblasts and Mitigate Inhibition of Differentiation and Maturation in Simulated Microgravity.
Microgravity is known to impact bone health, similar to mechanical unloading on Earth. In the absence of countermeasures, bone formation and mineral deposition are strongly inhibited in Space. There is an unmet need to identify nutritional countermeasures. Curcumin and carnosic acid are phytonutrients with anticancer, anti-inflammatory, and antioxidative effects and may exhibit osteogenic properties. Zinc is a trace element essential for bone formation. We hypothesized that these nutraceuticals could counteract the microgravity-induced inhibition of osteogenic differentiation and function. To test this hypothesis, we cultured 7F2 murine osteoblasts in simulated microgravity (SMG) in a Random Positioning Machine in the presence and absence of curcumin, carnosic acid, and zinc and evaluated cell proliferation, function, and differentiation. SMG enhanced cell proliferation in osteogenic medium. The nutraceuticals partially reversed the inhibitory effects of SMG on alkaline phosphatase (ALP) activity and did not alter the SMG-induced reduction in the expression of osteogenic marker genes in osteogenic medium, while they promoted osteoblast proliferation and ALP activity in the absence of traditional osteogenic media. We further observed a synergistic effect of the intermix of the phytonutrients on ALP activity. Intermixes of phytonutrients may serve as convenient and effective nutritional countermeasures against bone loss in space.


Short-Term Impact of Two Kinds of Vegetables to Exogenous Total Nitrate and Nitrite Intake: Is Antibacterial Mouthwash Influential?
Nitrate is a compound with adverse effects on human health that can exist also in vegetables. This study aimed to determine the intake of total nitrate/nitrite from lettuce and carrot as high and low nitrate content, respectively. Moreover, the effect of chlorhexidine mouthwash on the elimination of the nitrite level in saliva and urine was surveyed. This study was designed as a crossover based on the randomized selection method. Thirty-nine participants were divided into two groups; the lettuce and carrot juice consumers (control group). The case group was consumed these two vegetables, while they used antibacterial mouthwash. The background of nitrate/nitrite of the participants was determined before exposure. The intake of total nitrate and nitrite via lettuce and carrot juice consumption was investigated. The Griess colorimetric reaction was used for nitrate and nitrite determination in samples. Total nitrate concentrations in case and control groups were detected 0.79 and 0.78 mM in saliva and 1.78 and 1.38 mM in urine after lettuce consumption, respectively. However, it was determined 1.55 and 2.43 mM in saliva and 2.92 and 3.04 mM in urine after carrot ingestion. Salivary nitrite concentration 0.53 mM was decreased to 0.45 mM after antibacterial mouthwash application (P-value <0.05). This study indicated that the intake of total nitrate/nitrite via leafy vegetables was higher than rooty ones. The chlorhexidine mouthwash is an appropriate recommendation to reduce the nitrite concentration in the human body for preventing the probable side effects of nitrate metabolites such as N-nitrosamines forming.


Effects of disease misclassification on exposure-disease association.
We explore how misclassification in disease status can distort the exposure-disease association in a study with dichotomous disease and exposure status. We define the difference in population odds ratios between populations with and without disease misclassification as population-level bias and derive the bias as a function of sensitivity and specificity for observed disease status. The magnitude and direction of bias can be elucidated through analytic derivations, as illustrated with numerical examples. Patterns of bias exist not only for nondifferential misclassification but also for some differential misclassification scenarios. We have provided conditions defined in terms of sensitivity and specificity that correspond to each pattern of bias. Caution is needed in interpreting results when misclassification is present. Our findings can be used to assess the effects of disease misclassification in a population when sensitivity and specificity are known or can be estimated.


[The burned hand - innovations and current research].
Hand function is crucial for everyday and professional life. Even small burns can have a great impact on hand function, either from the injury itself or from scar contractions. Preservation and restoration of hand function are essential for mental and physical well-being of burn survivors. Reduced hand function can lead to social isolation and occupational invalidity. Even though one hand represents only 3 % of the total body surface area, hand burns are categorized as severe burn injuries and are a primary indication for treatment in a dedicated burn center. Hands are involved in more than 80 % of all severe burn injuries, making them the most affected body part. Independent of the severity of the overall burn, hand injuries need to be treated with highest priority.Novel approaches in acute and long-term care of burned hands should aim for long-term improvement in functional and aesthetic outcomes. All burn patients with hand involvement should be able to be reintegrated into society, perform activities of everyday life and return to their profession. The purpose of this review is to highlight recent advancements in research of the burned hand and to identify areas in which further research is needed. We summarized all relevant and recent original and review articles on hand burns; including acute treatment, aftercare, reconstruction, injuries due to E-cigarettes and methods for assessment of hand function. These findings were put into context of established methods in order to provide an outlook on possible future innovations.


Association between somatic cell count and serial locomotion score assessments in UK dairy cows.
This research investigated the effect of lameness, measured by locomotion score (LS) on the somatic cell count (SCC) of UK dairy cows. The data set consisted of 11,141 records of SCC and LS collected monthly on 12 occasions from 1,397 cows kept on 7 farms. The data were analyzed to account for the correlation of repeated measures of SCC within cow. Results were controlled for farm of origin, stage of lactation, parity, season, and test-day milk yield. Compared with the geometric mean SCC for cows with LS 1 on each farm, cows on farm 3 with LS 2 produced milk with 28,000 fewer somatic cells/mL, and cows with LS 2 on farm 6 produced milk with 30,000 fewer somatic cells/mL at a test day within 10 d. Cows that would have LS 3 six months later produced milk with 16,000 fewer somatic cells/mL compared with the geometric mean SCC for cows that would have LS 1 in 6 mo time. These results illustrate differences in disease dynamics between farms, highlight potential conflict between lameness and mastitis control measures, and emphasize the importance of developing farm-specific estimates of disease costs, and hence, health management plans in clinical practice.


Bone mineral content and levels of gonadotropins and estrogens in amenorrheic running women.
Serum gonadotropin and estrogen levels and their relationship to bone mineral content in exercise-related amenorrhea were studied in 11 amenorrheic women and 24 eumenorrheic women, all of whom were runners. Serum estradiol, LH, FSH, estrone, and testosterone were measured in serial blood samples obtained at 15-min intervals for 4 h. The amenorrheic women had lower estradiol, LH, FSH; and estrone levels as well as a higher estrone-estradiol ratio than did the eumenorrheic women. There was no difference in testosterone levels. The amenorrheic women had lower LH pulse amplitudes, whereas no differences were found in FSH pulse amplitudes. LH and FSH pulse frequencies did not differ between the two groups. Bone mineral content of the lumbar spine was lower in amenorrheic women and was positively correlated with estradiol levels in all women. There was no difference in bone mineral content of the radius. These data suggest that, in exercise-related amenorrhea, low serum LH, FSH, and estrogen levels reflect an alteration in the hypothalamic control of gonadotropin release. Reduced circulating estrogen levels in amenorrheic running women may be a cause of low mineral content of the spine.


In vitro functional testing of endothelial progenitor cells that overexpress thrombomodulin.
This study investigated the augmentation of endothelial progenitor cell (EPC) thromboresistance by using gene therapy to overexpress thrombomodulin (TM), an endothelial cell membrane glycoprotein that has potent anti-coagulant properties. Late outgrowth EPCs were isolated from peripheral blood of patients with documented coronary artery disease and transfected with an adenoviral vector containing human TM. EPC transfection conditions for maximizing TM expression, transfection efficiency, and cell viability were employed. TM-overexpressing EPCs had a fivefold increase in the rate of activated protein C production over native EPCs and EPCs transfected with an adenoviral control vector expressing β-galactosidase (p<0.05). TM upregulation caused a significant threefold reduction in platelet adhesion compared to native EPCs, and a 12-fold reduction compared to collagen I-coated wells. Additionally, the clotting time of TM-transfected EPCs incubated with whole blood was significantly extended by 19% over native cells (p<0.05). These data indicate that TM-overexpression has the potential to improve the antithrombotic performance of patient-derived EPCs for endothelialization applications.


Parents' preferences for respite care of children with medical complexity.
The number of children with medical complexity (CMC) is increasing worldwide. For these children and their families, various forms of support are legislated; among them, short-stay respite care has a great unmet need. We examined such children's parents' preferences for respite care and their willingness to pay. We used discrete choice experiments (DCEs) to estimate the parents' preferences and willingness to pay. Parents whose children used overnight short-stay respite services answered a questionnaire to compare two hypothetical facilities of respite care having seven attributes and three levels. The DCE data was analyzed using the conditional logit model. The willingness to pay was calculated based on DCE estimates. A total of 70 parents participated in this study and mean age of their children was 7.8 years (standard deviation [SD] 4.3). Among those children, 67 (96%) had the severest certification of disability, and 27 (38%) used a ventilator at home. We found that the parents' highest preferences was the best level of medical care level that can manage ventilators (coefficient 1.61, 95% confidence interval [CI]: 1.32-1.90). The better and best level of medical care, daily care, education/nursing, and emergency care were preferred over basic quality services. Willingness to pay for the best level of medical care was approximately 75,367 JPY per night. This study shows a need for respite care that can deliver high-level medical care, especially for the management of ventilators, to CMC. This finding can serve as a basis for promoting respite care services.


A Bifunctional Nucleoside Probe for the Inhibition of the Human Immunodeficiency Virus-Type 1 Reverse Transcriptase.
Nucleoside analogs have proven effective for the inhibition of viral polymerases and are the foundation of many antiviral therapies. In this work, the antiretroviral potential of 6-azauracil analogs was assessed using activity-based protein profiling techniques and functional assays. Probes based on the 6-azauracil scaffold were examined and found to bind to HCV polymerase and HIV-1 reverse transcriptase through covalent modification of residues near the active site. The modified sites on the HIV-1 RT were examined using a mass spectrometry approach, and it was discovered that the azauracil moieties modified the enzyme in proximity to its active site. However, these scaffolds gave little or no inhibition of enzyme activity. Instead, a bifunctional inhibitor was prepared using click chemistry to link the 6-azauracil moiety to azidothymidine (AzT) and the corresponding triphosphate (AzTTP). These bifunctional inhibitors were found to have potent inhibitory function through a mode of action that includes both alkylation and chain termination. An in vitro assay demonstrated that the bifunctional inhibitor was 23-fold more effective in inhibiting HIV-1 RT activity than the parent AzTTP. The bifunctional inhibitor was also tested in HIV-1 permissive T cells where it decreased Gag expression similarly to the front-line drug Efavirenz with no evidence of cytotoxicity. This new bifunctional scaffold represents an interesting tool for inhibiting HIV-1 by covalently anchoring a chain-terminating nucleoside analog in the active site of the reverse transcriptase, preventing its removal and abolishing enzymatic activity, and represents a novel mode of action for inhibiting polymerases including reverse transcriptases.


The Use of Systemic Treatment in the Maintenance of Patients with Non-Small Cell Lung Cancer: A Systematic Review.
Non-small cell lung cancer (NSCLC) is often diagnosed at later stages when treatment options are limited. Maintenance therapy may prolong the time to disease progression and potentially increase overall survival. Secondarily, it may increase the proportion of patients eligible for second-line therapy at the time of progression. The objective of this systematic review was to examine the use of systemic treatment in the maintenance of patients with NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for phase III randomized controlled trials comparing maintenance systemic treatment against another systemic treatment or placebo in patients with stage IIIB or IV NSCLC who had received a minimum of four prior cycles of platinum-based chemotherapy. Meta-analyses were conducted with clinically homogenous trials. Fourteen randomized controlled trials with 22 publications were included. The overall survival benefit was strongest for maintenance therapy with pemetrexed for patients with nonsquamous NSCLC (hazard ratio = 0.74, 95% confidence interval: 0.64-0.86) but not significant for patients with squamous NSCLC. There was also an overall survival benefit with maintenance therapy with epidermal growth factor receptor tyrosine kinase inhibitors, but the magnitude of the benefit was smaller than with pemetrexed (hazard ratio = 0.84, 95% confidence interval: 0.75-0.94). Docetaxel or gemcitabine as maintenance chemotherapies did not have an impact on overall survival. For patients with advanced, stable stage IIIB/IV NSCLC whose disease has not progressed after four to six cycles of platinum-based chemotherapy, the overall survival benefits were strongest for pemetrexed maintenance therapy followed by epidermal growth factor receptor tyrosine kinase inhibitor maintenance therapy.


Phylogeographic reconstruction of the marbled crayfish origin.
The marbled crayfish (Procambarus virginalis) is a triploid and parthenogenetic freshwater crayfish species that has colonized diverse habitats around the world. Previous studies suggested that the clonal marbled crayfish population descended as recently as 25 years ago from a single specimen of P. fallax, the sexually reproducing parent species. However, the genetic, phylogeographic, and mechanistic origins of the species have remained enigmatic. We have now constructed a new genome assembly for P. virginalis to support a detailed phylogeographic analysis of the diploid parent species, Procambarus fallax. Our results strongly suggest that both parental haplotypes of P. virginalis were inherited from the Everglades subpopulation of P. fallax. Comprehensive whole-genome sequencing also detected triploid specimens in the same subpopulation, which either represent evolutionarily important intermediate genotypes or independent parthenogenetic lineages arising among the sexual parent population. Our findings thus clarify the geographic origin of the marbled crayfish and identify potential mechanisms of parthenogenetic speciation.


Coreceptor-dependent inhibition of the cell fusion activity of simian immunodeficiency virus Env proteins.
The cytoplasmic tail (R peptide) sequence is able to regulate the fusion activity of the murine leukemia virus (MuLV) envelope (Env) protein. We have previously shown that this sequence exerts a profound inhibitory effect on the fusion activity of simian immunodeficiency virus (SIV)-MuLV chimeric Env proteins which contain the extracellular and transmembrane domains of the SIV Env protein. Recent studies have shown that SIV can utilize several alternative cellular coreceptors for its fusion and entry into the cell. We have investigated the fusion activity of SIV and SIV-MuLV chimeric Env proteins using cells that express different coreceptors. HeLa cells were transfected with plasmid constructs that carry the SIV or SIV-MuLV chimeric Env protein genes and were overlaid with either CEMx174 cells or Ghost Gpr15 cells, which express the Gpr15 coreceptor for SIV, or Ghost CCR5 cells, which express CCR5, an alternate coreceptor for SIV. The R-peptide sequence in the SIV-MuLV chimeric proteins was found to inhibit the fusion with CEMx174 cells or Ghost Gpr15 cells. However, a significant level of fusion was still observed when HeLa cells expressing the chimeric Env proteins were cocultivated with Ghost CCR5 cells. These results show that the R-peptide sequence exerts differential effects on the fusion activity of SIV Env proteins using target cells that express alternative coreceptors.


Structural Evolution of Ferroelectric and Ferroelastic Barium Sodium Niobate Tungsten Bronze.
The crystal structure of the ferroelastic and ferroelectric tungsten bronze Ba2NaNb5O15 (BNN) has been debated. Here, we re-examine the crystal structure of BNN by ambient powder X-ray diffraction combined with density functional theory calculations. We demonstrate that the room temperature space group is Cmm2 with significant cation disorder on the Ba and Na cation sublattices. Density functional theory calculations reveal a relatively flat energy landscape between structures of different symmetries, including the energetics of cation disorder. We also study the structural evolution and the ferroelectric and ferroelastic phase transitions by high-temperature X-ray diffraction and dilatometry. The ferroelectric phase transition at 570 °C is of first order and cause the cell to expand in the c direction, while the ferroelastic distortion starting at 270 °C takes place in the ab plane and does not affect the polarization. The phase transitions are not coupled, which means that BNN is a ferroic material with two primary and uncoupled order parameters.


Experimental Depth Profiles of Surfactants, Ions, and Solvent at the Angstrom Scale: Studies of Cationic and Anionic Surfactants and Their Salting Out.
Neutral impact ion scattering spectroscopy (NICISS) is used to measure the depth profiles of ionic surfactants, counterions, and solvent molecules on the angstrom scale. The chosen surfactants are 0.010 m tetrahexylammonium bromide (THA+/Br-) and 0.0050 m sodium dodecyl sulfate (Na+/DS-) in the absence and presence of 0.30 m NaBr in liquid glycerol. NICISS determines the depth profiles of the elements C, O, Na, S, and Br through the loss in energy of 5 keV He atoms that travel into and out of the liquid, which is then converted into depth. In the absence of NaBr, we find that THA+ and its Br- counterion segregate together because of charge attraction, forming a narrow double layer that is 10 Å wide and 150 times more concentrated than in the bulk. With the addition of NaBr, THA+ is "salted out" to the surface, increasing the interfacial Br- concentration by 3-fold and spreading the anions over a ∼30 Å depth. Added NaBr similarly increases the interfacial concentration of DS- ions and broadens their positions. Conversely, the dissolved Br- ions are significantly depleted over a depth of 0-40 Å from the surface because of charge repulsion from DS- ions within the interfacial region. These different interfacial Br- propensities correlate with previously measured gas-liquid reactivities: gaseous Cl2 readily reacts with Br- ions in the presence of THA+ but drops 70-fold in the presence of DS-, demonstrating that surfactant headgroup charge controls the reactivity of Br- through changes in its depth profile.


Homology modeling and docking evaluation of aminergic G protein-coupled receptors.
We report the development of homology models of dopamine (D(2), D(3), and D(4)), serotonin (5-HT(1B), 5-HT(2A), 5-HT(2B), and 5-HT(2C)), histamine (H(1)), and muscarinic (M(1)) receptors, based on the high-resolution structure of the beta(2)-adrenergic receptor. The homology models were built and refined using Prime. We have addressed the required modeling of extracellular loop 2, which is often implicated in ligand binding. The orthosteric sites of the models were optimized using induced fit docking, to allow for side-chain flexibility, and the resulting receptor models have been evaluated using protein validation tools. Of the nine homology models developed, six models showed moderate to good enrichment in virtual screening experiments (5-HT(2A), 5-HT(1B), D(2), 5-HT(2C), D(3), and M(1)). The 5-HT(2A) receptor displayed the highest enrichment in virtual screening experiments with enrichment factors of 6.1, 6.9, and 5.9 at 2, 5, and 10%, respectively, of the screened database. However, three of the models require further refinement (5-HT(2B), D(4), and H(1)), due to difficulties in modeling some of the binding site residues as well as the extracellular loop 2. Our effort also aims to supplement the limited number of tested G protein-coupled receptor homology models based on the beta(2) crystal structure that are freely available to the research community.


On the duality between interaction responses and mutual positions in flocking and schooling.
Recent research in animal behaviour has contributed to determine how alignment, turning responses, and changes of speed mediate flocking and schooling interactions in different animal species. Here, we propose a complementary approach to the analysis of flocking phenomena, based on the idea that animals occupy preferential, anysotropic positions with respect to their neighbours, and devote a large amount of their interaction responses to maintaining their mutual positions. We test our approach by deriving the apparent alignment and attraction responses from simulated trajectories of animals moving side by side, or one in front of the other. We show that the anisotropic positioning of individuals, in combination with noise, is sufficient to reproduce several aspects of the movement responses observed in real animal groups. This anisotropy at the level of interactions should be considered explicitly in future models of flocking and schooling. By making a distinction between interaction responses involved in maintaining a preferred flock configuration, and interaction responses directed at changing it, our work provides a frame to discriminate movement interactions that signal directional conflict from interactions underlying consensual group motion.