Trabeculectomy versus canaloplasty (TVC study) in the treatment of patients with open-angle glaucoma: a prospective randomized clinical trial.
To compare the outcomes of canaloplasty and trabeculectomy in open-angle glaucoma. This prospective, randomized clinical trial included 62 patients who randomly received trabeculectomy (n = 32) or canaloplasty (n = 30) and were followed up prospectively for 2 years. Primary endpoint was complete (without medication) and qualified success (with or without medication) defined as an intraocular pressure (IOP) of ≤18 mmHg (definition 1) or IOP ≤21 mmHg and ≥20% IOP reduction (definition 2), IOP ≥5 mmHg, no vision loss and no further glaucoma surgery. Secondary endpoints were the absolute IOP reduction, visual acuity, medication, complications and second surgeries. Surgical treatment significantly reduced IOP in both groups (p < 0.001). Complete success was achieved in 74.2% and 39.1% (definition 1, p = 0.01), and 67.7% and 39.1% (definition 2, p = 0.04) after 2 years in the trabeculectomy and canaloplasty group, respectively. Mean absolute IOP reduction was 10.8 ± 6.9 mmHg in the trabeculectomy and 9.3 ± 5.7 mmHg in the canaloplasty group after 2 years (p = 0.47). Mean IOP was 11.5 ± 3.4 mmHg in the trabeculectomy and 14.4 ± 4.2 mmHg in the canaloplasty group after 2 years. Following trabeculectomy, complications were more frequent including hypotony (37.5%), choroidal detachment (12.5%) and elevated IOP (25.0%). Trabeculectomy is associated with a stronger IOP reduction and less need for medication at the cost of a higher rate of complications. If target pressure is attainable by moderate IOP reduction, canaloplasty may be considered for its relative ease of postoperative care and lack of complications.


Pharmacologic sensitivity of paclitaxel to its delivery vehicles drives distinct clinical outcomes of paclitaxel formulations.
Paclitaxel, an effective antitumor agent, is formulated in various vehicles serving as carriers to deliver the hydrophobic paclitaxel to tissue. The approved formulations in the U.S. are paclitaxel formulated in Cremophor EL (currently known as Kolliphor EL) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel). Despite having the same active ingredient (paclitaxel), different formulations produce distinct products with unique efficacy and safety profiles. A semimechanistic model was developed to describe the pharmacologic sensitivity of paclitaxel under different formulations. Circulating paclitaxel concentration data from patients treated with nab-paclitaxel or Cremophor EL-paclitaxel were analyzed in NONMEM using a semimechanistic model with simultaneous disposition of paclitaxel-carrier complexes and the total paclitaxel released from the complexes. The key factors driving paclitaxel exposure in circulation and peripheral tissues were explored via sensitivity analysis. The rapid decline of total paclitaxel concentration following intravenous administration of nab-paclitaxel and Cremophor EL-paclitaxel was attributed to rapid tissue distribution of the paclitaxel-carrier complexes, with minor contribution of free and protein-bound paclitaxel. Distribution of nab-paclitaxel to peripheral tissue was 4-fold faster and 10-fold more extensive than that of Cremophor EL-paclitaxel micelles, resulting in distinct tissue paclitaxel profiles. Sensitivity analyses showed the plasma paclitaxel-time profile was insensitive to the rapid rates of tissue distribution and decomposition of paclitaxel-carrier complexes but that the tissue distribution profile of paclitaxel was highly sensitive. Tissue distribution of paclitaxel is carrier complex system-dependent. Different delivery systems result in distinct tissue paclitaxel profiles but similar paclitaxel concentration-time profiles in plasma or blood, rendering the paclitaxel plasma profile a poor surrogate for its clinical outcome.


Ankylosing hyperostosis with cervical spinal cord compression.
This report describes a patient whose clinical and radiological features conform to those of ankylosing hyperostosis. Posterior bridging osteophytes were also apparent and these have not been previously described in ankylosing hyperostosis. We have considered alternative explanations for this finding and concluded that they were manifestations of the hyperostotic process. This unusual feature occurring in the presence of a comparatively narrow spinal canal resulted in cord compression and a spastic tetraparesis and we would therefore suggest that ankylosing hyperostosis may sometimes have serious neurological consequences.


The spectrum of cognitive impairment in Lewy body diseases.
Cognitive impairment represents an important and often defining component of the clinical syndromes of Lewy body disorders: Parkinson's disease and dementia with Lewy bodies. The spectrum of cognitive deficits in these Lewy body diseases encompasses a broad range of clinical features, severity of impairment, and timing of presentation. It is now recognized that cognitive dysfunction occurs not only in more advanced Parkinson's disease but also in early, untreated patients and even in those patients with pre-motor syndromes, such as rapid eye movement behavior disorder and hyposmia. In recent years, the concept of mild cognitive impairment as a transitional or pre-dementia state in Parkinson's disease has emerged. This has led to much research regarding the diagnosis, prognosis, and underlying neurobiology of mild cognitive impairment in Parkinson's disease, but has also raised questions regarding the usefulness of this concept and its application in clinical and research settings. In addition, the conundrum of whether Parkinson's disease dementia and dementia with Lewy bodies represent the same or different entities remains unresolved. Although these disorders overlap in many aspects of their presentations and pathophysiology, they differ in other elements, such as timing of cognitive, behavioral, and motor symptoms; medication responses; and neuropathological contributions. This article examines the spectrum and evolution of cognitive impairment in Lewy body disorders and debates these controversial issues in the field using point-counterpoint approaches.


La Tunisie Medicale: bibliometric analysis of the articles cites 10 times or more in the Scopus database.
La Tunisie Medicale (Tunis Med) had a deep impact in nearly 100 years of publishing. A bibliometric study, which uses citation analyses to appraise the influence of articles, can be used to detect the most impactful articles in the Tunis Med's history. To identify and characterize the profile of the top-cited articles (≥10 times in Scopus) published in Tunis Med since 1949. Scopus database was used to classify, according to the frequency of citation, the articles published in Tunis Med from 1949 through 2019. Only articles cited ≥10 times were included in the analysis. Articles were evaluated for several characteristics including number of citations (in absolute) of annual citations, year of publication, article type, language of publication, country of origin and specialty of the first author. Among the 7555 articles classified in Scopus, only 105 (1.39%) were cited ≥10 times. The means±standard deviations of citations and annual citations were low, at 15.4±7.3 and 1.202±0.612, respectively. The profile of the most cited articles was an original article (92.38%), written in French (63.81%) and published between 2002 and 2011 (66.7%) by a first author specialist in community medicine (11.43%) or pediatrics (10.48%) who is affiliated to a research structure based in Tunisia (97.1%). This bibliometric analysis provides an overview of the Tunis Med publications that have shaped the scope and practice of medicine.


[Real-time polymerase chain reaction in the diagnosis of pulmonary tuberculosis].
To enhance the efficiency of diagnosis of oligo- and abacillar pulmonary tuberculosis and its differential diagnosis with other lung diseases, the authors studied the informative value of real-time polymerase chain reaction (PCR) used in 62 patients with different clinical forms of tuberculosis and 108 differentially diagnostic patients. Real-time PCR has been ascertained to be a significantly more sensitive and highly specific tool in tuberculosis diagnosis, which considerably improves the specific recognition of the etiology of a pathogenetic process in oligo- and abacillar patients. Particularly encouraging results have been obtained when examining differentially diagnostic patients with the rounded shadows being formed in the lung.


Quantitative Cell Biology of Neurodegeneration in Drosophila Through Unbiased Analysis of Fluorescently Tagged Proteins Using ImageJ.
With the rising prevalence of neurodegenerative diseases, it is increasingly important to understand the underlying pathophysiology that leads to neuronal dysfunction and loss. Fluorescence-based imaging tools and technologies enable unprecedented analysis of subcellular neurobiological processes, yet there is still a need for unbiased, reproducible, and accessible approaches for extracting quantifiable data from imaging studies. We have developed a simple and adaptable workflow to extract quantitative data from fluorescence-based imaging studies using Drosophila models of neurodegeneration. Specifically, we describe an easy-to-follow, semi-automated approach using Fiji/ImageJ to analyze two cellular processes: first, we quantify protein aggregate content and profile in the Drosophila optic lobe using fluorescent-tagged mutant huntingtin proteins; and second, we assess autophagy-lysosome flux in the Drosophila visual system with ratiometric-based quantification of a tandem fluorescent reporter of autophagy. Importantly, the protocol outlined here includes a semi-automated segmentation step to ensure all fluorescent structures are analyzed to minimize selection bias and to increase resolution of subtle comparisons. This approach can be extended for the analysis of other cell biological structures and processes implicated in neurodegeneration, such as proteinaceous puncta (stress granules and synaptic complexes), as well as membrane-bound compartments (mitochondria and membrane trafficking vesicles). This method provides a standardized, yet adaptable reference point for image analysis and quantification, and could facilitate reliability and reproducibility across the field, and ultimately enhance mechanistic understanding of neurodegeneration.


Size scaling of turbulent transport in magnetically confined plasmas.
Transport scaling with respect to device size in magnetically confined plasmas is critically examined for electrostatic ion-temperature-gradient turbulence using global gyrokinetic particle simulations. It is found, by varying device size normalized by ion gyroradius while keeping other dimensionless plasma parameters fixed, that fluctuation scale length is microscopic in the presence of zonal flows. The local transport coefficient exhibits a gradual transition from a Bohm-like scaling for device sizes corresponding to present-day experiments to a gyro-Bohm scaling for future larger devices.


The School as an Arena for Co-Creating Participation, Equity, and Well-Being-A Photovoice Study from Norway.
Schools may play an essential role as an arena for co-creating community activities that enhance well-being, equity, and citizenship. Still, there is limited knowledge about physical and non-physical factors that contribute to well-being within such approaches. The aim of this study was to identify important factors for well-being as perceived by pupils, school employees, and parents in a community school in Norway. The participatory method photovoice was used, and seven pupils, six employees, and four parents participated by taking photos used as the basis for six focus group discussions. Transcripts of the discussions were analyzed using Systematic Text Condensation. The analysis showed that the participants experienced that the school's built and natural environment, the activities happening there, and the human resources and organization at the school facilitated perceptions of safety, inclusion, and cohesion, which in turn contributed to well-being. Furthermore, the results showed that co-creating schools as a community arena could be an innovative way of ensuring participation, equity, and well-being in the community. Such an approach might be especially important in deprived areas or in multi-ethnic communities. An important prerequisite to succeed is the openness of the school's staff to engage in co-creation with other stakeholders in the community.


Spatial localization in nuclear spin-induced circular dichroism - a quadratic response function analysis.
Nuclear magneto-optic (NMO) effects are recently described phenomena originating from the interaction of light with local magnetic fields produced by nuclear spins. The phenomena border nuclear magnetic resonance and optical spectroscopy and are expected to provide rather unique spectroscopic features, borrowing from both localized response of the atomic nuclei as well as more global excitation properties of the whole molecule or its chromophore moieties. A number of quantum-chemical computational studies have been carried out, offering a reasonable agreement with nuclear magneto-optics experiments performed so far. However, the detailed structure-spectra relation is still poorly understood. In this report we address the question of locality of one of the NMO effects, namely nuclear spin-induced circular dichroism (NSCD). We implement an alternative computational approach for calculation of the NSCD intensities, based on residues of quadratic response functions, and use it to investigate the NSCD response of different nuclei in a model molecular system with well-defined separate chromophores. The results show that significant NSCD at a given energy only occurs at the nuclei which are located in the chromophore that is excited. We rationalize these findings using analysis via difference densities, and approximate sum-over-states calculations. This behaviour of NSCD opens a way to experimental studies of localization of excited states in molecules, potentially with resolution down to the order of bond-length.


Symbolic, Distributed, and Distributional Representations for Natural Language Processing in the Era of Deep Learning: A Survey.
Natural language is inherently a discrete symbolic representation of human knowledge. Recent advances in machine learning (ML) and in natural language processing (NLP) seem to contradict the above intuition: discrete symbols are fading away, erased by vectors or tensors called distributed and distributional representations. However, there is a strict link between distributed/distributional representations and discrete symbols, being the first an approximation of the second. A clearer understanding of the strict link between distributed/distributional representations and symbols may certainly lead to radically new deep learning networks. In this paper we make a survey that aims to renew the link between symbolic representations and distributed/distributional representations. This is the right time to revitalize the area of interpreting how discrete symbols are represented inside neural networks.


An analysis of cardiovascular health information in popular young women's magazines: what messages are women receiving?
This study evaluated the consistency of cardiovascular health information in popular women's magazines against the American Heart Association's (AHA) guidelines for nutrition, physical activity, weight management, and smoking. Six issues of four publications, Cosmopolitan, Glamour, Vogue, and Shape (24 total) were reviewed for inclusion. Content analysis was performed by two independent raters on 162 articles (283 instances of priority-related information). Articles were rated using a questionnaire developed from the AHA-recommended priorities. Results are presented primarily in qualitative form, supplemented by analyses of variance and correlation significance tests when appropriate. Physical activity was the most common topic, followed by nutrition, weight management, and cigarette smoking. Information about weight management was less consistent than other areas. Although publications varied widely in the frequency of coverage, there was no significant difference among them in overall consistency of the information. No articles gave information directly contrary to the AHA recommendations. Limitations include the subjective nature of the content analysis and the limited number of publications and time period for review. Women are receiving information related to diet, exercise, weight management, and cigarette smoking in popular magazines. However, the information is variable to the extent that it is consistent with evidence-based prevention guidelines.


The Changes of Cardiovascular Neurotransmitter Levels under Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve.
Our previous study has shown that stimulation of the vagus nerve with low-intensity focused ultrasound could modulate blood pressure (BP), but the underlying mechanisms remain unclear. This study investigated the changes of cardiovascular neurotransmitter levels to indirectly evaluate the responses of the autonomic nervous system and renin-angiotensin system under low-intensity focused ultrasound stimulation (FUS) of the vagus nerve. Cardiovascular neurotransmitter levels of epinephrine (EPI), norepinephrine (NE), and angiotensin II (ANGII) were measured and compared before and after the FUS in seven spontaneously hypertensive rats; and were also measured and compared between a target stimulation group (FUS, n = 6) and non-target stimulation group (Control, n = 5) after stimulation to exclude the influence of potential confounding factors. The t-test results showed that the levels of EPI, NE, and ANGII were significantly decreased (P < 0.05) after stimulation compared to before stimulation. Additionally, the levels of NE and EPI were significantly lower (P < 0.05) in the FUS group than in the Control group after stimulation, indicating that the activities of the sympathetic nervous system and renin-angiotensin system of the vagus nerve might be inhibited by FUS of the vagus nerve. These findings reveal the mechanism of BP lowing in response to FUS of the vagus nerve.Clinical Relevance-This study revealed the mechanism of BP lowering in response to focused ultrasound stimulation of the vagus nerve through analyzing the changes of cardiovascular neurotransmitter levels.


Advances in Head and Neck Cancer Pain.
Head and neck cancer (HNC) affects over 890,000 people annually worldwide and has a mortality rate of 50%. Aside from poor survival, HNC pain impairs eating, drinking, and talking in patients, severely reducing quality of life. Different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between cancers. Poor pathologic features (e.g., perineural invasion, lymph node metastasis) are associated with increased pain. The use of syngeneic/immunocompetent animal models, as well as a new mouse model of perineural invasion, provides novel insights into the pathobiology of HNC pain. Glial and immune modulation of the tumor microenvironment affect not only cancer progression but also pain signaling. For example, Schwann cells promote cancer cell proliferation, migration, and secretion of nociceptive mediators, whereas neutrophils are implicated in sex differences in pain in animal models of HNC. Emerging evidence supports the existence of a functional loop of cross-activation between the tumor microenvironment and peripheral nerves, mediated by a molecular exchange of bioactive contents (pronociceptive and protumorigenic) via paracrine and autocrine signaling. Brain-derived neurotrophic factor, tumor necrosis factor α, legumain, cathepsin S, and A disintegrin and metalloprotease 17 expressed in the HNC microenvironment have recently been shown to promote HNC pain, further highlighting the importance of proinflammatory cytokines, neurotrophic factors, and proteases in mediating HNC-associated pain. Pronociceptive mediators, together with nerve injury, cause nociceptor hypersensitivity. Oncogenic, pronociceptive mediators packaged in cancer cell-derived exosomes also induce nociception in mice. In addition to increased production of pronociceptive mediators, HNC is accompanied by a dampened endogenous antinociception system (e.g., downregulation of resolvins and µ-opioid receptor expression). Resolvin treatment or gene delivery of µ-opioid receptors provides pain relief in preclinical HNC models. Collectively, recent studies suggest that pain and HNC progression share converging mechanisms that can be targeted for cancer treatment and pain management.


Molecular characteristics of antibodies bearing an anti-DNA-associated idiotype.
Anti-double-stranded DNA antibodies are the hallmark of the disease systemic lupus erythematosus and are believed to contribute to pathogenesis. While a large number of anti-DNA antibodies from mice with lupus-like syndromes have been characterized and their variable region genes sequenced, few human anti-DNA antibodies have been reported. We describe here the variable region gene sequences of eight antibodies produced by Epstein-Barr virus (EBV)-transformed B cells that bear the 3I idiotype, an idiotype expressed on anti-DNA antibodies and present in high titer in patients with systemic lupus. The comparison of these antibodies to the light chains of 3I+ myeloma proteins and serum antibodies reveals that EBV transformation yields B cells producing antibodies representative of the expressed antibody repertoire. The analysis of nucleotide and amino acid sequences of these antibodies suggests the first complementarity determining region of the light chain may be important in DNA binding and that paradigms previously generated to account for DNA binding require modification. The understanding of the molecular genetics of the anti-DNA response requires a more complete description of the immunoglobulin germ line repertoire, but data reported here suggest that somatic diversification is a characteristic of the anti-DNA response.


Computer applications in dermatology.
Advances in computer technology both in hardwares and softwares has stimulated the proliferation of the use of computers in dermatology. The computers enable the voluminous medical literature and records to be compiled and accessed readily. Information technology enables dermatologists to conduct literature searches efficiently and helps in the management of patients. The information compiled in the computers as databases together with its capability to handle complex statistical analysis also enables dermatologists and computer scientists to develop expert systems to assist the dermatologist in the diagnosis and prognostication of diseases and to predict disease trends. Computers have also allowed dermatologists to assess visual images objectively, making it possible to study treatment response more accurately.


The emotion identification group.
Emotion identification is an individual's ability to be aware of affective responses that occur during varied daily interactions. Through a review of the literature, how patients often seem unclear about the relevance of "doing" therapy to "talking/feeling" therapy is documented, an then an attempt is made to show how the occupational therapy emotion identification group can reinforce the patients' real-life connection between doing, talking or feeling. The basic premises formulated for establishing a method to promote emotion identification, the group format that incorporates this method, and patient responses to the method are presented. How occupational therapy interfaces with Gestalt therapy and therapeutic community philosophies is shown and methods are described to apply the Gestalt process of one's getting in touch with and taking ownership for both needs and feelings in the emotion identification group and in occupational therapy task groups.


Epizootic hemorrhagic disease virus in Montana: isolation and serologic survey.
Epizootic hemorrhagic disease virus (EHDV) was isolated in Vero cell culture from the spleen and whole blood of a white-tailed deer (Odocoileus virginianus). A 10% spleen suspension caused acute hemorrhagic disease (HD) when inoculated into an experimental white-tailed deer and resulted in the recovery of EHDV from the blood of the experimental animal at 5 days after inoculation. The virus was identified as EHDV serotype 2 through indirect fluorescent antibody tests, electron microscopy, and reciprocal cross-neutralization tests. Approximately 73% (36/49) of the mule deer, 5% (2/42) of the white-tailed deer, and 79% (249/314) of the cattle samples tested from areas where HD had been reported were EHDV seropositive. Although none of the white-tailed deer was bluetongue virus seropositive, 29% of the mule deer and 3% of the cattle tested from "active" HD areas possessed bluetongue virus precipitating antibody.


Anti-CD25 antibody treatment of mice vaccinated and challenged with Borrelia spp. does not exacerbate arthritis but inhibits borreliacidal antibody production.
CD4(+) CD25(+) T cells are a population of regulatory T cells responsible for the modulation of the immune response in several autoimmune and infectious disease models. We previously showed that adoptive transfer of enriched CD4(+) CD25(+) T cells also plays a major role in the prevention of arthritis in Borrelia-vaccinated (Borrelia burgdorferi isolate 297) and -challenged (B. bissettii) mice. Here, we present evidence that administration of anti-CD25 antibody at the time of challenge or at later intervals fails to enhance the development of severe destructive osteoarthropathy in Borrelia-vaccinated C57BL mice. However, Borrelia-vaccinated and -challenged mice receiving anti-CD25 antibody developed decreased borreliacidal antibody titers compared to vaccinated and challenged controls. These findings suggest that additional mechanisms besides CD4(+) CD25(+) T cells are involved in the regulation of the immune response to Borrelia infection following vaccination.


The role of NF-κB signaling pathway in reactive astrocytes among neurodegeneration after methamphetamine exposure by integrated bioinformatics.
Methamphetamine (METH) is a highly addictive stimulant that has become one of the top five risk substances cause deaths from substance abuse. METH exposure increases the risk of neurodegenerative disease (ND), such as Parkinson's disease (PD), leading to disability and death. Activation of reactive astrocytes is an essential factor in neurodegeneration, and their complex role in METH exposure remains unclear. This study explored the role of reactive astrocyte overactivation in neurodegeneration after METH exposure. METH bulk RNA sequencing data (GSE107015 and GSE98793) and single-cell RNA sequencing data (GSE119861) were obtained from the GEO database. We performed immune infiltration analysis on the bulk RNA data. After cell clustering using the single-cell RNA data, astrocytes were extracted for downstream analysis. Differentially expressed genes (DEGs) were identified from the bulk and single-cell RNA sequencing datasets, and GO, KEGG, and GSEA pathway analyses were performed. The PPI network and random forest methods were performed on the overlapping genes of the DEGs to screen hub genes. To explore the common ground between METH exposure and neurodegenerative diseases, we applied a random forest algorithm to PD chip data (GSE99039 and GSE72267) to establish a diagnostic model using the hub genes in METH. New object recognition and the Morris water maze were used to examine cognitive function in mice exposed to METH for 14 days in vivo. Astrocytes were cocultured with neurons for the detection of intercellular crosstalk. DEGs in the METH group significantly enriched pathways related to NDs, inflammation, and the NF-κB signaling pathway. Immune infiltration analysis revealed significantly increased infiltration of monocytes, T cells, and NK cells and decreased infiltration of neutrophils in the METH group. An intersection of 44 hub genes was screened based on the PPI network and random forest algorithm. These genes suggest that there might be similar pathogenesis between METH exposure and PD. METH exposure resulted in learning memory impairment, hippocampal astrocyte activation, and upregulation of NF-κB expression in mice. Activation of reactive astrocytes cocultured with neurons causes neural damage. This study explored the crosstalk between astrocytes and neurons in METH exposure, providing a potential pathogenesis to explore the altered immune microenvironment involving reactive astrocytes after METH exposure.


The high prevalence of bipolar spectrum disorders in young adults with recurrent depression: toward an innovative diagnostic framework.
Young adults with early-onset major depressive disorder (MDD) may be at high risk of progression to bipolar disorder. Although hypomanic symptoms are common in young people with depression, many do not reach the strict DSM-IV and ICD-10 criteria for hypomania. We used an emerging innovative framework for bipolar spectrum to evaluate this question. Consecutive referrals to a psychiatric outpatient clinic at a university health service were assessed for recurrent episodes of depression. DSM-IV diagnoses were based on a SCID-1 interview. We used two approaches to delineate bipolar spectrum. The first focused on bipolar spectrum disorder (BSD, as defined by Ghaemi et al. [Can. J. Psychiatry 47 (2002) 125]), and the second on a symptoms perspective based on MDD with a history of hypomanic symptoms, using a 15-point hypomanic symptoms checklist with a cut-off > or =8 or more symptoms (modified from J. Affect. Disord. 73 (2003) 39 and J. Affect. Disord. 73 (2003) 73). Data were also obtained on family history of affective disorder, course and number of episodes of depression, symptom severity, psychosocial functioning, suicidality and deliberate self-harm, and drug and alcohol use. High rates of bipolar and bipolar spectrum disorder were identified. Under DSM-IV, 14 subjects (16.1%) had bipolar affective disorder and 73 subjects (83.9%) had recurrent MDD. Depending on the method used to diagnose bipolar spectrum, between 47.1% and 77.0% of the total cohort could be so diagnosed. Hypomanic symptom counts, irrespective of duration, yielded the highest estimates for bipolar spectrum. High rates of pharmacological hypomania were also identified: 12 subjects (16.4%) with recurrent MDD group reported this, and all could be diagnosed with bipolar spectrum. The reliability of using the 15-point hypomanic scale for the diagnostic assignments was not tested. All subjects were recruited from a university health service and, given the affluence of their parents, findings may not generalise to other populations. Most importantly, because bipolar family history and pharmacological hypomania were part of the diagnostic criteria of the BSD group, they could not be used as external validators for Ghaemi's BSD construct. Bipolar disorders emerge as extremely common in this cohort of young adults with recurrent depression. Antidepressant-induced hypomania and high scores on a hypomanic symptoms checklist help to identify patients who are likely to have a bipolar spectrum illness, but who do not meet DSM-IV criteria for bipolar disorder. This is a preliminary study, and further evidence from external validating strategies are needed to verify the bipolar status of these patients in a larger and unselected cohort representing a broader socio-economic demographic profile.


Copper-Catalyzed Oxygenative Skeletal Rearrangement of Tetrahydro-β-carbolines Using H2 O and O2 as Oxygen Sources.
Herein, we report an unprecedented skeletal rearrangement reaction of tetrahydro-β-carbolines enabled by copper-catalyzed single-electron oxidative oxygenation, in which H2 O and O2 act as oxygen sources to generate a unique 2-hydroxyl-3-peroxide indoline intermediate. The synthetic reactivity of 2-hydroxyl-3-peroxide indoline species was demonstrated by a unique multi-step bond cleavage and formation cascade. Using a readily available copper catalyst under open-air conditions, highly important yet synthetically difficult spiro[pyrrolidone-(3,1-benzoxazine)] products were obtained in a single operation. The synthetic utility of this methodology is demonstrated by the efficient synthesis of the natural products donaxanine and chimonamidine, as well as the 3-hydroxyl-pyrroloindoline scaffold, in just one or two steps.


Airway Obstruction Worsens in Young Adults with Asthma Who Become Obese.
Few studies have examined how developing obesity in early adulthood affects the course of asthma. We analyzed lung function and asthma impairment and risk among nonobese children with asthma, comparing those who were obese in young adulthood with those who remained nonobese. We carried out the post hoc analysis of 771 subjects with mild to moderate asthma who were not obese (pediatric definition, body mass index [BMI] < 95th percentile) when enrolled in the Childhood Asthma Management Program at ages 5-12 years. The subjects were then followed to age 20 years or more. For visits at ages 20 years or more, spirometry values as percent predicted and recent asthma symptom scores and prednisone exposure were compared between 579 subjects who were nonobese at all visits and 151 who were obese (adult definition of BMI ≥ 30 kg/m(2)) on at least 1 visit (median number of visits when obese = 4, IQR 2-7). Compared with participants who were nonobese (BMI 23.4 ± 2.6 kg/m(2)), those who became obese (BMI 31.5 ± 3.8 kg/m(2)) had significant decreases in forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) (P < .0003) and FEV1 (P = .001), without differences in FVC (P = .15) during visits at ages 20 years or more. For each unit increase of BMI, FEV1 percent predicted decreased by 0.29 (P = .0009). The relationship between BMI and lung function was not confounded by sex or BMI at baseline. Asthma impairment (symptom scores) and risk (prednisone use) did not differ between the 2 groups. Becoming obese in early adulthood was associated with increased airway obstruction, without impact on asthma impairment or risk.


Survival after implantable cardioverter-defibrillator implantation in the elderly.
The benefit of implantable cardioverter-defibrillators (ICDs) among elderly patients is controversial and may be attenuated by nonarrhythmic death. We examined the impact of age on device-delivered therapies and outcomes after primary or secondary prevention ICD. In a prospective, inclusive registry of 5399 ICD recipients in Ontario, Canada (February 2007 to September 2010), device-delivered therapies and complications were determined at routine clinic visits. Among primary prevention ICD recipients aged 18 to 49 (n=317), 50 to 59 (n=769), 60 to 69 (n=1336), 70 to 79 (n=1242), and ≥80 (n=275) years, mortality increased with age, as follows: 2.1, 3.0, 5.4, 6.9, and 10.2 deaths per 100 person-years, respectively (P<0.001). Secondary prevention ICD recipients aged 18 to 49 (n=114), 50 to 59 (n=244), 60 to 69 (n=481), 70 to 79 (n=462), and ≥80 (n=159) years also exhibited increasing mortality, as follows: 2.2, 3.8, 6.1, 8.7, and 15.5 deaths per 100 person-years, respectively (P<0.001). However, rates of appropriate shock were similar across age groups: from 6.7 (18-49 years) to 4.2 (≥80 years) per 100 person-years after primary prevention ICDs (P=0.139) and from 11.4 (18-49 years) to 11.9 (≥80 years) per 100 person-years after secondary prevention ICDs (P=0.993). Covariate-adjusted competing risk analysis demonstrated higher risk of death (Ptrend<0.001 for both primary and secondary prevention) but no significant decline in appropriate shocks with older age after primary (P=0.130) or secondary (P=0.810) prevention ICD implantation. Whereas elderly patients exhibited increased mortality after ICD implantation, rates of appropriate device shocks were similar across age groups. Decisions regarding ICD candidacy should not be based on age alone but should consider factors that predispose to mortality despite defibrillator implantation.


Endogenous nitric oxide modulates GABAergic transmission to granule cells in adult rat cerebellum.
Nitric oxide (NO) is a gaseous neurotransmitter which plays an important role in neuronal signalling and plasticity throughout the brain. In the cerebellum, NO synthase (NOS) is expressed in parallel fibres and within the internal granule cell layer (IGL). During development there are changes in NOS concentration, distribution and activity within the IGL, suggesting NO may play a role in IGL function. Therefore, the actions of NO in the IGL were investigated. The similar actions of a range of NOS inhibitors and NO scavengers strongly suggested the presence of a tonic level of endogenous NO in the IGL. Both the neuronal and inducible forms of NOS appeared to be sources of this endogenous NO. The effects observed following a reduction in the concentration of endogenous NO were consistent with enhanced granule cell GABAA receptor activation. For example, a reduction in NO concentration led to an increase in the frequency of action potential-dependent phasic GABAergic inhibitory postsynaptic currents (IPSCs) and produced a TTX-insensitive GABAA receptor-mediated current. A direct action of NO on Golgi cell membrane potential and input resistance accounted for the increase in the frequency of phasic GABA release. The mechanism underlying the tonic GABA current is unclear but does not appear to be via the modulation of GABA uptake or the activation of nicotinic acetylcholine receptors. NO is a potentially novel mechanism for tuning GABAergic signalling to granule cells and therefore modulating the throughput of an important cerebellar circuit.


Bacterial community structure of acid-impacted lakes: what controls diversity?
Although it is recognized that acidification of freshwater systems results in decreased overall species richness of plants and animals, little is known about the response of aquatic microbial communities to acidification. In this study we examined bacterioplankton community diversity and structure in 18 lakes located in the Adirondack Park (in the state of New York in the United States) that were affected to various degrees by acidic deposition and assessed correlations with 31 physical and chemical parameters. The pH of these lakes ranged from 4.9 to 7.8. These studies were conducted as a component of the Adirondack Effects Assessment Program supported by the U.S. Environmental Protection Agency. Thirty-one independent 16S rRNA gene libraries consisting of 2,135 clones were constructed from epilimnion and hypolimnion water samples. Bacterioplankton community composition was determined by sequencing and amplified ribosomal DNA restriction analysis of the clone libraries. Nineteen bacterial classes representing 95 subclasses were observed, but clone libraries were dominated by representatives of the Actinobacteria and Betaproteobacteria classes. Although the diversity and richness of bacterioplankton communities were positively correlated with pH, the overall community composition assessed by principal component analysis was not. The strongest correlations were observed between bacterioplankton communities and lake depth, hydraulic retention time, dissolved inorganic carbon, and nonlabile monomeric aluminum concentrations. While there was not an overall correlation between bacterioplankton community structure and pH, several bacterial classes, including the Alphaproteobacteria, were directly correlated with acidity. These results indicate that unlike more identifiable correlations between acidity and species richness for higher trophic levels, controls on bacterioplankton community structure are likely more complex, involving both direct and indirect processes.


Companion confidence in the balance of community-dwelling older adults: implications for physical activity promotion.
Positive social relationships may increase the intention of older adults to be physically active. In the presence of balance impairments, however, the potential influence of a familiar companion on an older adult's physical activity is not well understood. The purpose of this preliminary investigation was to explore companion confidence in the balance capability of an older adult as a potential determinant of older adult physical activity. The study employed a cross-sectional design, in which 40 dyads formed by a community-dwelling older adult and his or her close companion (eg, family member, friend, and caregiver) were recruited as a sample of convenience. Older adults completed the Activities-Specific Balance Confidence (ABC) scale and the Physical Activity Survey for the Elderly (PASE). Companions completed a modified version of the ABC scale, in which they were asked to rate their confidence in the older adult's balance. The agreement between and correspondence of paired ABC scores were analyzed using mean difference (95% confidence interval [CI]), dependent samples t test (α = 0.05), and the intraclass correlation coefficient 1-way random effects model. The Pearson product-moment correlation coefficient was used to characterize the relationship between companion confidence and older adult physical activity. Older adults were more confident in their balance capability (mean ABCOlder Adult = 70.0; 95% CI = 62.8-77.2) than their companions (mean ABCCompanion = 60.2; 95% CI = 50.6-69.8). The difference between group mean scores was significant (mean difference = 9.8; 95% CI = 2.3-17.3, t (39) = 2.38; P = 0.02). Discordance increased as the mean of paired ABC scores diminished. ABC scores were also significantly yet moderately associated (intraclass correlation coefficient (1,1) = 0.56; 95% CI = 0.31-0.74; P < 0.01). The association between ABCCompanion and PASE scores was stronger (r = 0.51; 95% CI = 0.23-0.79; P < 0.01) than the association between ABCOlder Adult and PASE scores (r = 0.33; 95% CI = 0.02-0.64; P = 0.04) and increased in cases for which companions were markedly less confident than older adults. Older adults and their companions did not necessarily share similar confidence in the older adult's balance capability. Companion confidence, especially when markedly less than older adult confidence, showed promise as a predictor of older adult physical activity. Study findings provided a foundation for future investigations that examine the effect of social relationships on the physical activity self-efficacy of older adults with balance impairments.


Distinguishing Self, Other, and Autonomy From Visual Feedback: A Combined Correlation and Acceleration Transfer Analysis.
In cognitive science, Theory of Mind (ToM) is the mental faculty of assessing intentions and beliefs of others and requires, in part, to distinguish incoming sensorimotor (SM) signals and, accordingly, attribute these to either the self-model, the model of the other, or one pertaining to the external world, including inanimate objects. To gain an understanding of this mechanism, we perform a computational analysis of SM interactions in a dual-arm robotic setup. Our main contribution is that, under the common fate principle, a correlation analysis of the velocities of visual pivots is shown to be sufficient to characterize "the self" (including proximo-distal arm-joint dependencies) and to assess motor to sensory influences, and "the other" by computing clusters in the correlation dependency graph. A correlational analysis, however, is not sufficient to assess the non-symmetric/directed dependencies required to infer autonomy, the ability of entities to move by themselves. We subsequently validate 3 measures that can potentially quantify a metric for autonomy: Granger causality (GC), transfer entropy (TE), as well as a novel "Acceleration Transfer" (AT) measure, which is an instantaneous measure that computes the estimated instantaneous transfer of acceleration between visual features, from which one can compute a directed SM graph. Subsequently, autonomy is characterized by the sink nodes in this directed graph. This study results show that although TE can capture the directional dependencies, a rectified subtraction operation denoted, in this study, as AT is both sufficient and computationally cheaper.


IoT, Cloud Computing and Big Data: Integrated Framework for Healthcare in Disasters.
Currently, healthcare in disaster management context faces a number of challenges mostly due to the lack of availability of reliable data from diverse sources required to be accessible by appropriate authorities. Therefore, the main objective of this study is the introduction of a framework based on the integration of three technologies, Internet of Things (IoT), cloud computing and big data to solve this issue in all disaster phases and provide precise and effective healthcare. This framework supports healthcare managers by enabling data sharing among them and assists them in performing analytical calculations to discover meaningful, logical and accurate trend(s) required for strategic planning and better preparedness in the face of disasters. Also, the outcome of the framework may help decision makers to identify and predict the health consequences of the disasters for any specific geographical location in any country based on its geographical properties and disaster background.


Smoking, but not smokers: identity among college students who smoke cigarettes.
Cigarette smoking in college is often described as social smoking, but the term lacks definition and implicitly discounts dependence. We report on college students' use of the terms social smoker and smoker. Students who currently smoked cigarettes were asked whether they considered themselves smokers, and whether they smoked because they were social smokers. The survey was conducted during 1999-2004 at eight colleges; analysis was limited to 1,401 students aged 18-24 years. More than half of students (56.3%) denied being smokers ("deniers") despite current smoking behavior. Half of deniers, and fewer than half of admitters, called themselves social smokers. Deniers were highly likely to smoke infrequently, to say they were not addicted to cigarettes, to have mostly nonsmokers as close friends, to prefer dating nonsmokers, and to smoke for reasons other than stress relief. In contrast, social-smoker identity was associated only weakly with any attitude, behavior, or belief. Smoker and social-smoker identities were not significantly correlated with each other. Regardless of identity, more than half of the respondents wanted to quit smoking by graduation. Results suggest that denying being a smoker may be a widespread dissonance among college students who smoke. The possibility should be evaluated using population-level research, because it has potentially undermining implications for smoking cessation campaigns. Campus health centers should avoid using "smoker" self-assessment items on pre-exam questionnaires. Further research is needed to explore the psychosocial mechanisms involved with denier identity, to clarify the implications for public health communications, and to develop appropriate intervention strategies.


Characterization of ligand-induced conformational states in the beta 2 adrenergic receptor.
Drugs acting at G protein coupled receptors can be classified in biological assays as either agonists, partial agonists, neutral antagonists, or as inverse agonists. Very little is known about the actual molecular events and structural changes that occur in the receptor following ligand binding and during transmission of a signal across the membrane. Therefore, the structural basis for the biological classification of drug action remains unknown. To date, the conformational state of G protein coupled receptors has been inferred from the activity of the effector enzyme modulated by the G protein. We have used two different approaches to monitor conformational changes in beta 2 adrenergic receptor. Fluorescence spectroscopy can be used to directly monitor structural changes in purified beta 2 adrenergic receptor in real-time. The emission from many fluorescent molecules is strongly dependent on the polarity of the environment in which they are located. Thus, fluorescent probes covalently bound to proteins can be used as sensitive indicators of conformational changes and protein-protein interactions. In addition, we examined functional differences between agonists and partial agonists using fusion proteins between wild-type beta 2 receptor or a constitutively active beta 2 receptor mutant and Gs alpha. These receptor-G protein fusion proteins guarantee highly efficient coupling with a defined stoichiometry. The results of these experiments will be discussed in the context of current models of G protein coupled receptor activation.


"Deseos y Dolores": mapping desire, suffering, and (dis)loyalty within transnational partnerships.
This piece considers the deseos -- wants, desires, needs -- and dolores -- pain or sorrow -- of individuals in US-Mexico transnational partnerships. For transnational Mexicans, "desire" manifests as diverse, even contradictory, expressions of emotion. Migration is intertwined with multiple desires within intimate relationships, but is also tied to suffering across borders. Conflicting articulations of deseos y dolores reveal gender politics as well as the broader socioeconomic inequalities that drive migration and result in the transborder movement that separates couples and family members in a transnational space.


Learning Rotation-Invariant Local Binary Descriptor.
In this paper, we propose a rotation-invariant local binary descriptor (RI-LBD) learning method for visual recognition. Compared with hand-crafted local binary descriptors, such as local binary pattern and its variants, which require strong prior knowledge, local binary feature learning methods are more efficient and data-adaptive. Unlike existing learning-based local binary descriptors, such as compact binary face descriptor and simultaneous local binary feature learning and encoding, which are susceptible to rotations, our RI-LBD first categorizes each local patch into a rotational binary pattern (RBP), and then jointly learns the orientation for each pattern and the projection matrix to obtain RI-LBDs. As all the rotation variants of a patch belong to the same RBP, they are rotated into the same orientation and projected into the same binary descriptor. Then, we construct a codebook by a clustering method on the learned binary codes, and obtain a histogram feature for each image as the final representation. In order to exploit higher order statistical information, we extend our RI-LBD to the triple rotation-invariant co-occurrence local binary descriptor (TRICo-LBD) learning method, which learns a triple co-occurrence binary code for each local patch. Extensive experimental results on four different visual recognition tasks, including image patch matching, texture classification, face recognition, and scene classification, show that our RI-LBD and TRICo-LBD outperform most existing local descriptors.


Karyotype Evolution and Phylogenetic Relationships of Cricetulus sokolovi Orlov et Malygin 1988 (Cricetidae, Rodentia) Inferred from Chromosomal Painting and Molecular Data.
Sokolov's dwarf hamster (Cricetulus sokolovi) is the least studied representative of the striped hamsters (Cricetulus barabensis species group), the taxonomy of which remains controversial. The species was described based on chromosome morphology, but neither the details of the karyotype nor the phylogenetic relationships with other Cricetulus are known. In the present study, the karyotype of C. sokolovi was examined using cross-species chromosome painting. Molecular and cytogenetic data were employed to determine the phylogenetic position of Sokolov's hamster and to analyze the potential pathways of chromosome evolution in Cricetulus. Both the chromosome and molecular data support the species status of Sokolov's hamster. Phylogenetic analysis of the CYTB data placed C. sokolovi as sister to all other striped hamsters (sequence divergence of 8.1%). FISH data revealed that the karyotype of C. sokolovi is highly rearranged, with the most parsimonious scenario of its origin implying at least 4 robertsonian events and a centromere shift. Comparative cytogenetic data on Cricetinae suggest that their evolutionary history includes both periods of chromosomal conservatism and episodes of rapid chromosomal change.


Corrections and clarifications.
The price listed for Franco Pavese and Gianfranco Molinar's Modern Gas-Based Temperature and Pressure Measurements (Plenum Press) in the Books Received column of 6 November (p. 1015) was incorrect. The price of the book is $110.


RASSF4/AD037 is a potential ras effector/tumor suppressor of the RASSF family.
Activated Ras proteins interact with a broad range of effector proteins to induce a diverse series of biological consequences. Although typically associated with enhanced growth and transformation, activated Ras may also induce growth antagonistic effects such as senescence or apoptosis. It is now apparent that some of the growth-inhibitory properties of Ras are mediated via the RASSF family of Ras effector/tumor suppressors. To date, four members of this family have been identified (Nore1, RASSF1, RASSF2, and RASSF3). We now identify a fifth member of this group, RASSF4 (AD037). RASSF4 shows approximately 25% identity with RASSF1A and 60% identity with RASSF2. RASSF4 binds directly to activated K-Ras in a GTP-dependent manner via the effector domain, thus exhibiting the basic properties of a Ras effector. Overexpression of RASSF4 induces Ras-dependent apoptosis in 293-T cells and inhibits the growth of human tumor cell lines. Although broadly expressed in normal tissue, RASSF4 is frequently down-regulated by promoter methylation in human tumor cells. Thus, RASSF4 appears to be a new member of the RASSF family of potential Ras effector/tumor suppressors.


Covalent inhibitors: a rational approach to drug discovery.
Covalent inhibitors are recognized as an important component in drug discovery and therapeutics. Since the first appearance of covalent inhibitors in the late 18th century, the field has advanced significantly and currently about 30% of the marketed drugs are covalent inhibitors. The numerous advantages of covalent inhibitors are counteracting the initial concerns regarding potential off-target toxicity. Thus, continuous research, especially for cancer targets is reported. The aim of this review is to provide a short historic overview and focus on recently developed covalent inhibitors (2011-2019), including structural aspects and examples on challenging targets.


Exploring cross-protective effects between cold and immune stress in Drosophila melanogaster.
It is well established that environmental and biotic stressors like temperature and pathogens/parasites are essential for the life of small ectotherms. There are complex interactions between cold stress and pathogen infection in insects. Possible cross-protective mechanisms occur between both stressors, suggesting broad connectivity in insect stress responses. In this study, the functional significance of these interactions was tested, as well as the potential role of newly uncovered candidate genes, turandot. This was done using an array of factorial experiments exposing Drosophila melanogaster flies to a combination of different cold stress regimes (acute or chronic) and infections with the parasitic fungus Beauveria bassiana. Following these crossed treatments, phenotypic and molecular responses were assessed by measuring 1) induced cold tolerance, 2) immune resistance to parasitic fungus, and 3) activation of turandot genes. We found various responses in the phenotypic outcomes according to the various treatment combinations with higher susceptibility to infection following cold stress, but also significantly higher acute cold survival in flies that were infected. Regarding molecular responses, we found overexpression of turandot genes in response to most treatments, suggesting reactivity to both cold and infection. Moreover, maximum peak expressions were distinctly observed in the combined treatments (infection plus cold), indicating a marked synergistic effect of the stressors on turandot gene expression patterns. These results reflect the great complexity of cross-tolerance reactions between infection and abiotic stress, but could also shed light on the mechanisms underlying the activation of these responses.


Treatment of von Willebrand disease.
von Willebrand disease is the most frequent of inherited bleeding disorders (1:100 affected individuals in the general population). The aim of treatment is to correct the dual defects of haemostasis, i.e., abnormal coagulation expressed by low levels of factor VIII and abnormal platelet adhesion expressed by a prolonged bleeding time. There are two main options available for the management of von Willebrand disease: desmopressin and transfusion therapy with blood products. Desmopressin is the treatment of choice in patients with type 1 von Willebrand disease, who account for approximately 80% of cases. This pharmacological compound raises endogenous factor VIII and von Willebrand factors and thereby corrects the intrinsic coagulation defect and the prolonged bleeding time in most type 1 patients. In type 3 and in the majority of type 2 patients desmopressin is not effective, and it is necessary to resort to plasma concentrates containing factor VIII and von Willebrand factor. Treated with virucidal methods, these concentrates are effective and currently safe, but the bleeding time defect is not always corrected by them. Platelet concentrates or desmopressin can be used as adjunctive treatments when poor correction of the bleeding time after concentrates is associated with continued bleeding.


HPMC supplementation reduces abdominal fat content, intestinal permeability, inflammation, and insulin resistance in diet-induced obese mice.
The effects of hydroxypropyl methylcellulose (HPMC), a highly viscous nonfermentable soluble dietary fiber, were evaluated on adipose tissue inflammation and insulin resistance in diet-induced obese (DIO) mice fed a high-fat (HF) diet supplemented with either HPMC or insoluble fiber. DIO C57BL/6J mice were fed a HF diet supplemented with 6% HPMC or 6% microcrystalline cellulose (MCC). Gene expression analyses of epididymal adipose tissue by exon microarray and real-time PCR along with glucose and insulin tolerance and intestinal permeability were assessed. HPMC-fed mice exhibited significantly reduced body weight gain and adipose tissue weight as well as reduced areas under the curve for 2-h insulin and glucose responses. HPMC significantly decreased HF diet-induced intestinal permeability. Overall, HPMC enhanced insulin sensitivity and glucose metabolism and downregulated genes related to inflammation and immune response, adipogenesis, and oxidative stress markers. Pathway analysis of microarray data identified lipid metabolism, inflammatory disease, and acute phase response pathways as being differentially regulated by HPMC. These results suggest HPMC consumption ameliorates HF diet effects on obesity-induced insulin resistance, adipose tissue inflammatory and immune responses, weight gain, as well as intestinal permeability.


A randomised controlled trial to investigate the efficacy of an oxalate strip for the management of dentine hypersensitivity pain.
To compare a 3.14% potassium oxalate strip and 8% arginine calcium carbonate toothpaste for the reduction of dentine hypersensitivity after 2 and 4 weeks. This was an examiner-blind, parallel study in 80 healthy adults with dentine hypersensitivity (Schiff score >2) in >1 tooth. After acclimatisation, participants were randomised to the oxalate desensitising strip with fluoride toothpaste or the arginine desensitising toothpaste control which also contained fluoride. Products were applied under supervision of study staff after measuring baseline sensitivity, thereafter the strip or control toothpaste (fingertip application) was applied after 1 and 2 weeks, and teeth brushed twice-daily with the fluoride (test group) or the fluoridated arginine control toothpaste. Sensitivity was assessed following airblast (Schiff and VAS) and tactile stimuli (Yeaple probe) at baseline, 2 and 4 weeks. Both groups showed significant reductions from baseline in VAS, Schiff and Yeaple sensitivity scores after 2 and 4 weeks (p < 0.0005). The oxalate group had significantly lower Schiff and higher Yeaple probe scores compared to control after both time points (p < 0.0002 and p < 0.05), but while scores favoured the oxalate group, there were no significant differences in VAS. This study demonstrated application of a 3.14% potassium oxalate strip combined with toothbrushing with paste was more effective in pain management of dentine hypersensitivity than brushing with arginine toothpaste. Treatment of sensitive teeth with the oxalate strip reduced dentine hypersensitivity after 2 and 4 weeks to a significantly greater degree than a positive control sensitivity toothpaste demonstrating that oxalate strips are an effective targeted treatment for dentine hypersensitivity sufferers.


Clinicopathological characteristics and mutation profile of BRAF and NRAS mutation in cutaneous melanomas in the Western Turkish population
Background/aim: Malignant melanoma is the most common cause of death due to skin cancers. The most common mutations in RAFRAS pathway from tumor oncogenes are BRAF and NRAS. In this study, we analyzed the frequency of BRAF and NRAS gene mutations and investigated their association with clinicopathological features of melanomas in the Turkish population. Materials and methods: 65 primary cutaneous melanoma were included in the study. The mutations were evaluated with real-time PCRbased PCR-array through allele-specific amplification, and the results were correlated with various clinicopathological characteristics. Results: 52.3% of the patients were female and 47.7% were male. The mean age of the patients with a mutation was lower than those without mutation. 16 patients had BRAF mutation. 12 patients had NRAS mutation. NRAS mutation was statistically more common in men (P = 0.036). The number of mitoses increased with the increase of the tumor thickness (P = 0.003). There was more mitosis in the presence of ulceration (P = 0.05). A total of 41.7% of NRAS mutations had adjuvant chemotherapy. Conclusion: We found lower mutation rate when compared to regional studies. NRAS mutation was common in men. This is the first study from our region evaluating the prognostic value of clinical stage and necessity of adjuvant treatment with the presence of BRAF and NRAS mutations.


Epithelial sodium channel inhibition by AMP-activated protein kinase in oocytes and polarized renal epithelial cells.
The epithelial Na(+) channel (ENaC) regulates epithelial salt and water reabsorption, processes that require significant expenditure of cellular energy. To test whether the ubiquitous metabolic sensor AMP-activated kinase (AMPK) regulates ENaC, we examined the effects of AMPK activation on amiloride-sensitive currents in Xenopus oocytes and polarized mouse collecting duct mpkCCD(c14) cells. Microinjection of oocytes expressing mouse ENaC (mENaC) with either active AMPK protein or an AMPK activator inhibited mENaC currents relative to controls as measured by two-electrode voltage-clamp studies. Similarly, pharmacological AMPK activation or overexpression of an activating AMPK mutant in mpkCCD(c14) cells inhibited amiloride-sensitive short circuit currents. Expression of a degenerin mutant beta-mENaC subunit (S518K) along with wild type alpha and gamma increased the channel open probability (P(o)) to approximately 1. However, AMPK activation inhibited currents similarly with expression of either degenerin mutant or wild type mENaC. Single channel recordings under these conditions demonstrated that neither P(o) nor channel conductance was affected by AMPK activation. Moreover, expression of a Liddle's syndrome-type beta-mENaC mutant (Y618A) greatly enhanced ENaC whole cell currents relative to wild type ENaC controls and prevented AMPK-dependent inhibition. These findings indicate that AMPK-dependent ENaC inhibition is mediated through a decrease in the number of active channels at the plasma membrane (N), presumably through enhanced Nedd4-2-dependent ENaC endocytosis. The AMPK-ENaC interaction appears to be indirect; AMPK did not bind ENaC in cells, as assessed by in vivo pull-down assays, nor did it phosphorylate ENaC in vitro. In summary, these results suggest a novel mechanism for coupling ENaC activity and renal Na(+) handling to cellular metabolic status through AMPK, which may help prevent cellular Na(+) loading under hypoxic or ischemic conditions.


Transforming growth factor beta 1 has differential effects on B cell proliferation and activation antigen expression.
There is accumulating evidence that TGF beta 1 is an important immunoregulatory molecule. Here we report evidence that TGF beta 1 has potent effects on murine B cells. It is profoundly inhibitory to the proliferation of quiescent B cells activated in model systems using both thymus-independent and thymus-dependent stimuli and arrests cells predominantly at the G1 cell-cycle stage. It also blocks the proliferation of B cell blasts, with a similar accumulation at stage G1. In parallel with this antiproliferative effect, TGF beta 1 inhibits induction of the expression of a series of "activation Ag" including transferrin receptor, RL388, and Ly-6, in mitogen-stimulated B cells. It also inhibits the induction of Ly-6 expression by IL-4, a nonmitogenic stimulus. In contrast to these negative influences, TGF beta 1 induces modestly increased expression of MHC class II Ag in quiescent B cells, and more marked increases in both B cell blasts and mitogen-stimulated cells. We speculate that in the appropriate context TGF beta 1 may be a cytokine that promotes productive B cell-Th cell interaction.


[Folic acid relieves rat cardiomyocyte injury induced by homocystein through DNA methylation].
Objective To investigate the effect of homocysteine (Hcy) on the cardiomyocytes cultured in vitro, and to analyze the role of folic acid in DNA methylation to explore the protective effect and mechanism of folic acid during Hcy exposure of H9C2 cardiomyocytes. Methods H9C2 cells were treated with Hcy at different concentrations (0, 0.5, 1, 2) mmol/L for 24 hours. Cell viability was tested by CCK-8 assay. The apoptosis was detected by flow cytometry. H9C2 cells were divided into 2 mmol/L Hcy group, 0.1 mmol/L folic acid combined with 2 mmol/L Hcy group, 0.1 mmol/L folic acid group and DMSO control group. The above corresponding treatment lasted 24 hours. Then we detected the cell viability and apoptosis. The total DNA methylation level was determined by MethylFlash ELISA kit. DNMT1, DNMT3a, DNMT3b mRNA and protein expression were detected by real-time quantitative PCR and Western blot analysis. Results The number of H9C2 cells treated with different concentrations of Hcy for 24 hours decreased with the increase of Hcy concentration. Compared with the control group, the activity and apoptosis of the cells in the 2 mmol/L Hcy treatment group were reduced, and the number of cells in the folic acid combined with Hcy treatment group was significantly higher than that in the Hcy treatment group. Compared with the other groups, the total apoptosis rate of Hcy treatment group increased, methylation level decreased significantly, and the level of DNA methylation increased in the folic acid combined with Hcy treatment group. The level of DNMT1 mRNA significantly increased only in the folic acid treatment group, and the levels of DNMT1, DNMT3a and DNMT3b were not significantly changed. Conclusion Folic acid can relieve the damage of Hcy to myocardial cells by DNA methylation.


Report of a girl with vacterl syndrome and right pulmonary agenesis.
Report of a girl with VACTERL syndrome and right pulmonary agenesis: VACTERL syndrome is a combination of vertebral anomalies (V), anal atresia (A), congenital heart defects (C), tracheo-esophageal fistula (T), esophageal atresia (E), abnormalities of kidneys (renal anomalies, R) and limbs (L). In the present patient right pulmonary agenesis is co-occurring with VACTERL syndrome. We report on this case because the association of right pulmonary agenesis and VACTERL syndrome is rare.


When chemotherapy fails: Emotionally charged experiences faced by family caregivers of patients with advanced cancer.
To explore family caregivers' emotional experiences while caring for patients with advanced cancer and navigating distressing information, awareness of dying, and difficult decisions. Qualitative descriptive study of semi-structured interviews with 92 bereaved caregivers of patients with advanced cancer. Interviews explored caregivers' experiences as patients transitioned out of active cancer treatment and neared the end of life. Included in caregivers' characterization of this transition time were three particularly emotionally charged experiences. The first occurred when caregivers felt jolted into awareness that patients were dying.They were startled to realize that patients would die sooner than expected; some expressed frustration that they had not been adequately warned. In the second, caregivers felt conflicted when involved in decisions that pitted patients' preferences against what caregivers felt patients needed, resulting in ambivalence, guilt, and grief. Thirdly, caregivers who felt they did their best for patients expressed fulfillment and gratitude. Caregivers of patients with advanced cancer face unique, emotionally charged experiences that can lead to distress and affect care at the end of life. Awareness of these situations may help oncology teams to provide sufficient guidance and support, partner with caregivers to clarify patients' needs, and deliver higher quality care.


[Styles of nurses' caring in Intensive Therapy mediated by technology].
The objective was to identify the social representations of the intensive therapy nurses about the care practices in face of the technology. Participant observation and interviews were conducted with twenty one nurses of an intensive therapy center, at a Rio de Janeiro public hospital. Lexical analysis was applied, using the Alceste 2010. The results were organized in two categories, each of them with three lexical classes. The first brought the meaning of the technology in intensive therapy and the organization of the styles of caring; the second showed the client's condition and its impact on nurses' care practices. It was concluded that the technology organizes the nurses' styles of caring, that are built on client assistance in the work context. These lead nurses to assign meaning to their practices driving them to the elaboration of ways of acting in face of the technologies.


Cyclosporine A inhibits herpes simplex virus-induced cell fusion but not virus penetration into cells.
The effects of the immunosuppressive peptide cyclosporine A on virus-induced cell fusion and virus penetration into cell were studied. Cyclosporine totally inhibited polykaryocyte formation by a syncytial strain of HSV-1 (MP). In contrast, a number of other hydrophobic peptides which inhibit the replication of orthomyxo- and paramyxoviruses and which were less effective in inhibiting fusion in model systems had little effect on HSV-induced cell fusion. Virus replication as measured by the yield of infectious virus and by incorporation of [35S]methionine into viral proteins was unaffected by treating cells with cyclosporine. Cyclosporine did not quantitatively inhibit cell surface expression of HSV glycoproteins or plaque formation of syncytial or nonsyncytial virus strains. However, plaques formed by HSV-1 (MP) on cyclosporine-treated monolayers were smaller than those on untreated monolayers and were morphologically similar to plaques produced by the nonsyncytial HSV strain F. Surprisingly, cyclosporine did not inhibit penetration of HSV, a process also thought to involve membrane fusion. Therefore, HSV-1-induced cell fusion and penetration of virus into cells either proceed by mutually exclusive mechanisms or are differentially sensitive to cyclosporine.


Sex and Sleep Disruption as Contributing Factors in Alzheimer's Disease.
Alzheimer's disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD.


Gynecomastia attributable to human chorionic gonadotropin-secreting giant cell carcinoma of lung.
To describe a patient with human chorionic gonadotropin (hCG)-secreting giant cell carcinoma of the lung manifesting as painful gynecomastia, which resolved after surgical treatment. We present the clinical, radiologic, and clinical course of our patient, who presented with painful gynecomastia. A 51-year-old man presented with a lung mass and rapidly progressing bilateral painful gynecomastia. Hormonal evaluation revealed high levels of hCG beta subunit, estradiol, and total and free testosterone and suppressed levels of luteinizing hormone and follicle-stimulating hormone. The patient underwent resection of the right upper and middle lobes of the lung. After the surgical procedure, the levels of hCG and estradiol rapidly decreased, and the gynecomastia resolved completely within 3 months. Fluctuation in the levels of serum hCG paralleled the clinical course of the lung tumor. Although gynecomastia is a common disorder, hormonal work-up including hCG beta subunit should be done in an adult male patient presenting with rapidly progressing or recent onset of painful gynecomastia. Lung cancer should be considered in the differential diagnosis of gynecomastia attributable to ectopic production of hCG beta subunit.


National Trends and In-Hospital Outcomes of Patients With Solid Organ Transplant Undergoing Spinal Fusion.
A retrospective analysis of population-based national hospital discharge data collected for the Nationwide Inpatient Sample. To examine the demographics and in-hospital outcomes of patients with solid organ transplant (SOT) undergoing spinal fusion on a national level. Solid organ transplantation has become more common in recent years and some of these patients undergo spinal fusion surgery. There is, however, little information regarding the trends and outcomes in such patients. Clinical data were derived from the US Nationwide Inpatient Sample between 2000 and 2009. Patients with or without SOT who underwent spinal fusion were identified. Data regarding, patient- and healthcare system-related characteristics, comorbidities, in-hospital complications, and mortality were retrieved and analyzed. In-hospital outcomes were compared between patients with or without SOT and analyzed with the use of multivariate logistic regression. A total of 5984 patients with SOT underwent spinal fusion in the United States during the last decade. From 2000 to 2009, population growth-adjusted incidence of patients with SOT who underwent spinal fusion has increased more than two fold (0.102 in 2000 to 0.236 in 2009, per 100,000, P < 0.001). Comparison between patients with or without SOT showed that patients with SOT had significantly higher overall in-hospital complication rate (22.4% vs. 9.5%) and in-hospital mortality rate (1.3% vs. 0.3%). Graft versus host disease occurred in 0.7% of patients with SOT undergoing spinal fusion. Patients with SOT had a significant higher risk of urinary and renal complications and overall in-hospital complications. During the last decade, the incidence of patients with SOT undergoing spinal fusion has increased in the United States. In-hospital outcomes of patients with SOT undergoing spinal fusion were inferior to those of patients without SOT. 3.


The relationship of epicardial adipose tissue thickness to clinical and biochemical features in women with polycystic ovary syndrome.
The amount of epicardial adipose tissue (EAT), a component of body visceral adiposity, has been linked to the presence and severity of cardiovascular disease through multiple mechanisms. Polycystic ovary syndrome (PCOS) is characterized by insulin resistance and subclinical inflammation, which participate in the mechanism of atherosclerosis. We searched if the patients with PCOS have increased EAT thickness (EATT), along with its relation to the measures of adiposity and insulin sensitivity. A total of 41 subjects with PCOS and 46 age and body mass index (BMI) matched healthy controls were enrolled. EAT was measured by echocardiography above the free wall of the right ventricle. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) formula, and plasma adiponectin level was measured by ELISA. Compared to healthy controls EATT and HOMA-IR score were significantly higher (p=0.0001 for both) while plasma adiponectin concentration was significantly lower (p=0.048) in women with PCOS. EATT correlated positively with total cholesterol, triglyceride, luteinizing hormone (LH) and negatively with sex hormon binding globuline (p<0.05 for all), whereas it displayed no correlation to plasma adiponectin level (p=0.924). Triglyceride level was the significant determinant of EATT in logistic regression analysis (p=0.035). Thickness of the EAT is increased in patients with PCOS in conjunction with hyperandrogenity. Prospective studies are required to identify the relation of EAT and cardiovascular risk in patients with PCOS.


Anesthesiologist: The silent force behind the scene.
The Anesthesiologist provides continuous medical care before, during, and after operation to permit the surgeons to perform surgeries; sometimes quite challenging that could otherwise cause substantial threats to the patient's survival. Anesthesiologists, because of their combination of skills are uniquely qualified to care for dying patients suffering from end diseases like cancer. These skills include knowledge of analgesic and sedative pharmacology for the management of pain, awareness of perceptual alterations along with well-known skills in drug titration and experience with critically ill and highly anxious, often agitated patients under stressful circumstances. Anesthesiologists are physicians who provide medical care to patients in a wide variety of situations. This includes preoperative evaluation, consultation with the surgical team, creation of a plan for the anesthesia (which is different in each patient), airway management, intraoperative life support, pain control, intraoperative stabilization of all the vitals, postoperative pain management. Outside the operating room, Anesthesiologist's spectrum of action includes with general emergencies, trauma, intensive care units, acute and chronic pain management. In spite of providing these highly skilled services, Anesthesiologists are facing a lot of stress these days which predisposes them to burnout, fatigue, substance abuse, and suicide. The practice of anesthesia in Indian scenario is different as compared to the western countries. In India, the Anesthesiologists are dependent on surgeons for their work. The degree of stress faced is due to a number of factors like the type and quality of work, his/her relationship with surgeons and the support he/she receives from colleagues and family.


Enzyme-catalysed peptide amidation. Isolation of a stable intermediate formed by reaction of the amidating enzyme with an imino acid.
A series of hydrazones and semicarbazones of glyoxylic acid were shown to have a potent inhibitory effect on the enzyme-catalysed conversion of D-Tyr-Val-Gly to D-Tyr-Val-NH2. Among the derivatives tested, the inhibitory activity was increased by the presence of hydrophobic substituents and decreased by polar substituents. The inhibition produced by glyoxylic acid phenylhydrazone was shown to be competitive. No inhibition was obtained with pyruvic acid phenylhydrazone, which possesses a methyl group in place of the alpha-H of glyoxylic acid phenylhydrazone. The inhibitory potencies of these non-peptide substances are in accord with the specificity exhibited by the amidating enzyme in its reaction with peptide substrates. The inhibition produced by the glyoxylic acid derivatives was shown to be due to their ability to act as substrates for the peptide-amidating enzyme. The product formed from [14C]glyoxylic acid phenylhydrazone was identified as oxalic acid phenylhydrazide by co-chromatography in three chromatographic systems. The results demonstrate that the enzyme-catalysed oxidation of glyoxylic acid phenylhydrazone takes place by a mechanism involving hydroxylation. It is implicit that peptide amidation catalysed by the same enzyme proceeds by a similar mechanism.


Restoration of cell-mediated immunity to animals blocked by a humoral response.
The T cells which mediate delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) are blocked by a normal humoral response and cannot be made to function by further immunization. They can be rescued to some extent by treatment with immunopotentiating agents such as cyclophosphamide (CY) which suppresses the antibody response selectively, or by BCG which interferes with the action of serum blocking factors. These two agents together can restore cell-mediated immunity completely, but a further antigenic stimulus is needed to reestablish DTH in mice blocked by a long period of continuous exposure to SRBC.


Narrow-band loss - a novel loss function focused on target boundary.
Loss functions widely employed in medical image segmentation, e.g., Dice or Generalized Dice, treat each pixel of segmentation target(s) equally. These region-based loss functions are concerned with the overall segmentation accuracy. However, in clinical applications, the focus of attention is often the boundary area of the target organ(s). Existing region-based loss functions lack attention to boundary areas. We designed narrow-band loss, which computes the integration of the predicted probability within the narrow-band around the target boundary. From the aspect of how it's derived, Narrow-band loss belongs to the region-based loss function. The difference from normal region-based loss is that Narrow-band loss calculates based on the degree of coincidence of the region surrounding the organ boundary. The advantage is that narrow-band loss can guide networks to focus on the target's boundary and neighborhood. We also generalize narrow-band loss to multi-target segmentation. We tested narrow-band loss on two datasets of different parts of the human body: the brain dataset with 416 cases, each case with 35 labels, and the abdominal dataset with 50 cases, each case with 12 labels. Narrow-band loss has improved greatly in hd95 metric and dice metric compared with baseline, which is dice loss only.


Bisexual people's utilization of sexual health services at an LGBTQ Community Center in Chicago.
Bisexual people are at increased risk for sexually transmitted infections (STIs), including HIV. In STI data collection, bisexual people are often miscategorized as or conflated with heterosexual or gay/lesbian people. Such poor data capture practices invisibilize bisexual people and prevent the tailoring of HIV and STI services to cater to bisexual populations. The Center on Halsted (COH) is an LGBTQ community center in Chicago. COH's HIV & STD Services Department provides HIV testing to people who present for HIV screening services age 12 and older. COH also administers the State of Illinois AIDS, HIV, & STD Hotline. This manuscript reports HIV-related service access patterns of COH clients by sexual identity, with an emphasis on reporting patterns among bisexual and other non-monosexual (e.g., "bi+") populations in comparison with other sexual minority populations. Among COH's HIV testing clients who were sexual minorities in fiscal years 2018 and 2019, 15.42% in 2018 and 16.71% in 2019 identified as bisexual, respectively. Among sexual minority hotline callers, approximately one quarter (25.1% in 2018 and 28.8% in 2019) identified as bisexual. Given that bisexual individuals comprise over half of sexual minority populations, these findings indicate that bi+ individuals may be underrepresented in accessing HIV and STI services at COH. These results provide previously unknown insight into the sexual identities of populations accessing HIV- and STD-related services within a LGBTQ community setting. Funders of HIV and STI surveillance services should change reporting requirements to make visible the HIV services access patterns and outcomes of bisexual populations.


Biophysical Interaction Landscape of Mycobacterial Mycolic Acids and Phenolic Glycolipids with Host Macrophage Membranes.
Lipidic adjuvant formulations consisting of immunomodulatory mycobacterial cell wall lipids interact with host cells following administration. The impact of this cross-talk on the host membrane's structure and function is rarely given enough consideration but is imperative to rule out nonspecific perturbation underlying the adjuvant. In this work, we investigated changes in the plasma membranes of live mammalian cells after exposure to mycobacterial mycolic acid (MA) and phenolic glycolipids, two strong candidates for lipidic adjuvant therapy. We found that phenolic glycolipid 1 softened the plasma membrane, lowering membrane tension and stiffness, but MA did not significantly change the membrane characteristics. Further, phenolic glycolipid 1 had a fluidizing impact on the host plasma membrane, increasing the fluidity and the abundance of fluid-ordered-disordered coexisting lipid domains. Notably, lipid diffusion was not impacted. Overall, MA and, to a lesser extent, phenolic glycolipid 1, due to minor disruption of host cell membranes, may serve as appropriate lipids in adjuvant formulations.


Efficacy of robotic-assisted prostatectomy in localized prostate cancer: a systematic review of clinical trials.
Background. Radical prostatectomy is an effective treatment for clinically localized prostate cancer. The three approaches in current use have been extensively compared in observational studies, which have methodological limitations. Objective. To compare the efficacy and safety of three radical prostatectomy approaches in patients with localized prostate cancer: open, laparoscopic, and robotic-assisted laparoscopic surgery. Materials and Methods. A systematic review of the literature was carried out. Databases MEDLINE, EMBASE, LILACS, and CENTRAL were searched for randomized clinical trials that directly compared two or more radical prostatectomy approaches. Selection criteria, methodological rigor, and risk of bias were evaluated by two independent researchers using Cochrane Collaboration's tools. Results. Three trials were included. In one study, laparoscopic surgery was associated with fewer blood loss and transfusion rates than the open procedure, in spite of longer operating time. The other two trials compared laparoscopic and robotic-assisted surgery in which no differences in perioperative outcomes were detected. Nevertheless, robotic-assisted prostatectomy showed more favorable erectile function and urinary continence recovery. Conclusion. At the present time, no clear advantage can be attributed to any of the existing prostatectomy approaches in terms of oncologic outcomes. However, some differences in patient-related outcomes favor the newer methods. Larger trials are required.


Generation of quasi-monoenergetic electron beams with small normalized divergences angle from a 2 TW laser facility.
We report the generation of a 6 pC, 23 MeV electron bunch with the energy spread ± 3.5% by using 2 TW, 80 fs high contrast laser pulses interacting with helium gas targets. Within the optimized experimental condition, we obtained quasi-monoenergetic electron beam with an ultra-small normalized divergence angle of 92 mrad, which is at least 5 times smaller than the previous LPA-produced bunches. We suggest the significant decrease of the normalized divergence angles is due to smooth transfer from SM-LWFA to LWFA. Since the beam size in LPA is typically small, this observation may explore a simple way to generate ultralow normalized emittance electron bunches by using small-power but high-repetition-rate laser facilities.


Quantum systems under frequency modulation.
We review the physical phenomena that arise when quantum mechanical energy levels are modulated in time. The dynamics resulting from changes in the transition frequency is a problem studied since the early days of quantum mechanics. It has been of constant interest both experimentally and theoretically since, with the simple two-state model providing an inexhaustible source of novel concepts. When the transition frequency of a quantum system is modulated, several phenomena can be observed, such as Landau-Zener-Stückelberg-Majorana interference, motional averaging and narrowing, and the formation of dressed states with the appearance of sidebands in the spectrum. Adiabatic changes result in the accumulation of geometric phases, which can be used to create topological states. In recent years, an exquisite experimental control in the time domain was gained through the parameters entering the Hamiltonian, and high-fidelity readout schemes allowed the state of the system to be monitored non-destructively. These developments were made in the field of quantum devices, especially in superconducting qubits, as a well as in atomic physics, in particular in ultracold gases. As a result of these advances, it became possible to demonstrate many of the fundamental effects that arise in a quantum system when its transition frequencies are modulated. The purpose of this review is to present some of these developments, from two-state atoms and harmonic oscillators to multilevel and many-particle systems.


Computational design of experimentally validated multi-epitopes vaccine against hepatitis E virus: An immunological approach.
Hepatitis E virus (HEV) is one of the leading acute liver infections triggered by viral hepatitis. Patients infected with HEV usually recover and the annual death rate is negligible. Currently, there is no HEV licensed vaccine available globally. This study was carried out to design a multi-epitope HEV peptide-based vaccine by retrieving already experimentally validated epitopes from ViPR database leading to epitope prioritization. Epitopes selected as potential vaccine candidates were non-allergen, immunogenic, soluble, non-toxic and IFN gamma positive. The epitopes were linked together by AAY linkers and the linker EAAAK was used to join adjuvant with epitopes. Toll-like receptor (TLR)-4 agonist was used as an adjuvant to boost efficacy of the vaccine. Furthermore, codon optimization followed by disulfide engineering was performed to analyse the designed vaccine's structural stability. Computational modeling of the immune simulation was done to examine the immune response against the vaccine. The designed vaccine construct was docked with TLR-3 receptor for their interactions and then subjected to molecular dynamic simulations. The vaccine model was examined computationally towards the capability of inducing immune responses which showed the induction of both humoral and cell mediated immunity. Taken together, our study suggests an In-silico designed HEV based multi-epitope peptide-based vaccine (MEPV) that needs to be examined in the wet lab-based data that can help to develop a potential vaccine against HEV.


Fatal injury: characteristics and prevention of deaths at the scene.
Almost half of all trauma deaths occur at the scene. It is important to determine if these deaths can be prevented. Penetrating or blunt force trauma deaths were identified through the Office of the Medical Examiner during a 2-year period. Data were also obtained through review of these records. There were 312 deaths at the scene that received no medical care. Almost 60% were firearm-related. About 80% of the victims were men, and 55% of these deaths occurred in people between 20 and 49 years old. Suicide accounted for nearly half of these deaths. Eighty percent of these injured people had Abbreviated Injury Scale scores of 5 or 6. Almost 60% of deaths at the scene occurred at the same time as injury and reflect severe injury to vital regions of the body. These findings suggest that primary prevention of the initial event causing injury may be more important than definitive prehospital emergency medical care to prevent these deaths.


The role of mitochondria in protection of the heart by preconditioning.
A prolonged period of ischaemia followed by reperfusion irreversibly damages the heart. Such reperfusion injury (RI) involves opening of the mitochondrial permeability transition pore (MPTP) under the conditions of calcium overload and oxidative stress that accompany reperfusion. Protection from MPTP opening and hence RI can be mediated by ischaemic preconditioning (IP) where the prolonged ischaemic period is preceded by one or more brief (2-5 min) cycles of ischaemia and reperfusion. Following a brief overview of the molecular characterisation and regulation of the MPTP, the proposed mechanisms by which IP reduces pore opening are reviewed including the potential roles for reactive oxygen species (ROS), protein kinase cascades, and mitochondrial potassium channels. It is proposed that IP-mediated inhibition of MPTP opening at reperfusion does not involve direct phosphorylation of mitochondrial proteins, but rather reflects diminished oxidative stress during prolonged ischaemia and reperfusion. This causes less oxidation of critical thiol groups on the MPTP that are known to sensitise pore opening to calcium. The mechanisms by which ROS levels are decreased in the IP hearts during prolonged ischaemia and reperfusion are not known, but appear to require activation of protein kinase Cepsilon, either by receptor-mediated events or through transient increases in ROS during the IP protocol. Other signalling pathways may show cross-talk with this primary mechanism, but we suggest that a role for mitochondrial potassium channels is unlikely. The evidence for their activity in isolated mitochondria and cardiac myocytes is reviewed and the lack of specificity of the pharmacological agents used to implicate them in IP is noted. Some K(+) channel openers uncouple mitochondria and others inhibit respiratory chain complexes, and their ability to produce ROS and precondition hearts is mimicked by bona fide uncouplers and respiratory chain inhibitors. IP may also provide continuing protection during reperfusion by preventing a cascade of MPTP-induced ROS production followed by further MPTP opening. This phase of protection may involve survival kinase pathways such as Akt and glycogen synthase kinase 3 (GSK3) either increasing ROS removal or reducing mitochondrial ROS production.


Arthritis in sarcoidosis.
Sarcoidosis is systemic granulomatous disorder. Articular manifestations have received little attention in the literature. Case records of patients with sarcoidosis, presenting with articular symptoms between 1990-1999, were retrospectively analysed. Twenty nine patients, 15 males and 14 females, median age 44 years (range 15-67 years) and median duration of articular symptoms of eight months diagnosed clinically (n=9) and on biopsy (n=20) were studied. Twenty five patients had arthritis as the presenting manifestation. Fifteen patients had chronic arthritis (> six months). Lofgren's syndrome was seen in 7% of the patients. Acute arthritis was episodic (n=4), more common in males (M:F = 9:5), predominantly affected lower limb joints and mimicked reactive arthritis. Chronic arthritis was more frequently observed in females (M:F = 1:2) and presented with involvement of bilateral symmetric hand joints, mimicking rheumatoid arthritis. Extra-articular manifestations like neuropathy and constitutional symptoms were observed in acute arthritis. Skin plaque, splenomegaly and interstitial lung disease were seen with chronic arthritis. At a median follow up of 12 months, 10/14 and 5/15 achieved complete remission whereas 2/14 and 9/15 achieved partial remission of the articular symptoms in the acute and chronic groups, respectively. Arthritis in sarcoidosis is an early manifestation of disease and may mimic reactive or rheumatoid arthritis. Unsatisfactory response in chronic arthritis highlights the need for immunosuppressive drugs in addition to steroids.