Early intracellular signaling events induced by in vitro metreleptin administration in cardiac myocytes and uterine smooth muscle cells.
Intracellular signaling pathways regulated by leptin have largely been studied in metabolically important organs such as adipose tissue and peripheral blood mononuclear cells, suggesting that leptin plays a key role in pathophysiology of insulin resistance. However, whether synthetic analog of leptin, metreleptin, has similar effects on cardiac myocytes (CM) and uterine smooth muscle cells (USMC) has not yet been studied. Hence, in order to address these questions, we extended previous observations and investigated in vitro signaling study whether metreleptin may activate key signaling pathways. We observed that metreleptin activates Jak2 and STAT3 signaling pathways in dose- and time-dependent manner in CM and USMC. Also, we found that metreleptin increases ERK1/2, JNK and/or p38 phosphorylation in CM. In vitro metreleptin administration also increased ERK1/2 and/or p38 phosphorylation in USMC. By contrast, JNK was not regulated by in vitro metreleptin administration in USMC. Moreover, metreleptin-activated all signaling pathways were blocked by pre-treatment of PD98095 (ERK inhibitor), SB203580 (p38 inhibitor) and/or SP600125 (JNK inhibitor), respectively. Finally, metreleptin increased cell size (hypertrophy) in both CM and USMC. Our data provide novel insights into the role of Jak2, STAT3, ERK1/2, JNK and/or p38 as probable mediators of the action of leptin in regulating hypertrophy in CM and USMC.


Chemotherapy of Plasmodium vivax in Saimiri and Aotus models.
Three standard antimalarial compounds were tested against trophozoite or sporozoite induced infections of the Panamanian Achiote strain of Plasmodium vivax in two species of monkeys. In Saimiri sciureus (24 subjects) and Aotus trivirgatus (11 subjects), parasite clearance from the peripheral blood averaged 3 days after initiating chloroquine therapy (total dose of 25 mg base/kg body weight over 3 days or single dose of 10 mg base/kg. Trophozoite induced infections were cured in all of 10 Saimiri and all of 6 Aotus, as indicated by the absence of relapses. Relapses did occur in 3 of 11 tests with Saimiri and 3 of 5 tests with Aotus against sporozoite induced infections. Subpatent periods ranged from 38 to 111 days among intact and splenectomized hosts. This is the first chemotherapeutic evidence for the persistence of exoerythrocytic stages of P. vivax in New World monkeys. Pyrimethaminr (single dose of 1 mg/kg) cured trophozoite induced infections in all of five Saimiri hosts. Radical cure of sporozoite induced infections was accomplished in each of six trials with chloroquine (25 mg base/kg) plus primaquine (1 mg base/kg for 14 days). The primary attack or relapse was treated. These models warrant further investigation in chemotherapy.


Adding silver to the rainbow: the development of the nurses' health education about LGBT elders (HEALE) cultural competency curriculum.
In 2009, the Howard Brown Health Center received funding from the US Department of Health and Human Services, and Health Resources and Services Administration to develop and disseminate a peer-reviewed, six-module curriculum entitled, Health Education about LGBT (lesbian, gay, bisexual and transgender) Elders (HEALE). The HEALE curriculum targets nurses and health-care staff and is focused on the treatment of LGBT elders, a population that is largely misunderstood and discriminated against in health-care settings. The HEALE curriculum was presented in hospital academic centres, community-based clinics and nursing homes over a three-year period, and training staff provided education to over 500 nurses and health-care providers. A pre-test and post-test was administered to participants, and all data were collected and archived to measure knowledge gained. Participants also completed an evaluation at the conclusion of the training to report change in personal attitude and individual response to the curriculum. From March 2011 to June 2012, 848 individuals attended HEALE curriculum sessions at 23 locations in Chicago and surrounding areas. Participants were 40% white, 25% black, 9% Hispanic/Latino and 25% Asian race/ethnicity. The majority of participants were female and approximately 25% were under the age of 30 years. There were statistically significant gains in knowledge in each of the six modules both in nursing home/home health-care settings and in hospital/educational settings, although participants in nursing home/home health care settings had lower pre-test scores and smaller knowledge gains in each of the six modules than those in hospital/educational settings. Mean increases ranged from 6.4 points (an 8.7% increase) in module 1-14.6 points (a 26.2% increase) in Module 6 (P < 0.01). The HEALE curriculum sets a standard for best practices in nursing management and for LGBT cultural competency in geriatric education. As such, implementation of this cultural competency training will go a long way to establish fundamental concepts regarding LGBT elder care and provide long-term strategies for providing culturally sensitive patient care.


Optimization and characterization of a high repetition rate, high intensity Nd:YLF regenerative amplifier.
Solid state regenerative amplifiers have proved to be a reliable source for producing stable millijoule pulses as short as a few picoseconds at repetition rates ranging from a few hertz to several kilohertz. Here we report on the operation of a cw pumped Nd:YLF regenerative amplifier that uses a convex-concave design to optimize output energy and stability while minimizing the energy density on critical intracavity optical components. The amplifier yields stable 5-mJ 40-ps pulses at 700 Hz and has achieved 1-mJ output at a 3.5-kHz repetition rate. Results and analysis of the beam profile and contrast ratio for this system are also presented. Our results are contrasted to the general design considerations of regenerative amplifiers.


An asbestos-exposed family with multiple cases of pleural malignant mesothelioma without inheritance of a predisposing BAP1 mutation.
We report a family with domestic exposure to asbestos and diagnosis of multiple cancers, including eight pleural malignant mesotheliomas and several other lung or pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A, and BARD1, also revealed no mutation. DNA microarray analysis of tissue from two mesotheliomas revealed multiple genomic imbalances, including consistent losses of overlapping segments in 2q, 6q, 9p, 14q, 15q, and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, we discuss the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family. Because the incidence of mesothelioma in this family is higher than that expected even in workers heavily exposed to asbestos, we conclude that both asbestos exposure and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural or lung cancers seen in this family.


E-cadherin interactome complexity and robustness resolved by quantitative proteomics.
E-cadherin-mediated cell-cell adhesion and signaling plays an essential role in development and maintenance of healthy epithelial tissues. Adhesiveness mediated by E-cadherin is conferred by its extracellular cadherin domains and is regulated by an assembly of intracellular adaptors and enzymes associated with its cytoplasmic tail. We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin. In addition, we used proteomics to identify proteins associated with E-cadherin-containing adhesion plaques from a cell-glass interface, which enabled the assignment of cellular localization to putative E-cadherin-interacting proteins. Moreover, by tagging identified proteins with GFP (green fluorescent protein), we determined the subcellular localization of 83 putative E-cadherin-proximal proteins and identified 24 proteins that were previously uncharacterized as part of adherens junctions. We constructed and characterized a comprehensive E-cadherin interaction network of 79 published and 394 previously uncharacterized proteins using a structure-informed database of protein-protein interactions. Finally, we found that calcium chelation, which disrupts the interaction of the extracellular E-cadherin domains, did not disrupt most intracellular protein interactions with E-cadherin, suggesting that the E-cadherin intracellular interactome is predominantly independent of cell-cell adhesion.


Phenotypic screens as a renewed approach for drug discovery.
The significant reduction in the number of newly approved drugs in the past decade has been partially attributed to failures in discovery and validation of new targets. Evaluation of recently approved new drugs has revealed that the number of approved drugs discovered through phenotypic screens, an original drug screening paradigm, has exceeded those discovered through the molecular target-based approach. Phenotypic screening is thus gaining new momentum in drug discovery with the hope that this approach may revitalize drug discovery and improve the success rate of drug approval through the discovery of viable lead compounds and identification of novel drug targets.


Personalization of Energy Expenditure Estimation in Free Living Using Topic Models.
We introduce an approach to personalize energy expenditure (EE) estimates in free living. First, we use topic models to discover activity composites from recognized activity primitives and stay regions in daily living data. Subsequently, we determine activity composites that are relevant to contextualize heart rate (HR). Activity composites were ranked and analyzed to optimize the correlation to HR normalization parameters. Finally, individual-specific HR normalization parameters were used to normalize HR. Normalized HR was then included in activity-specific regression models to estimate EE. Our HR normalization minimizes the effect of individual fitness differences from entering in EE regression models. By estimating HR normalization parameters in free living, our approach avoids dedicated individual calibration or laboratory tests. In a combined free-living and laboratory study dataset, including 34 healthy volunteers, we show that HR normalization in 14-day free-living data improves accuracy compared to no normalization and normalization based on activity primitives only ( 29.4% and 19.8 % error reduction against lab reference). Based on acceleration and HR, both recorded from a necklace, and GPS acquired from a smartphone, EE estimation error was reduced by 10.7 % in a leave-one-participant-out analysis.


Adults Hospitalized With Coronavirus Disease 2019 (COVID-19)-United States, March-June and October-December 2020: Implications for the Potential Effects of COVID-19 Tier-1 Vaccination on Future Hospitalizations and Outcomes.
Because of the increased risk for severe coronavirus disease 2019 (COVID-19), the Advisory Committee on Immunization Practices (ACIP) initially prioritized COVID-19 vaccination for persons in long-term care facilities (LTCF), persons aged ≥65 years, and persons aged 16-64 years with high-risk medical conditions when there is limited vaccine supply. We compared characteristics and severe outcomes of hospitalized patients with COVID-19 in the United States between early and later in the pandemic categorized by groups at higher risk of severe COVID-19. Observational study of sampled patients aged ≥18 years who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and admitted to one of 14 academic hospitals in the United States during March-June and October-December 2020. Demographic and clinical information were gathered from electronic health record data. Among 647 patients, 91% met ≥1 of the following risk factors for severe COVID-19 [91% March-June (n = 434); 90% October-December (n = 213)]; 19% were LTCF residents, 45% were aged ≥65-years, and 84% had ≥1 high-risk condition. The proportion of patients who resided in a LTCF declined significantly (25% vs 6%) from early to later pandemic periods. Compared with patients at lower risk for severe COVID-19, in-hospital mortality was higher among patients at high risk for severe COVID-19 (20% vs 7%); these differences were consistently observed between March-June and October-December. Most adults hospitalized with COVID-19 were those recommended to be prioritized for vaccination based on risk for developing severe COVID-19. These findings highlight the continued urgency to vaccinate patients at high risk for severe COVID-19 and monitor vaccination impact on hospitalizations and outcomes.


Dopaminergic reward system: a short integrative review.
Memory is an essential element to adaptive behavior since it allows consolidation of past experience guiding the subject to consider them in future experiences. Among the endogenous molecules that participate in the consolidation of memory, including the drug-seeking reward, considered as a form of learning, is dopamine. This neurotransmitter modulates the activity of specific brain nucleus such as nuclei accumbens, putamen, ventral tegmental area (VTA), among others and synchronizes the activity of these nuclei to establish the neurobiological mechanism to set the hedonic element of learning. We review the experimental evidence that highlights the activity of different brain nuclei modulating the mechanisms whereby dopamine biases memory towards events that are of motivational significance.


Molecular body imaging: MR imaging, CT, and US. part I. principles.
Molecular imaging, generally defined as noninvasive imaging of cellular and subcellular events, has gained tremendous depth and breadth as a research and clinical discipline in recent years. The coalescence of major advances in engineering, molecular biology, chemistry, immunology, and genetics has fueled multi- and interdisciplinary innovations with the goal of driving clinical noninvasive imaging strategies that will ultimately allow disease identification, risk stratification, and monitoring of therapy effects with unparalleled sensitivity and specificity. Techniques that allow imaging of molecular and cellular events facilitate and go hand in hand with the development of molecular therapies, offering promise for successfully combining imaging with therapy. While traditionally nuclear medicine imaging techniques, in particular positron emission tomography (PET), PET combined with computed tomography (CT), and single photon emission computed tomography, have been the molecular imaging methods most familiar to clinicians, great advances have recently been made in developing imaging techniques that utilize magnetic resonance (MR), optical, CT, and ultrasonographic (US) imaging. In the first part of this review series, we present an overview of the principles of MR imaging-, CT-, and US-based molecular imaging strategies.


Genomic analyses of pneumococci reveal a wide diversity of bacteriocins - including pneumocyclicin, a novel circular bacteriocin.
One of the most important global pathogens infecting all age groups is Streptococcus pneumoniae (the 'pneumococcus'). Pneumococci reside in the paediatric nasopharynx, where they compete for space and resources, and one competition strategy is to produce a bacteriocin (antimicrobial peptide or protein) to attack other bacteria and an immunity protein to protect against self-destruction. We analysed a collection of 336 diverse pneumococcal genomes dating from 1916 onwards, identified bacteriocin cassettes, detailed their genetic composition and sequence diversity, and evaluated the data in the context of the pneumococcal population structure. We found that all genomes maintained a blp bacteriocin cassette and we identified several novel blp cassettes and genes. The composition of the 'bacteriocin/immunity region' of the blp cassette was highly variable: one cassette possessed six bacteriocin genes and eight putative immunity genes, whereas another cassette had only one of each. Both widely-distributed and highly clonal blp cassettes were identified. Most surprisingly, one-third of pneumococcal genomes also possessed a cassette encoding a novel circular bacteriocin that we called pneumocyclicin, which shared a similar genetic organisation to well-characterised circular bacteriocin cassettes in other bacterial species. Pneumocyclicin cassettes were mainly of one genetic cluster and largely found among seven major pneumococcal clonal complexes. These detailed genomic analyses revealed a novel pneumocyclicin cassette and a wide variety of blp bacteriocin cassettes, suggesting that competition in the nasopharynx is a complex biological phenomenon.


Neonatal erythropoietin mitigates impaired gait, social interaction and diffusion tensor imaging abnormalities in a rat model of prenatal brain injury.
Children who are born preterm are at risk for encephalopathy of prematurity, a leading cause of cerebral palsy, cognitive delay and behavioral disorders. Current interventions are limited and none have been shown to reverse cognitive and behavioral impairments, a primary determinant of poor quality of life for these children. Moreover, the mechanisms of perinatal brain injury that result in functional deficits and imaging abnormalities in the mature brain are poorly defined, limiting the potential to target interventions to those who may benefit most. To determine whether impairments are reversible after a prenatal insult, we investigated a spectrum of functional deficits and diffusion tensor imaging (DTI) abnormalities in young adult animals. We hypothesized that prenatal transient systemic hypoxia-ischemia (TSHI) would induce multiple functional deficits concomitant with reduced microstructural white and gray matter integrity, and tested whether these abnormalities could be ameliorated using postnatal erythropoietin (EPO), an emerging neurorestorative intervention. On embryonic day 18 uterine arteries were transiently occluded for 60min via laparotomy. Shams underwent anesthesia and laparotomy for 60min. Pups were born and TSHI pups were randomized to receive EPO or vehicle via intraperitoneal injection on postnatal days 1 to 5. Gait, social interaction, olfaction and open field testing was performed from postnatal day 25-35 before brains underwent ex vivo DTI to measure fractional anisotropy, axial diffusivity and radial diffusivity. Prenatal TSHI injury causes hyperactivity, impaired gait and poor social interaction in young adult rats that mimic the spectrum of deficits observed in children born preterm. Collectively, these data show for the first time in a model of encephalopathy of prematurity that postnatal EPO treatment mitigates impairments in social interaction, in addition to gait deficits. EPO also normalizes TSHI-induced microstructural abnormalities in fractional anisotropy and radial diffusivity in multiple regions, consistent with improved structural integrity and recovery of myelination. Taken together, these results show behavioral and memory deficits from perinatal brain injury are reversible. Furthermore, resolution of DTI abnormalities may predict responsiveness to emerging interventions, and serve as a biomarker of CNS injury and recovery.


The role of TNFRSF11B in development of osteoarthritic cartilage.
OA is a complex genetic disease with different risk factors contributing to its development. One of the genes, TNFRSF11B, previously identified with gain-of-function mutation in a family with early-onset OA with chondrocalcinosis, is among the highest upregulated genes in lesioned OA cartilage (RAAK-study). Here, we determined the role of TNFRSF11B overexpression in development of OA. Human primary articular chondrocytes (9 donors RAAK study) were transduced using lentiviral particles with or without TNFRSF11B. Cells were cultured for 1 week in a 3 D in-vitro chondrogenic model. TNFRSF11B overexpression was confirmed by RT-qPCR, immunohistochemistry and ELISA. Effects of TNFRSF11B overexpression on cartilage matrix deposition, matrix mineralization, and genes highly correlated to TNFRSF11B in RNA-sequencing dataset (r >0.75) were determined by RT-qPCR. Additionally, glycosaminoglycans and collagen deposition were visualized with Alcian blue staining and immunohistochemistry (COL1 and COL2). Overexpression of TNFRSF11B resulted in strong upregulation of MMP13, COL2A1 and COL1A1. Likewise, mineralization and osteoblast characteristic markers RUNX2, ASPN and OGN showed a consistent increase. Among 30 genes highly correlated to TNFRSF11B, expression of only eight changed significantly, with BMP6 showing the highest increase (9-fold) while expression of RANK and RANKL remained unchanged indicating previously unknown downstream pathways of TNFRSF11B in cartilage. Results of our 3D in vitro chondrogenesis model indicate that upregulation of TNFRSF11B in lesioned OA cartilage may act as a direct driving factor for chondrocyte to osteoblast transition observed in OA pathophysiology. This transition does not appear to act via the OPG/RANK/RANKL triad common in bone remodeling.


Intervention randomized controlled trials involving wrist and shoulder arthroscopy: a systematic review.
Although arthroscopy of upper extremity joints was initially a diagnostic tool, it is increasingly used for therapeutic interventions. Randomized controlled trials (RCTs) are considered the gold standard for assessing treatment efficacy. We aimed to review the literature for intervention RCTs involving wrist and shoulder arthroscopy. We performed a systematic review for RCTs in which at least one arm was an intervention performed through wrist arthroscopy or shoulder arthroscopy. PubMed and Cochrane Library databases were searched up to December 2012. Two researchers reviewed each article and recorded the condition treated, randomization method, number of randomized participants, time of randomization, outcomes measures, blinding, and description of dropouts and withdrawals. We used the modified Jadad scale that considers the randomization method, blinding, and dropouts/withdrawals; score 0 (lowest quality) to 5 (highest quality). The scores for the wrist and shoulder RCTs were compared with the Mann-Whitney test. The first references to both wrist and shoulder arthroscopy appeared in the late 1970s. The search found 4 wrist arthroscopy intervention RCTs (Kienböck's disease, dorsal wrist ganglia, volar wrist ganglia, and distal radius fracture; first 3 compared arthroscopic with open surgery). The median number of participants was 45. The search found 50 shoulder arthroscopy intervention RCTs (rotator cuff tears 22, instability 14, impingement 9, and other conditions 5). Of these, 31 compared different arthroscopic treatments, 12 compared arthroscopic with open treatment, and 7 compared arthroscopic with nonoperative treatment. The median number of participants was 60. The median modified Jadad score for the wrist RCTs was 0.5 (range 0-1) and for the shoulder RCTs 3.0 (range 0-5) (p = 0.012). Despite the increasing use of wrist arthroscopy in the treatment of various wrist disorders the efficacy of arthroscopically performed wrist interventions has been studied in only 4 randomized studies compared to 50 randomized studies of significantly higher quality assessing interventions performed through shoulder arthroscopy.


Catalytic formation of luminescent lanthanide complexes using an entropy-driven DNA circuit.
Two DNA conjugates modified with ethylenediaminetetraacetic acid and 1,10-phenanthroline were prepared as a pair of split probes. They were designed to form a duplex with their auxiliary groups facing each other, providing a microenvironment to accommodate lanthanide ions. The luminescent signal was amplified by catalytic duplex formation based on an entropy-driven DNA circuit.


HIV-1 protease and reverse transcriptase control the architecture of their nucleocapsid partner.
The HIV-1 nucleocapsid is formed during protease (PR)-directed viral maturation, and is transformed into pre-integration complexes following reverse transcription in the cytoplasm of the infected cell. Here, we report a detailed transmission electron microscopy analysis of the impact of HIV-1 PR and reverse transcriptase (RT) on nucleocapsid plasticity, using in vitro reconstitutions. After binding to nucleic acids, NCp15, a proteolytic intermediate of nucleocapsid protein (NC), was processed at its C-terminus by PR, yielding premature NC (NCp9) followed by mature NC (NCp7), through the consecutive removal of p6 and p1. This allowed NC co-aggregation with its single-stranded nucleic-acid substrate. Examination of these co-aggregates for the ability of RT to catalyse reverse transcription showed an effective synthesis of double-stranded DNA that, remarkably, escaped from the aggregates more efficiently with NCp7 than with NCp9. These data offer a compelling explanation for results from previous virological studies that focused on i) Gag processing leading to nucleocapsid condensation, and ii) the disappearance of NCp7 from the HIV-1 pre-integration complexes. We propose that HIV-1 PR and RT, by controlling the nucleocapsid architecture during the steps of condensation and dismantling, engage in a successive nucleoprotein-remodelling process that spatiotemporally coordinates the pre-integration steps of HIV-1. Finally we suggest that nucleoprotein remodelling mechanisms are common features developed by mobile genetic elements to ensure successful replication.


Modeling of heterodyne efficiency for coherent laser radar in the presence of aberrations.
Heterodyne efficiency of a coherent lidar system reflects the matching of phase and amplitude between a local oscillator (LO) beam and received signal beam and is, therefore, an indicator of system performance. One aspect of a lidar system that affects heterodyne efficiency is aberrations present in optical components. A method for including aberrations in the determination of heterodyne efficiency is presented. The effect of aberrations on heterodyne efficiency is demonstrated by including Seidel aberrations in the mixing of two perfectly matched gaussian beams. Results for this case are presented as animations that illustrate the behavior of the mixing as a function of time. Extension of this method to propagation through lidar optical systems is discussed.


[Neurobiology of consciousness].
Disorders of consciousness have captivated neurologists, neuroscientists, and philosophers for decades, but few consistent studies have been conducted on these conditions due to their difficult experimental approach. In recent years, an increasing number of cognitive neuroscience research groups have examined the physiology of consciousness from an experimental perspective, despite the methodological and epistemological complexities of the field. While describing consciousness can be challenging, a close definition must acknowledge a combination of wakefulness and awareness. Form a neurobiological standpoint, it has been argued that the ascending reticular system and its thalamic projections are critical in modulating awareness and wakefulness sleep cycles. Awareness may be a function of the neural networks within the cortex, the thalamus, and the cortico-cortical system. Different models have been employed to tackle this difficult problem, including non-invasive in vivo studies, examination of conscious patients with brain lesions, and studies on both animals and patients with disorders of consciousness. This article reviews the scientific evidence for the neural basis of conscious and unconscious processes in different states of consciousness, focusing on patients in the vegetative and minimally conscious state.


Double-blind, randomized trial of a calf lung surfactant extract administered at birth to very premature infants for prevention of respiratory distress syndrome.
Organic solvent extraction of surfactant obtained by lavage of calf lungs yields a highly surface-active material. A double blind, randomized clinical trial to determine the effect of this material on respiratory distress syndrome in premature infants was initiated in the Neonatal Intensive Care Unit at the University of Rochester in December 1983. Infants 25 to 29 weeks gestational age were eligible for entry into the trial. At the time of this interim analysis 32 patients had been randomly selected and entered into the trial, 16 surfactant-treated patients and 16 in a control group who received only saline. At birth, intrapulmonary instillation of the calf lung surfactant extract dispersed in saline or saline alone occurred in the delivery room immediately after intubation and prior to ventilation; infants were then ventilated and treated as usual. At 6, 12, 24, 48, and 72 hours after birth, the severity of respiratory distress was categorized as either minimal, intermediate, or severe based on oxygen and mean airway pressure requirements. Differences observed at six hours after birth were of marginal significance, but at 12 and 24 hours the surfactant-treated group had significantly (P less than .01) less severe respiratory distress compared with the control group. Differences between treated and control infants were not statistically significant at 48 and 72 hours after birth. In four surfactant-treated infants the severity of respiratory distress worsened between 24 and 48 hours after birth, suggesting that one dose of surfactant at birth may not be sufficient for some infants.


Optimising coherence estimation to assess the functional correlation of tremor-related activity between the subthalamic nucleus and the forearm muscles.
Application of coherence estimation needs not only to correctly estimate coherence values but also to efficiently test the statistical significance of the estimates. In the present report, we have explained the approach of optimising a coherence estimator by restricting its normalised bias error and random error. In addition to the commonly used independence threshold, two more tests based on the probability of detection and the exact confidence interval have been proposed for detecting the significance of the coherence estimates. All three methods have been used to evaluate the significant functional correlation between oscillatory field potentials (FPs) in the subthalamic nucleus (STN) and the surface electromyogram (EMG) of the forearm muscles during tremor in Parkinson's disease.


Thyrocyte HLA-DR expression and interferon-gamma production in autoimmune thyroid disease.
We examined the expression of HLA-DR antigen induced by mitogen, mitogen-free supernatants from mitogen-stimulated peripheral blood mononuclear cells (PBMC), or autologous and allogeneic PBMC on thyrocytes cultured for 1-2 weeks (precultured) before the addition of the stimulant. Leucoagglutinin (LAG) and concanavalin A, but not lipopolysaccharide induced HLA-DR expression on thyrocytes from normal subjects (NC) and patients with Graves' disease (GD) and Hashimoto's thyroiditis (HT). The degree of DR expression induced by LAG was significantly less in GD than in NC thyrocytes. This response was dependent on contaminating T cells, especially suppressor-cytotoxic T (Ts/c) cells, NK cells, and HLA-DR+ cells, but not helper-inducer T (Th/i) cells or B cells, in the thyrocyte cultures. OKT3 monoclonal antibody, which activates T cells specifically in the presence of monocytes, also induced thyrocyte HLA-DR expression. Furthermore, interferon-gamma (IFN-gamma) was detected in culture supernatants from LAG-stimulated thyrocytes. Anti-IFN-gamma monoclonal antibody eliminated the ability of LAG to induce HLA-DR. Mitogen-free supernatants from mitogen-stimulated PBMC also induced thyrocyte HLA-DR expression, which was inhibited by anti-IFN-gamma. The supernatants of concanavalin A- or LAG-stimulated PBMC from either untreated or recently treated patients with GD or hypothyroid HT induced less thyrocyte DR expression than NC PBMC. Indeed, the levels of IFN-gamma in supernatants from such patients were lower than those in NC, and the correlation between DR expression and IFN-gamma levels was significant. This IFN-gamma production by PBMC required Th/i cells, NK cells, and HLA-DR+ cells. Before the addition of autologous or allogeneic PBMC, only precultured HT thyrocytes expressed HLA-DR, whereas GD and NC thyrocytes did not. The induction or enhancement of DR expression on autologous thyrocytes by direct coculture with PBMC occurred within 8 days in GD and HT, but not in NC. There was a significant correlation between the serum titer of antithyroid microsomal antibodies and the degree of DR expression. Allogeneic normal PBMC also induced DR expression on NC and GD thyrocytes within 8 days, the effect on the latter being more pronounced than with autologous GD PBMC. Thyrocyte HLA-DR expression induced by autologous GD PBMC and allogeneic normal PBMC required monocytes. Th/i, and NK cells and was blocked by anti-IFN-gamma. However, the enhancement of thyrocyte DR expression by autologous HT PBMC did not require monocytes.(ABSTRACT TRUNCATED AT 400 WORDS)


Self-organized criticality theory of autoimmunity.
The cause of autoimmunity, which is unknown, is investigated from a different angle, i.e., the defect in immune 'system', to explain the cause of autoimmunity. Repeated immunization with antigen causes systemic autoimmunity in mice otherwise not prone to spontaneous autoimmune diseases. Overstimulation of CD4(+) T cells led to the development of autoantibody-inducing CD4(+) T (aiCD4(+) T) cell which had undergone T cell receptor (TCR) revision and was capable of inducing autoantibodies. The aiCD4(+) T cell was induced by de novo TCR revision but not by cross-reaction, and subsequently overstimulated CD8(+) T cells, driving them to become antigen-specific cytotoxic T lymphocytes (CTL). These CTLs could be further matured by antigen cross-presentation, after which they caused autoimmune tissue injury akin to systemic lupus erythematosus (SLE). Systemic autoimmunity appears to be the inevitable consequence of over-stimulating the host's immune 'system' by repeated immunization with antigen, to the levels that surpass system's self-organized criticality.


Thalamic volumes in patients with first-episode schizophrenia.
The thalamus, a highly evolved sensory and motor gateway to the cortex, has been implicated in the pathophysiology of several illnesses, including schizophrenia. Several studies have suggested thalamic volume differences in patients with schizophrenia, although only a few studies have examined thalamic structure in new-onset patients. The authors used magnetic resonance imaging to measure thalamic volumes in previously untreated patients with first-episode schizophrenia (N=16) relative to those of healthy comparison subjects (N=25). The age range of the patients and comparison subjects was 15 to 45 years of age. Thalamic volumes in the right and left hemispheres were segmented and analyzed, both separately and as total thalamic volume, by a rater blind to clinical data. The thalamus was further segmented into regions that roughly reflected individual thalamic nuclei. Analysis of covariance was used to control for intracranial volume. Right, left, and total thalamic volumes of the patients with schizophrenia were significantly smaller than those of the comparison subjects. Significantly smaller volumes were found in the left central medial subdivision of the patients as well as a smaller volume in the right central medial subdivision that approached significance. These regions primarily comprised the dorsomedial nucleus, a thalamic nucleus thought to be an important component of aberrant circuitry in schizophrenia. Significant volume differences were also seen in the left anterior, right anterior, and right posterior medial subdivisions. These findings suggest significant thalamic volumetric differences between patients with newly diagnosed schizophrenia and healthy comparison subjects. Future analysis of individual thalamic nuclei may reveal important, specific relationships between thalamic abnormalities and schizophrenia.


Weighted expectation maximization reconstruction algorithms for thermoacoustic tomography.
Thermoacoustic tomography (TAT) is an emerging imaging technique with potential for a wide range of biomedical imaging applications. In this correspondence, we propose an infinite family of weighted expectation maximization (EM) algorithms for reconstruction of images from temporally truncated TAT measurement data. The weighted EM algorithms are equivalent mathematically to the conventional EM algorithm, but are shown to propagate data inconsistencies in different ways. Using simulated and experimental TAT measurement data, we demonstrate that suitable choices of weighted EM algorithms can effectively mitigate image artifacts that are attributable to temporal truncation of the TAT data function.


The food industry and self-regulation: standards to promote success and to avoid public health failures.
Threatened by possible government regulation and critical public opinion, industries often undertake self-regulatory actions, issue statements of concern for public welfare, and assert that self-regulation is sufficient to protect the public. The food industry has made highly visible pledges to curtail children's food marketing, sell fewer unhealthy products in schools, and label foods in responsible ways. Ceding regulation to industry carries opportunities but is highly risky. In some industries (e.g., tobacco), self-regulation has been an abject failure, but in others (e.g., forestry and marine fisheries), it has been more successful. We examined food industry self-regulation in the context of other self-regulatory successes and failures and defined 8 standards that should be met if self-regulation is to be effective.


Safeguarding genome stability: RASSF1A tumor suppressor regulates BRCA2 at stalled forks.
While it has been widely established that defective fork restart after exposure to stress results in increased genomic instability, the importance of fork protection during stalling for safeguarding genomic integrity has recently been fully appreciated. BRCA2, Breast tumor suppressor, has dual functionality promoting not only DNA repair but also preventing DNA lesions at stalled forks. In response to replication stress, BRCA2 recruits RAD51 onto nascent DNA at stalled forks, protecting nascent DNA from nucleolitic cleavage. Phosphorylation of the BRCA2 C-terminal RAD51 binding site by CDK2 promotes RAD51 filament disassembly, leading to nucleolitic cleavage of newly synthesized DNA and compromised fork integrity. Recently we uncovered how the core Hippo pathway components RASSF1A, MST2 and LATS1 regulate CDK2 activity towards BRCA2, in response to fork stalling. In complex with LATS1, CDK2 exhibits reduced kinase activity which results in low levels of pBRCA2-S3291 and stable RAD51 filaments protecting nascent DNA from MRE11 cleavage. In the absence of the RASSF1A/MST2/LATS1/CDK2 pathway increased resection of newly synthesized DNA leads to chromosomal instability and malignant transformation. This function of RASSF1A in stalled replication fork protection adds to the role of RASSF1A as a tumor suppressor and builds up evidence for RASSF1A status and its prognostic and predictive value in cancer.


Bone mineral density changes in young women: a two year study.
Achievement of a high peak bone mass is considered a pivotal preventive strategy against future osteoporotic fractures. The ostensible interaction between physiology and lifestylefor the development of bone mass over time is sparsely outlined among young women. The aim of this study was to follow bone density and bone resorption over time among healthy young women in relation to lifestyle factors and to evaluate the perceived influence of other factors. Data were collected in 1999 and in 2001. Healthy young women (n=152) were given a structured questionnaire, a heel bone scanner (dual X-ray absorptiometry) performed bone mineral density measurements and deoxypyridinoline was measured in urine. Data were analyzed by linear, multiple and logistic regression analysis. Mean bone mineral density (BMD) was 0.562 g/cm2 (+/-0.090). Bone density at baseline was the best predictorfor the bone density atfollow-up. Bone density at baseline together with smoking and alcohol (dichotomized) accounted for 86.5% of the variation in bone density 2 years later. Of the participants 62% had decreased/unchanged bone density and 38% had increased their bone density from 1999 to 2001. Use of oral contraceptives or alcohol at baseline was associated with an increased risk of belonging to the group who decreased their bone density. Deoxypyridinoline was not a strongpredictor to bone density and all potential predictors of deoxypyridinoline had a minor influence (<10%). In conclusion, lifestyle behaviors such as use of oral contraceptives, smoking and alcohol consumption seem to have a negative influence on BMD development among young women and warrant further scrutiny.


The origins of SPECT and SPECT/CT.
Single photon emission computed tomography (SPECT) has a long history of development since its initial demonstration by Kuhl and Edwards in 1963. Although clinical utility has been dominated by the rotating gamma camera, there have been many technological innovations with the recent popularity of organ-specific dedicated SPECT systems. The combination of SPECT and CT evolved from early transmission techniques used for attenuation correction with the initial commercial systems predating the release of PET/CT. The development and acceptance of SPECT/CT has been relatively slow with continuing debate as to what cost/performance ratio is justified. Increasingly, fully diagnostic CT is combined with SPECT so as to facilitate optimal clinical utility.


Effects of sustained stimulation with multi-wall carbon nanotubes on immune and inflammatory responses in mice.
Possible effects of multi-wall carbon nanotubes (MWCNTs) on immune and inflammatory responses were examined in mice. Female ICR mice were given a single intraperitoneal administration (2 mg/kg body weight) of either MWCNTs, carbon black (CB), or crocidolite (blue asbestos) and controls received a vehicle of 2% sodium carboxymethyl cellulose (CMC Na). In the peritoneal cavity of MWCNT-administered mice, the liver had changed to a rounded shape and fibrous adhesions were seen on internal organs. Peritoneal cells overexpressed mRNA for genes of T helper (Th)2 cytokines (interleukin [IL]-4, IL-5, and IL-13), Th17 cytokine (IL-17), pro-inflammatory cytokines/chemokines (IL-1β, IL-33, tumor necrosis factor α, and monocyte chemotactic protein-1), and myeloid differentiation factor 88 for at least 2 weeks after the administration of MWCNTs, while those of Th1 cytokine genes (IL-2 and interferon γ) were overexpressed several weeks later and expression levels remained high up to 20 weeks. In MWCNT-treated mice, the numbers of leukocytes, monocytes, and granulocytes in the peripheral blood and the expression of the leukocyte adhesion molecules, cluster of differentiation (CD)49d and CD54, on granulocytes were increased 1 week after administration and remained high up to week 20. Production of ovalbumin-specific IgM and IgG(1) was enhanced by MWCNTs. These changes were not observed after CB or crocidolite administration. Thus, this study showed that MWCNTs exhibited sustained stimulating effects on immune and inflammatory responses, unlike the other mineral fibers with structural similarities.


HER-2/neu over expression in gall bladder adenocarcinoma: A quest for potential therapeutic target.
Gall bladder carcinoma (GBC) is an aggressive malignancy with high mortality and aggressive course, with palliation as the only available option. To evaluate frequency of HER-2/neu overexpression in GBC and to seek its correlation, if any with conventional clinicopathological parameters and survival. Immunohistochemistry (IHC) was performed on 200 cases of GBC, 32 cases of dysplasia, and 100 cases of chronic cholecystitis. Fluorescent in situ hybridization (FISH) was performed on 30 randomly selected cases of GBC to validate IHC. HER-2/neu overexpression (IHC 3+/FISH amplification ≥2.2) was correlated with clinicopathological parameters by Chi-square test.P < 0.05 was considered significant. Survival analysis was done by log-rank test and Kaplan-Meier analysis. HER-2/neu overexpression was seen in 14% (28/200) GBC cases but was not found in dysplasia and chronic cholecystitis. Majority of these cases were ≤grade 2 and in advanced stage, however this was not statistically significant. A lower mean survival in HER-2/neu positive group as compared to HER-2/neu negative group (17.1 ± 2.3 month versus 67.6 ± 8.5 month, respectively) was observed. Concordance between IHC and FISH was seen in 18/19 cases. This study delineates a subset of GBC patients with HER-2/neu overexpression, in whom targeted therapy can offer a survival benefit.


Is online case-based learning effective in helping undergraduate medical students choose the appropriate antibiotics to treat important infections?
Medical students are frequently confused about indication for and choice of antibiotic. We developed an online learning resource that focused on antibiotic stewardship and important infections where medical students could practise their antibiotic decision-making skills safely. The resource was made available to third-year undergraduate medical students via their virtual learning environment. It covered the theory and fundamentals of antibiotic stewardship and five clinical cases covering important infections. We assessed the number of attempts taken to achieve the required level of understanding to pass each activity and surveyed a selection of students for their feedback. Of 310 students, over 80% engaged with the theory-based components, with an average score exceeding 90% (range 93.4%-99.7%). Eighty-three percent (258/310) engaged with the first two cases (Clostridioides difficile infection and pyelonephritis) but only 61% (189/310) of students completed the fifth case on bacterial meningitis. Only 49.4% (153/310) of students completed all five cases, with 48% (73/153) of these achieving ≥90% on their first attempt of the associated quizzes. Fifty-nine percent (23/39) agreed or strongly agreed that the quality of the learning resource was excellent. Seventy-two percent (28/39) agreed or strongly agreed that the objectives of the resource were relevant to their needs as undergraduate medical students. Only 33% (13/39) reported the resource would change their practice. Student feedback was positive but engagement with the cases needs improvement. Highlighting the utility of case-based technology-enhanced learning as a safe place to practise antibiotic decision-making skills among students may improve this.


Prevalence, determinants, and misclassification of myocardial infarction in the elderly.
We evaluated the prevalence, determinants, and misclassification of different types of myocardial infarction in 3,272 men and women age 55 years or older. We defined self-reported myocardial infarction with electro-cardiographic evidence as "typical myocardial infarction." We defined self-reported myocardial infarction without electrocardiographic evidence, but verified with additional clinical information, as "non-Q-wave myocardial infarction." Finally, we defined myocardial infarction detected by electrocardiogram that was not self-reported as "silent myocardial infarction," after verification of absence of symptoms. Overall, the prevalence of typical myocardial infarction was 4.1% [95% confidence interval (CI) = 3.5-4.9], of non-Q-wave myocardial infarction 2.8% (95% CI = 2.2-3.4), and of silent myocardial infarction 3.9% (95% CI = 3.2-4.5). Silent myocardial infarction was more prevalent in women, hypertensives, cigarette smokers, and those with higher post-load blood glucose. Self-reported myocardial infarction without electrocardiographic characteristics could be verified as myocardial infarction by means of additional clinical information in 56% of the cases. We conclude that myocardial infarction occurs frequently in the elderly without typical symptoms or electrocardiographic changes. As all these manifestations of myocardial infarction convey an increased risk of symptomatic heart disease or death, they require further attention. Misclassification due to limited sources of information can be considerable and should be taken into account in the design and interpretation of epidemiologic studies.


Contact lenses and the rate of evaporation measured in vitro; the influence of wear, squalene and wax.
Accelerated evaporation of tears may contribute to dry eye symptoms. It is not clear whether contact lenses decrease or increase the rate of evaporation of tears. In this study, the rates of evaporation through contact lenses (ERTCL) were measured in vitro to gain insight to this question. Contact lenses were equilibrated with various solutions to determine if they influenced ERTCL in vitro. ERTCL was measured gravimetrically. ERTCL measured in vitro for used contact lenses was about 20% faster than for buffer alone suggesting that natural tear components bound to the lenses changed the ERTCL. One natural tear component that binds to contact lenses is waxes. Equilibration of contact lenses with wax increased the ERTCL by about 30% suggesting that waxes might potentially increase ERTCL in vivo. Squalene, found in sebum and possibly meibum was infused into the contact lenses as a step toward decreasing the ERTCL. Squalene decreased ERTCL by over 60% in vitro. Soaking a contact lens in DuraSite(®) with benzalkonium chloride (BAK) did not alter the ERTCL. ERTCL were about 40% higher than the evaporation rate of DuraSite(®) alone or without BAK. In addition to lowering the ERTCL, the squalene in contact lenses could be a source of terpenoids to replace the terpenoids deficient in patients with MGD. If the ERTCL could be minimized in vivo, contact lenses could potentially be used to relieve dry eye symptoms in patients with evaporative dry eye.


[Cardiotoxicity of anticancer therapies. Towards the implementation of cardio-oncology units].
Recently, we have witnessed major improvements in cancer treatment. Early diagnosis and development of new therapies have reduced cancer-related mortality. However, these new therapies, along with greater patient survival, are associated with an increase in untoward effects, particularly in the cardiovascular system. Although cardiotoxicity induced by oncologic treatments affects predominantly the myocardium, it can also involve other structures of the cardiovascular system, becoming one of the main causes of morbidity and mortality in those who survive cancer. The main objective of cardio-oncology is to achieve the maximum benefits of oncologic treatments while minimizing their deleterious cardiovascular effects. It harbors the stratification of patients at risk of cardiotoxicity, the implementation of diagnostic tools (imaging techniques and biomarkers) for early diagnosis, preventive strategies and early treatment options for the complications. Herein, we discuss the basic knowledge for the implementation of cardio-oncology units and their role in the management of cancer patients, the diagnostic tools available to detect cardiotoxicity and the present therapeutic options.


Measurement Validity of the Low Vision Independence Measure (LVIM).
This study's objective was to test the psychometrics of Smith's (2013) Low Vision Independence Measure (LVIM) using the Rasch model. A cohort design was used with 93 participants receiving occupational therapy for low vision. Confirmatory factor analysis (CFA) with a parceling approach was used to test the LVIM factors and Rasch analysis to examine item-level psychometrics. Participants' average age was 78.9 yr (standard deviation = 12.1), and the majority were female (72.8%) with macular degeneration (62.3%). The CFA revealed two measurement factors: visual field or scotoma (n = 28) and visual acuity (n = 24). We removed six misfitting items, and the two factors of the revised LVIM demonstrated good rating scale function, good internal consistency (person reliability: visual field, .87; visual acuity, .90), good precision (person strata: visual field, 3.91; visual acuity, 4.40), no ceiling or floor effects, and no differential item functioning. The revised LVIM demonstrates good psychometrics on the Rasch model and can be used as a valid outcome measure in low vision rehabilitation.


Mitochondrial injury and dysfunction in hypertension-induced cardiac damage.
Hypertension remains an important modifiable risk factor for cardiovascular disease, associated with increased morbidity and mortality. Deciphering the mechanisms involved in the pathogenesis of hypertension is critical, as its prevalence continues increasing worldwide. Mitochondria, the primary cellular energy producers, are numerous in parenchymal cells of the heart, kidney, and brain, major target organs in hypertension. These membrane-bound organelles not only maintain cellular respiration but also modulate several functions of the cell including proliferation, apoptosis, generation of reactive oxygen species, and intracellular calcium homeostasis. Therefore, mitochondrial damage and dysfunction compromise overall cell functioning. In recent years, significant advances increased our understanding of mitochondrial morphology, bioenergetics, and homeostasis, and in turn of their role in several diseases, so that mitochondrial abnormalities and dysfunction have been identified in experimental models of hypertension. In this review, we summarize current knowledge of the contribution of dysfunctional mitochondria to the pathophysiology of hypertension-induced cardiac damage, as well as available evidence of mitochondrial injury-induced damage in other organs. Finally, we discuss the capability of antihypertensive therapy to ameliorate hypertensive mitochondrial injury, and the potential position of mitochondria as therapeutic targets in patients with hypertension.


Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models.
Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645-1648) in the design of B-domain-deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector-based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy.


Radiotherapy in congenital vulvar lymphangioma circumscriptum.
Congenital lymphangioma circumscriptum (LC) of the vulva is a rare disorder with unknown etiology. Treatment options include ablative approaches such as laser therapy, sclerotherapy, and surgery. Radiotherapy has been shown to be effective in the management of congenital lymphangioma especially in the thoracic and abdominal lesions. In this report, we describe a patient with persistent vulvar LC despite sclerosing therapy and several surgical excisions. She was treated with a course of external radiotherapy and showed a dramatic objective response with relief of all symptoms.


Clinical perspectives on platinum resistance.
The platinum compounds cisplatin and carboplatin are widely used in the treatment of a number of solid malignancies. Although some platinum-sensitive tumours may be cured by combination chemotherapy (e.g. testicular cancer), most will relapse and subsequently prove resistant to platinum compounds. The mechanisms of platinum resistance in patients are still poorly understood. Clearly, when a tumour relapses a long time after successful first-line treatment, there is a high chance that it will still be sensitive to platinum compounds. A number of studies have attempted to assess the role of drug transport, the glutathione system, DNA repair and apoptosis genes in the development of resistance in tumours, but no conclusive evidence is available. Approaches to increasing the potency of platinum therapy (to overcome resistance) have been devised and some have proved to be effective; in particular, intraperitoneal administration of cisplatin has shown superiority over intravenous administration in selected patients with ovarian cancer. The development of drugs and techniques to reduce the adverse effects of platinum chemotherapy has greatly improved their administration. Investigations attempting to modulate platinum activity and toxicity have also been performed. Further investigation of in vivo resistance mechanisms should be valuable in allowing prediction of clinical response to chemotherapy and may identify new treatments with the potential to improve outcomes for patients with a variety of platinum-resistant tumour types.


Withdrawal from Buprenorphine/Naloxone and Maintenance with a Natural Dopaminergic Agonist: A Cautionary Note.
While numerous studies support the efficacy of methadone and buprenorphine for the stabilization and maintenance of opioid dependence, clinically significant opioid withdrawal symptoms occur upon tapering and cessation of dosage. We present a case study of a 35 year old Caucasian female (Krissie) who was prescribed increasing dosages of prescription opioids after carpel tunnel surgery secondary to chronic pain from reflex sympathetic dystrophy and fibromyalgia. Over the next 5 years, daily dosage requirements increased to over 80 mg of Methadone and 300 ug/hr Fentanyl transdermal patches, along with combinations of 12-14 1600 mcg Actig lollipop and oral 100 mg Morphine and 30 mg oxycodone 1-2 tabs q4-6hr PRN for breakthrough pain. Total monthly prescription costs including supplemental benzodiazepines, hypnotics and stimulants exceeded $50,000. The patient was subsequently transferred to Suboxone® in 2008, and the dosage was gradually tapered until her admission for inpatient detoxification with KB220Z a natural dopaminergic agonist. We carefully documented her withdrawal symptoms when she precipitously stopped taking buprenorphine/naloxone and during follow-up while taking KB220Z daily. We also genotyped the patient using a reward gene panel including (9 genes 18 alleles): DRD 2,3,4; MOA-A; COMT; DAT1; 5HTTLLR; OPRM1; and GABRA3. At 432 days post Suboxone® withdrawal the patient is being maintained on KB220Z, has been urine tested and is opioid free. Genotyping data revealed a moderate genetic risk for addiction showing a hypodopaminergic trait. This preliminary case data suggest that the daily use of KB220Z could provide a cost effective alternative substitution adjunctive modality for Suboxone®. We encourage double-blind randomized -placebo controlled studies to test the proposition that KB220Z may act as a putative natural opioid substitution maintenance adjunct.


Surgical treatment of patients with low-grade astrocytomas and medically intractable seizures.
Low-grade astrocytomas can present with seizures that respond poorly to antiseizure medications, with a consequent reduction in the quality of life, because of both seizures and the medication's side-effects. We report our experience with operative treatment of such patients. Five patients (two children and three adults) with supratentorial low-grade astrocytomas associated with severe seizures were operated on. We followed the effects of the operation on post-operative neurological deficit, seizure frequency and the quality of life. No serious neurological complications followed the operations. The patients were followed for a median period of 12 months (6-46). Post-operatively, three of the patients became seizure-free, one experiences only auras, and one had a great reduction in seizure frequency and severity. All patients reported great improvement in their quality of life. Resections of low-grade astrocytomas in patients with medically intractable seizures are safe procedures that effectively control seizures in the majority of patients, resulting in significant improvement in the patients' quality of life.


Mesenchymal Stromal Cell-Derived Factors Promote Tissue Repair in a Small-for-Size Ischemic Liver Model but Do Not Protect against Early Effects of Ischemia and Reperfusion Injury.
Loss of liver mass and ischemia/reperfusion injury (IRI) are major contributors to postresectional liver failure and small-for-size syndrome. Mesenchymal stromal cell- (MSC-) secreted factors are described to stimulate regeneration after partial hepatectomy. This study investigates if liver-derived MSC-secreted factors also promote liver regeneration after resection in the presence of IRI. C57BL/6 mice underwent IRI of 70% of their liver mass, alone or combined with 50% partial hepatectomy (PH). Mice were treated with MSC-conditioned medium (MSC-CM) or unconditioned medium (UM) and sacrificed after 6 or 24 hours (IRI group) or after 48 hours (IRI + PH group). Blood and liver tissue were analyzed for tissue injury, hepatocyte proliferation, and gene expression. In the IRI alone model, serum ALT and AST levels, hepatic tissue damage, and inflammatory cytokine gene expression showed no significant differences between both treatment groups. In the IRI + PH model, significant reduction in hepatic tissue damage as well as a significant increase in hepatocyte proliferation was observed after MSC-CM treatment. Mesenchymal stromal cell-derived factors promote tissue regeneration of small-for-size livers exposed to ischemic conditions but do not protect against early ischemia and reperfusion injury itself. MSC-derived factors therefore represent a promising treatment strategy for small-for-size syndrome and postresectional liver failure.


Associations between T1 white matter lesion volume and regional white matter microstructure in aging.
White matter lesions, typically manifesting as regions of signal intensity abnormality (WMSA) on MRI, increase in frequency with age. However, the role of this damage in cognitive decline and disease is still not clear, as lesion volume has only loosely been associated with clinical status. Diffusion tensor imaging (DTI) has been used to examine the quantitative microstructural integrity of white matter, and has applications in the examination of subtle changes to tissue that appear visually normal on conventional imaging. The primary goal of this study was to determine whether major macrostructural white matter damage, (total WMSA volume), is associated with microstructural integrity of normal appearing white matter, and if these macrostructural changes fully account for microstructural changes. Imaging was performed in 126 nondemented individuals, ages 43-85 years, with no history of cerebrovascular disease. Controlling for age, greater WMSA volume was associated with decreased fractional anisotropy (FA) in widespread brain regions. Patterns were similar for FA and radial diffusivity but in contrast, WMSA was associated with axial diffusivity in fewer areas. Age was associated with FA in several regions, and many of these effects remained even when controlling for WMSA volume, suggesting the etiology of WMSAs does not fully account for all age-associated white matter deterioration. These results provide evidence that WMSA volume is associated with the integrity of normal-appearing white matter. In addition, our results suggest that overt lesions may not account for the association of increasing age with decreased white matter tissue integrity.


Emergence of pregnancy-related listeriosis amongst ethnic minorities in England and Wales.
Listeriosis is a rare but severe food-borne disease that predominantly affects pregnant women, the unborn, newborns, the elderly and immunocompromised people. Following a large outbreak in the 1980s, specific food safety advice was provided to pregnant women and the immunocompromised in the United Kingdom. Following two coincident yet unconnected cases of pregnancy-related listeriosis in eastern European women in 2008, a review of the role of ethnicity in pregnancy-related listeriosis in England and Wales was undertaken in 2009. Cases reported to the national listeriosis surveillance scheme were classified as 'ethnic', belonging to an ethnic minority, or 'non-ethnic' based on their name, and trends were examined. Between 2001 and 2008, 1,510 cases of listeriosis were reported in England and Wales and, of these, 12% were pregnancy-related cases. The proportion of pregnancy-related cases classified as ethnic increased significantly from 16.7% to 57.9% (chi-square test for trend p=0.002). The reported incidence among the ethnic population was higher than that among the non-ethnic population in 2006, 2007 and 2008 (Relative Risk: 2.38, 95% confidence interval: 1.07 to 5.29; 3.82, 1.82 to 8.03; 4.33, 1.74 to 10.77, respectively). This effect was also shown when analysing data from January to September 2009, using extrapolated live births as denominator. Increased immigration and/or economic migration in recent years appear to have altered the population at risk of pregnancy-related listeriosis in England and Wales. These changes need to be taken into account in order to target risk communication strategies appropriately.


A national study of the association between traffic-related air pollution and adverse pregnancy outcomes in Canada, 1999-2008.
Numerous studies have examined the association of air pollution with preterm birth and birth weight outcomes. Traffic-related air pollution has also increasingly been identified as an important contributor to adverse health effects of air pollution. We employed a national nitrogen dioxide (NO2) exposure model to examine the association between NO2 and pregnancy outcomes in Canada between 1999 and 2008. National models for NO2 (and particulate matter of median aerodynamic diameter <2.5µm (PM2.5) as a covariate) were developed using ground-based monitoring data, estimates from remote-sensing, land use variables and, for NO2, deterministic gradients relative to road traffic sources. Generalized estimating equations were used to examine associations with preterm birth, term low birth weight (LBW), small for gestational age (SGA) and term birth weight, adjusting for covariates including infant sex, gestational age, maternal age and marital status, parity, urban/rural place of residence, maternal place of birth, season, year of birth and neighbourhood socioeconomic status and per cent visible minority. Associations were reduced considerably after adjustment for individual covariates and neighbourhood per cent visible minority, but remained significant for SGA (odds ratio 1.04, 95%CI 1.02-1.06 per 20ppb NO2) and term birth weight (16.2g reduction, 95% CI 13.6-18.8g per 20ppb NO2). Associations with NO2 were of greater magnitude in a sensitivity analysis using monthly monitoring data, and among births to mothers born in Canada, and in neighbourhoods with higher incomes and a lower proportion of visible minorities. In two pollutant models, associations with NO2 were less sensitive to adjustment for PM2.5 than vice versa, and there was consistent evidence of a dose-response relationship for NO2 but not PM2.5. In this study of approximately 2.5 million Canadian births between 1999 and 2008, we found significant associations of NO2 with SGA and term birth weight which remained significant after adjustment for PM2.5, suggesting that traffic may be a particularly important source with respect to the role of air pollution as a risk factor for adverse pregnancy outcomes.


Micro-encapsulated pirimiphos-methyl shows high insecticidal efficacy and long residual activity against pyrethroid-resistant malaria vectors in central Côte d'Ivoire.
The wide-scale implementation of insecticide-treated nets and indoor residual spraying (IRS) has contributed to a considerable decrease of malaria morbidity and mortality in sub-Saharan Africa over the last decade. Due to increasing resistance in Anopheles gambiae sensu lato mosquitoes to dichlorodiphenyl trichloroethane (DDT) and pyrethroids, alternative insecticide formulations for IRS with long-lasting residual activity are required to sustain the gains obtained in most malaria-endemic countries. Three experimental capsule suspension (CS) formulations of the organophosphate pirimiphos-methyl were evaluated together with Actellic 50 EC, an emulsifiable concentrate (EC) of pirimiphos-methyl, and the pyrethroid ICON 10 CS, a lambda-cyhalothrin CS formulation, in an experimental hut trial. The formulations were tested on two types of surfaces: mud and cement. The study with a 12-month follow-up was carried out in Bouaké, central Côte d'Ivoire, where An. gambiae mosquitoes show high levels of resistance against pyrethroids, DDT and carbamates. Residual activity was also tested in cone bioassays with the susceptible An. gambiae KISUMU strain. One of the CS formulations of pirimiphos-methyl, CS BM, outperformed all other formulations tested. On cement surfaces, the odds ratios of overall insecticidal effect on An. gambiae s.l. of pirimiphos-methyl CS BM compared to Actellic 50 EC were 1.4 (95% confidence interval (CI): 1.2-1.7) for the first three months, 5.6 (95% CI: 4.4-7.2) for the second three months, and 3.6 (95% CI: 3.0-4.4) for the last six months of follow-up. On mud surfaces, the respective odds ratios were 2.5 (95% CI: 1.9-3.3), 3.5 (95% CI: 2.7-4.5), and 1.7 (95% CI: 1.4-2.2). On cement, the residual activity of pirimiphos-methyl CS BM measured using cone tests was similar to that of lambda-cyhalothrin and for both treatments, mortality of susceptible Kisumu laboratory strain was not significantly below the World Health Organization pre-set threshold of 80% for 30 weeks after spraying. Residual activity was shorter on mud surfaces, mortality falling below 80% on both pirimiphos-methyl CS BM and lambda-cyhalothrin treated surfaces at 25 weeks post-treatment. CS formulations of pirimiphos-methyl are promising alternatives for IRS, as they demonstrate prolonged insecticidal effect and residual activity against malaria mosquitoes.


Cocaine binds to a common site on open and inactivated human heart (Na(v)1.5) sodium channels.
The inhibition by cocaine of the human heart Na+ channel (Na(v)1.5) heterologously expressed in Xenopus oocytes was investigated. Cocaine produced little tonic block of the resting channels but induced a characteristic, use-dependent inhibition during rapid, repetitive stimulation, suggesting that the drug preferentially binds to the open or inactivated states of the channel. To investigate further the state dependence, depolarizing pulses were used to inactivate the channels and promote cocaine binding. Cocaine produced a slow, concentration-dependent inhibition of inactivated channels, which had an apparent K(D) of 3.4 microM. Mutations of the interdomain III-IV linker that remove fast inactivation selectively abolished this high-affinity component of cocaine inhibition, which appeared to be linked to the fast inactivation of the channels. A rapid component of cocaine inhibition persisted in the inactivation-deficient mutant that was enhanced by depolarization and was sensitive to changes in the concentration of external Na+, properties that are consistent with a pore-blocking mechanism. Cocaine induced a use-dependent inhibition of the non-inactivating mutant and delayed the repriming at hyperpolarized voltages, indicating that the drug slowly dissociated when the channels were closed. Mutation of a conserved aromatic residue (Y1767) of the D4S6 segment weakened both the inactivation-dependent and the pore-blocking components of the cocaine inhibition. The data indicate that cocaine binds to a common site located within the internal vestibule and inhibits cardiac Na+ channels by blocking the pore and by stabilizing the channels in an inactivated state.


Visual narrative structure.
Narratives are an integral part of human expression. In the graphic form, they range from cave paintings to Egyptian hieroglyphics, from the Bayeux Tapestry to modern day comic books (Kunzle, 1973; McCloud, 1993). Yet not much research has addressed the structure and comprehension of narrative images, for example, how do people create meaning out of sequential images? This piece helps fill the gap by presenting a theory of Narrative Grammar. We describe the basic narrative categories and their relationship to a canonical narrative arc, followed by a discussion of complex structures that extend beyond the canonical schema. This demands that the canonical arc be reconsidered as a generative schema whereby any narrative category can be expanded into a node in a tree structure. Narrative "pacing" is interpreted as a reflection of various patterns of this embedding: conjunction, left-branching trees, center-embedded constituencies, and others. Following this, diagnostic methods are proposed for testing narrative categories and constituency. Finally, we outline the applicability of this theory beyond sequential images, such as to film and verbal discourse, and compare this theory with previous approaches to narrative and discourse.


Spreading the message of antimicrobial resistance: a detailed account of a successful public engagement event.
The increase in Antimicrobial resistance (AMR) microorganisms has been exacerbated by exposure to antimicrobial drugs (e.g. antibiotics). A solution to AMR may require academic researchers to not only contribute to the drug discovery pipeline through laboratory research, but also to engage and inform non-specialist audiences using a variety of interventions in order to change behaviour towards our use of antibiotics. In this paper, the authors describe a hands-on public engagement event focusing on AMR. 'A Spoonful of Soil', was created by drawing on the past experiences of the delivering team (also described), with planning focusing on clear concise messages, selection of an appropriate audience and ensuring the event would be of significant interest to the audience. The event had a significant footfall of over 300 visitors. Key messages which aimed to raise awareness of AMR and educate visitors on the actions and behaviours that can help address the global issue of AMR were delivered by appropriate experts successfully, however success in reaching audience cannot be concluded from the feedback and evaluation gathered.


Defects During Mecp2 Null Embryonic Cortex Development Precede the Onset of Overt Neurological Symptoms.
MeCP2 is associated with several neurological disorders; of which, Rett syndrome undoubtedly represents the most frequent. Its molecular roles, however, are still unclear, and data from animal models often describe adult, symptomatic stages, while MeCP2 functions during embryonic development remain elusive. We describe the pattern and timing of Mecp2 expression in the embryonic neocortex highlighting its low but consistent expression in virtually all cells and show the unexpected occurrence of transcriptional defects in the Mecp2 null samples at a stage largely preceding the onset of overt symptoms. Through the deregulated expression of ionic channels and glutamatergic receptors, the lack of Mecp2 during early neuronal maturation leads to the reduction in the neuronal responsiveness to stimuli. We suggest that such features concur to morphological alterations that begin affecting Mecp2 null neurons around the perinatal age and become evident later in adulthood. We indicate MeCP2 as a key modulator of the transcriptional mechanisms regulating cerebral cortex development. Neurological phenotypes of MECP2 patients could thus be the cumulative result of different adverse events that are already present at stages when no obvious signs of the pathology are evident and are worsened by later impairments affecting the central nervous system during maturation and maintenance of its functionality.


Functional dysphagia therapy and PEG treatment in a clinical geriatric setting.
Functional dysphagia therapy (FDT) is a noninvasive procedure that can accompany percutaneous endoscopic gastrostomy (PEG) treatment and supports transitioning from tube to oral feeding. In this retrospective study, we investigated the outcome of FDT with or without PEG feeding. Patients with dysphagia were divided into two groups: those with PEG feeding (N = 117) and those with exclusively oral feeding (N = 105). Both groups received functional training (oral motor skills/sensation, compensatory swallowing techniques) from speech-language therapists. Functional oral intake, weight, Barthel index, and speech and language abilities were evaluated pre- and post-training. The non-PEG group showed a significant post-treatment improvement in functional oral intake, with diet improvement from pasty consistency to firm meals in most cases. However, even severely disordered patients (with PEG feeding) showed a significant increase in functional oral intake, still requiring PEG feeding post-treatment but able to take some food orally. The sooner a PEG was placed, the more functional oral intake improved. Significantly more complications and higher mortality occurred in the PEG group compared to the group with exclusively oral feeding. Dysphagia treatment in the elderly requires a multiprofessional setting, differentiated assessment, and functional training of oral motor skills and sensation and swallowing techniques.


Long-term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer.
The long-term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment-refractory advanced esophageal cancer who participated in an open-label, single-arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand-1 (PD-L1) and CD8+ status of tumors and tumor-infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end-points included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long-term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD-L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.


Inactivation of Lrp5 in osteocytes reduces young's modulus and responsiveness to the mechanical loading.
Low-density-lipoprotein receptor-related protein 5 (Lrp5) is a co-receptor in Wnt signaling, which plays a critical role in development and maintenance of bone. Osteoporosis-pseudoglioma syndrome, for instance, arises from loss-of-function mutations in Lrp5, and global deletion of Lrp5 in mice results in significantly lower bone mineral density. Since osteocytes are proposed to act as a mechanosensor in the bone, we addressed a question whether a conditional loss-of-function mutation of Lrp5 selective to osteocytes (Dmp1-Cre;Lrp5(f/f)) would alter responses to ulna loading. Loading was applied to the right ulna for 3 min (360 cycles at 2Hz) at a peak force of 2.65 N for 3 consecutive days, and the contralateral ulna was used as a non-loaded control. Young's modulus was determined using a midshaft section of the femur. The results showed that compared to age-matched littermate controls, mice lacking Lrp5 in osteocytes exhibited smaller skeletal size with reduced bone mineral density and content. Compared to controls, Lrp5 deletion in osteocytes also led to a 4.6-fold reduction in Young's modulus. In response to ulna loading, mineralizing surface, mineral apposition rate, and bone formation rate were diminished in mice lacking Lrp5 in osteocytes by 52%, 85%, and 69%, respectively. Collectively, the results support the notion that the loss-of-function mutation of Lrp5 in osteocytes causes suppression of mechanoresponsiveness and reduces bone mass and Young's modulus. In summary, Lrp5-mediated Wnt signaling significantly contributes to maintenance of mechanical properties and bone mass.


Elastic response and phase behavior in binary liquid crystal mixtures.
Utilizing density-of-states simulations, we perform a full mapping of the phase behavior and elastic responses of binary liquid crystalline mixtures represented by the multicomponent Lebwohl-Lasher model. Our techniques are able to characterize the complete phase diagram, including nematic-nematic phase separation predicted by mean-field theories, but previously not observed in simulations. Mapping this phase diagram permits detailed study of elastic properties across the miscible nematic region. Importantly, we observe for the first time local phase separation and disordering driven by the application of small linear perturbations near the transition temperature and more significantly through nonlinear stresses. These findings are of key importance in systems of blended nematics which contain particulate inclusions, or are otherwise confined.


In-situ detection of density alteration in non-physiological cells with polarimetric tilted fiber grating sensors.
Tilted fiber Bragg grating (TFBG) biosensors can be used as a cost-effective and relatively simple-to-implement alternative to well established biosensor platforms for high sensitivity biological sample measurements in situ or possibly in vivo. The fiber biosensor presented in this study utilizes an in-fiber 12° tilted Bragg grating to excite a strong evanescent field on the surface of the sensor over a large range of external medium refractive indices. The devices have minimal cross-sensitivity to temperature and their fabrication does not impact the structural integrity of the fiber and its surface functionalization. Human acute leukemia cells with different intracellular densities and refractive index (RI) ranging from 1.3342 to 1.3344 were clearly discriminated in-situ by using the differential transmission spectrum between two orthogonal polarizations for the last guided mode resonance before "cut-off", with an amplitude variation sensitivity of 1.8 × 10(4) dB/RIU, a wavelength shift sensitivity of 180 nm/RIU, and a limit of detection of 2 × 10(-5)RIU. The detection process was precisely controlled with a micro-fluidic chip which allows the measurement of nL-volumes of bio-samples. The proposed in-fiber polarimetric biosensor is an appealing solution for rapid, sub-microliter dose and highly sensitive detection of analytes at low concentrations in medicine, chemical and environmental monitoring.


The association between the PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis update.
The aim of this study was to determine whether the protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T polymorphism confers susceptibility to rheumatoid arthritis (RA) in populations with different ethnicities. A meta-analysis was conducted on the PTPN22 C1858T polymorphism involving eighteen studies, which in total contained 20344 RA patients and 21828 controls. Meta-analysis revealed an association between the PTPN22 C1858T polymorphism T allele and RA in all subjects (odds ratio [OR] = 1.637, 95% confidence interval [CI] = 1.514-1.770, P < 0.001). After stratification by ethnicity, analysis indicated that the PTPN22 C1858T polymorphism T allele was significantly associated with RA in Europeans and Non-Europeans (OR = 1.587, 95% CI = 1.486-1.696, P < 0.001; OR = 1.748, 95% CI = 1.274-2.398, P < 0.001). Meta-analysis of the CT + TT genotype showed the same result patterns as that shown by the PTPN22 C1858T polymorphism T allele. Furthermore, a direct comparison between rheumatoid factor (RF)-positive and -negative subjects revealed a significant association with the T allele in RA patients with RF, but not in subjects without RF. In conclusion, this meta-analysis confirms that the PTPN22 C1858T polymorphism is associated with RA susceptibility in different ethnic groups, especially in Europeans, and the PTPN22 C1858T polymorphism T allele is significantly more prevalent in RF-positive patents than in RF-negative patients.


New data-driven method from 3D confocal microscopy for calculating phytoplankton cell biovolume.
Confocal laser scanner microscopy coupled with an image analysis system was used to directly determine the shape and calculate the biovolume of phytoplankton organisms by constructing 3D models of cells. The study was performed on Biceratium furca (Ehrenberg) Vanhoeffen, which is one of the most complex-shaped phytoplankton. Traditionally, biovolume is obtained from a standardized set of geometric models based on linear dimensions measured by light microscopy. However, especially in the case of complex-shaped cells, biovolume is affected by very large errors associated with the numerous manual measurements that this entails. We evaluate the accuracy of these traditional methods by comparing the results obtained using geometric models with direct biovolume measurement by image analysis. Our results show cell biovolume measurement based on decomposition into simple geometrical shapes can be highly inaccurate. Although we assume that the most accurate cell shape is obtained by 3D direct biovolume measurement, which is based on voxel counting, the intrinsic uncertainty of this method is explored and assessed. Finally, we implement a data-driven formula-based approach to the calculation of biovolume of this complex-shaped organism. On one hand, the model is obtained from 3D direct calculation. On the other hand, it is based on just two linear dimensions which can easily be measured by hand. This approach has already been used for investigating the complexities of morphology and for determining the 3D structure of cells. It could also represent a novel way to generalize scaling laws for biovolume calculation.


Towards Designing a Secure Exchange Platform for Diabetes Monitoring and Therapy.
Diabetes mellitus is one of the most prominent examples of chronic conditions that requires an active patient self-management and a network of specialists. The aim of this study was to analyze the user and legal requirements and develop a rough technology concept for a secure and patient-centered exchange platform. To this end, 14 experts representing different stakeholders were interviewed and took part in group discussions at three workshops, the pertinent literature and legal texts were analyzed. The user requirements embraced a comprehensive set of use cases and the demand for "one platform for all" which is underlined by the right for data portability according to new regulations. In order to meet these requirements a distributed ledger technology was proposed. We will therefore focus on a patient-centered application that showcases self-management and exchange with health specialists.


Stress Management and Resilience Intervention in a Women's Heart Clinic: A Pilot Study.
Background: In general, women report higher stress levels than men. High baseline anxiety, depression, and stress levels are associated with greater risk of cardiovascular diseases. Current evidence for efficacy of stress management interventions for women is limited. This study aimed at assessing the effect of a stress management and resiliency training (SMART) program for decreasing stress, anxiety, and depressive symptoms. Methods: Fifty moderately or severely stressed Women's Heart/Preventive Cardiology Clinic patients consented to the SMART intervention delivered online (n = 36) or in-person (n = 9). Primary outcome measures were the observed changes between baseline and at 12 weeks for the following psychometric tools: General Anxiety Disorder-7 (GAD-7), Patient Health Questionnaires (PHQ-9), Perceived Stress Scale (PSS), and Brief Resiliency Scale (BRS). Results: Forty-five patients completed the study. We observed significant improvements in PSS and GAD-7, but not in PHQ-9 or BRS, after the SMART intervention. When assessing outcomes among those with depressive symptoms at baseline (PHQ-9 > 15), we observed significant changes in PSS, GAD-7, and PHQ-9. No differences between online and in-person program delivery methods were found (all p-values >0.05). Conclusions: Training exposure using the SMART program to decrease stress and anxiety in women seeking preventive cardiology services was feasible and similarly effective, whether delivered online or in a single in-person session. Impacts on depression and resilience likely require a more intensive approach. In the future, larger randomized clinical trials with additional training and longer follow-up are warranted.


Parts exchange: tuning the flagellar motor to fit the conditions.
Many cellular activities are driven by complex protein machines. By measuring the behaviour of fluorescent protein fusions in real time in living cells it has become apparent that many of these complexes are not fixed, but are dynamic. To some extent this might be expected, for example, for cell division complexes, as defining mid-cell is linked to growth and cell cycle, but perhaps comes as more of a surprise with a complex anchored machine like the bacterial flagellar motor. The assumption has been that once made it remains intact. However, the dynamics of this structure is strongly supported in two manuscripts in this issue of Molecular Microbiology. The stator units which form a peptioglycan anchored ring around the rotor, generating torque in response to the ion motive force, clearly disengage when conditions change. The driving ion is shown to be important in both engagement of the stator to the rotor and the selection of the type of stator unit. These new results provide an insight into the mechanisms underlying motor function, which might rely on dynamic processes, and clearly illustrate the need to move away from a static view of cellular structures.


Contextual Influences on the Sentencing of Individuals Convicted of Sexual Crimes.
This study examines effects of court and community contextual factors on sentencing outcomes for individuals convicted of sexual crimes using indicators from two perspectives-focal concerns and populist punitiveness. Sourced from the Pennsylvania Commission on Sentencing, the sample includes 9,431 persons convicted of sexual crimes and a precision-matched sample of persons convicted of non-sexual violent crimes for comparison. Based on multilevel hurdle regression models for both incarceration and sentence length decisions, results indicate that individuals convicted of sexual crimes face enhanced sentence severity in judicial districts with smaller courts, increased jail capacity, stronger political competition, and higher religious homogeneity. The results also suggest statistically significant differences between effects for persons convicted of sexual crimes and a matched sample of persons convicted of violent crimes. Overall, results suggest that specific contextual factors have a distinguishable impact on sentencing of individuals convicted of sexual crimes.


Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.


On-site, serial exposure of female fathead minnows to the Elkhorn River, Nebraska, USA, spring agrichemical pulse.
In the Midwestern United States, waterways such as the Elkhorn River experience an annual spring pulse of runoff that carries sediments, nutrients, and organic compounds downstream. The objective of the present study was to elucidate relationships between contaminant load in Elkhorn River water and biological impacts on female fathead minnows throughout the entire spring agrichemical pulse. Fish were maintained in on-site outdoor microcosms at the Elkhorn River Research Station. The start of the spring pulse was determined using commercially available atrazine strips that detected atrazine when concentrations exceeded 3 ppb. Once the pulse began, 5 serial 7-d exposures were conducted. Concentrations of atrazine, its metabolites, and 5 other herbicides were quantified using gas chromatography-mass spectrometry. Agrichemicals peaked during the first and second weeks of the pulse, with a smaller peak occurring during week 4, but the peaks were not directly associated with runoff events (as estimated from river discharge). Elevated agrichemical concentrations were associated with biological impacts, but not solely responsible. In the present study, differences in the abiotic environment were found to play a significant role in the defeminization of exposed female fathead minnows.


Comparison of length measurements provided by a femtosecond optical frequency comb.
This paper presents a comparison of length measurements between the wavelength and the adjacent pulse repetition interval length (APRIL) provided by a femtosecond optical frequency comb. A theoretical estimation of the frequency stability for stabilizing the wavelength and APRIL, the frequency parameters that affect the stability of the APRIL in air, and the ambiguity in the length measurement by the APRIL are investigated. We find that the APRIL can be used as a low-cost measurement for the absolute length over a range of hundreds of meters in laboratory conditions.


Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence.
About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer's disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches.