Differential autonomic mechanisms underlying early morning and daytime transient myocardial ischaemia in patients with stable coronary artery disease.
To see whether autonomic regulatory mechanisms play a part in transient myocardial ischaemia in patients treated with beta blockers. Prospective study. Outpatients' clinic. 51 consecutive patients with angiographically documented coronary artery disease, stable angina, and transient myocardial ischaemia despite beta blockade. 24 hour ambulatory electrocardiographic monitoring for analysis of variability in ST depression and heart rate. Numbers of episodes of ischaemia, with an ST depression of > or = 0.1 mV 80 ms after the J point that lasted > or = 60 s at an interval of > or = 60 s from a previous ischaemic episode. Heart rate at onset of ischaemia. Normalised spectral analysis of heart rate variability; ratio of low to high frequency power to assess the sympathovagal balance. Despite treatment, 258 episodes of transient ischaemia were recorded. At heart rates at onset of ischaemia of < 70 beats per minute a high ratio of low to high frequency power accompanied the ischaemic events and was paralleled by a remarkably reduced high frequency power. The high ratio--that is, enhanced sympathetic tone during ischaemia--was mainly found in the early morning. By contrast, ischaemic episodes with heart rates at onset of > or = 70 beats per minute were not associated with significant changes in the parameters of autonomic function. During beta blockade the residual transient ischaemia is associated with decreased variability in heart rate. In particular, in ischaemic episodes with a low heart rate at onset the neural regulation of the heart plays a part. Apparently, variability in heart rate is not sufficiently modified by beta blockers to prevent all ischaemia. The ischaemia related change in the autonomic nervous system during the early morning is in agreement with previous studies, showing increased cardiovascular risk at this time of the day.


Cannulation in the diseased aorta: a safe approach using the Seldinger technique.
The Seldinger technique is a method of femoral cannulation that has been used to establish cardiopulmonary bypass. Reports of cannulation of the ascending aorta for antegrade perfusion using the Seldinger method are anecdotal. To the best of our knowledge, the approach described herein for direct cannulation of the ascending aorta with use of the Seldinger technique for antegrade perfusion has not been previously described in the English-language medical literature. This method is helpful when the surgeon is treating a patient who has a calcified ascending aorta, complicated aortic dissection, calcified femoral vessels, or a diseased thoracoabdominal aorta. In such cases, retrograde perfusion has been associated with severe complications as a result of atheromatous embolization from the descending thoracic aorta. Herein, we describe our approach to cannulation for cardiopulmonary bypass, which entails insertion of an aortic cannula into the ascending aorta by means of the Seldinger technique. A soft-tip guidewire is inserted through an arterial entry catheter that has been used to puncture a hole in the wall of the vessel. Then the aortic cannula is introduced into the vessel, sliding along the guidewire. Guided by transesophageal echocardiography, the tip of the cannula is positioned carefully and is then advanced into the descending aorta. This positioning of the cannula decreases the chance of arterial embolization, thereby improving cerebral protection. If cannulation of the ascending aorta is not feasible, the transverse aortic arch or proximal descending aorta can be used.


Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain.
Pain is one of the most severe and debilitating symptoms associated with several forms of cancer. Various types of carcinomas and sarcomas metastasize to skeletal bones and cause spontaneous bone pain and hyperalgesia, which is accompanied by bone degradation and remodeling of peripheral nerves. Despite recent advances, the molecular mechanisms underlying the development and maintenance of cancer-evoked pain are not well understood. Several types of non-hematopoietic tumors secrete hematopoietic colony-stimulating factors that act on myeloid cells and tumor cells. Here we report that receptors and signaling mediators of granulocyte- and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF) are also functionally expressed on sensory nerves. GM-CSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP release and caused sprouting of sensory nerve endings in the skin. Interruption of G-CSF and GM-CSF signaling in vivo led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain. The key significance of GM-CSF signaling in sensory neurons was revealed by an attenuation of tumor-evoked pain following a sensory nerve-specific knockdown of GM-CSF receptors. These results show that G-CSF and GM-CSF are important in tumor-nerve interactions and suggest that their receptors on primary afferent nerve fibers constitute potential therapeutic targets in cancer pain.


Organizing community research partnerships in the struggle against AIDS.
Despite pharmaceutical advances, AIDS remains a health problem difficult to treat, leaving preventive interventions as the primary means of promoting risk avoidance. Increasing the capacity of university-based researchers to develop culturally, developmentally, and contextually appropriate AIDS prevention strategies requires the collaboration of community service and advocacy partners. To date, neither university researchers nor community providers have a great deal of partnership experience. Thus, a common language and set of experiences are yet to be developed. This article reviews the history of university-community and researcher-community collaboration for AIDS research and intervention, placing the innovative work of the University of California, San Francisco (UCSF) Center for AIDS Prevention Studies and its community and foundation partnerships among those efforts at the forefront of the community-university dialogue. It concludes with suggestions derived from the collaborative work of UCSF researchers and community service partners to strengthen efforts to develop theory, research methods, and results that are immediately useful and productive of long-term prevention research efforts.


Investigation on an application of silver substrates for sensitive surface plasmon resonance imaging detection.
A surface plasmon resonance (SPR) imaging biosensor based on silver substrates was investigated to demonstrate that silver could be used as a substrate material for sensitive detection of biomolecular interactions, despite its poor chemical stability. The calculation results showed that oxidation of silver film may lead to a decrease in the sensitivity due to a variation in SPR characteristics such as a broader curve width and shallower minimum reflectance at resonance. The effect of a change in the refractive index of target analytes on the sensitivity was also explored. In particular, it is noteworthy that Ag/Au bimetallic substrates with a thin gold protection layer to prevent oxidation of a silver film can provide a significant amplification of SPR imaging signals in comparison with conventional gold substrates.


Circulating betatrophin levels are increased in patients with type 2 diabetes and associated with insulin resistance.
Betatrophin has recently attracted increasing interests as a potential β-cell regenerative therapy in diabetes. However, differences in betatrophin profiles in patients with type 2 diabetes mellitus (T2DM) remain unclear. The objective of the study was to examine circulating betatrophin levels in subjects with different glucose tolerance status and its correlation with insulin resistance. Serum betatrophin levels were measured using an ELISA in age-, sex-, body mass index-, and blood lipid-matched subjects with normal glucose tolerance (n = 137), isolated impaired fasting glucose (n = 69), isolated impaired glucose tolerance (n = 120), and newly diagnosed T2DM (n = 112) from the Risk Evaluation of Cancers in Chinese Diabetic Individuals: A Longitudinal study. Serum betatrophin levels were elevated in patients with T2DM compared with subjects with normal glucose tolerance, isolated impaired fasting glucose, or isolated impaired glucose tolerance (798.6 ± 42.5 vs 692.7 ± 29.0, P < .05, vs 682.7 ± 43.0, P < .05, vs 646.8 ± 34.3 pg/mL, P < .01). Betatrophin levels positively correlated with the index of homeostasis model assessment of insulin resistance (partial r = 0.11); inversely correlated with quantitative insulin sensitivity check index (partial r = -0.11), the Gutt insulin sensitivity index (partial r = -0.12), and the Matsuda insulin sensitivity index (partial r = -0.11) after controlling for age, sex, body mass index, and blood lipid in all participants (all values of P < .05). Circulating betatrophin levels are increased in patients with T2DM and associated with indexes of insulin resistance.


Broad sarbecovirus neutralizing antibodies define a key site of vulnerability on the SARS-CoV-2 spike protein.
Broadly protective vaccines against known and pre-emergent coronaviruses are urgently needed. Critical to their development is a deeper understanding of cross-neutralizing antibody responses induced by natural human coronavirus (HCoV) infections. Here, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a new target for the rational design of pan-sarbecovirus vaccines.


Dissecting abdominal aortic aneurysm in Angiotensin II-infused mice: the importance of imaging.
Since the initial publication in 2000, Angiotensin II-infused mice have become one of the most popular models to study abdominal aortic aneurysm in a pre-clinical setting. We recently used phase contrast X-ray based computed tomography to demonstrate that these animals develop an apparent luminal dilatation and an intramural hematoma, both related to mural ruptures in the tunica media in the vicinity of suprarenal side branches. The aim of this narrative review was to provide an extensive overview of small animal applicable techniques that have provided relevant insight into the pathogenesis and morphology of dissecting AAA in mice, and to relate findings from these techniques to each other and to our recent PCXTM-based results. Combining insights from recent and consolidated publications we aimed to enhance our understanding of dissecting AAA morphology and anatomy. We analyzed in vivo and ex vivo images of aortas obtained from macroscopic anatomy, histology, high-frequency ultrasound, contrast-enhanced micro-CT, micro-MRI and PCXTM. We demonstrate how in almost all publications the aorta has been subdivided into a part in which an intact lumen lies adjacent to a remodeled wall/hematoma, and a part in which elastic lamellae are ruptured and the lumen appears to be dilated. We show how the novel paradigm fits within the existing one, and how 3D images can explain and connect previously published 2D structures. We conclude that PCXTM-based findings are in line with previous results, and all evidence points towards the fact that dissecting AAAs in Angiotensin II-infused mice are actually caused by ruptures of the tunica media in the immediate vicinity of small side branches.


Evaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites.
Mosquito-borne viruses are a growing global threat. Initial viral inoculation occurs in the skin via the mosquito 'bite', eliciting immune responses that shape the establishment of infection and pathogenesis. Here we assess the cutaneous innate and adaptive immune responses to controlled Aedes aegypti feedings in humans living in Aedes-endemic areas. In this single-arm, cross-sectional interventional study (trial registration #NCT04350905), we enroll 30 healthy adult participants aged 18 to 45 years of age from Cambodia between October 2020 and January 2021. We perform 3-mm skin biopsies at baseline as well as 30 min, 4 h, and 48 h after a controlled feeding by uninfected Aedes aegypti mosquitos. The primary endpoints are measurement of changes in early and late innate responses in bitten vs unbitten skin by gene expression profiling, immunophenotyping, and cytokine profiling. The results reveal induction of neutrophil degranulation and recruitment of skin-resident dendritic cells and M2 macrophages. As the immune reaction progresses T cell priming and regulatory pathways are upregulated along with a shift to Th2-driven responses and CD8+ T cell activation. Stimulation of participants' bitten skin cells with Aedes aegypti salivary gland extract results in reduced pro-inflammatory cytokine production. These results identify key immune genes, cell types, and pathways in the human response to mosquito bites and can be leveraged to inform and develop novel therapeutics and vector-targeted vaccine candidates to interfere with vector-mediated disease.


Recommendations for burns care in mass casualty incidents: WHO Emergency Medical Teams Technical Working Group on Burns (WHO TWGB) 2017-2020.
Health and logistical needs in emergencies have been well recognised. The last 7 years has witnessed improved professionalisation and standardisation of care for disaster affected communities - led in part by the World Health Organisation Emergency Medical Team (EMT) initiative. Mass casualty incidents (MCIs) resulting in burn injuries present unique challenges. Burn management benefits from specialist skills, expert knowledge, and timely availability of specialist resources. With burn MCIs occurring globally, and wide variance in existing burn care capacity, the need to strengthen burn care capability is evident. Although some high-income countries have well-established disaster management plans, including burn specific plans, many do not - the majority of countries where burn mass casualty events occur are without such established plans. Developing globally relevant recommendations is a first step in addressing this deficit and increasing preparedness to deal with such disasters. Global burn experts were invited to a succession of Technical Working Group on burns (TWGB) meetings to: 1) review literature on burn care in MCIs; and 2) define and agree on recommendations for burn care in MCIs. The resulting 22 recommendations provide a framework to guide national and international specialist burn teams and health facilities to support delivery of safe care and improved outcomes to burn patients in MCIs.


Crises and Resilience at the Frontline-Public Health Facility Managers under Devolution in a Sub-County on the Kenyan Coast.
Public primary health care (PHC) facilities are for many individuals the first point of contact with the formal health care system. These facilities are managed by professional nurses or clinical officers who are recognised to play a key role in implementing health sector reforms and facilitating initiatives aimed at strengthening community involvement. Little in-depth research exists about the dimensions and challenges of these managers' jobs, or on the impact of decentralisation on their roles and responsibilities. In this paper, we describe the roles and responsibilities of PHC managers-or 'in-charges' in Kenya, and their challenges and coping strategies, under accelerated devolution. The data presented in this paper is part of a wider set of activities aimed at understanding governance changes under devolution in Kenya, under the umbrella of a 'learning site'. A learning site is a long term process of collaboration between health managers and researchers deciding together on key health system questions and interventions. Data were collected through seven formal in depth interviews and observations at four PHC facilities as well as eight in depth interviews and informal interactions with sub-county managers from June 2013 to July 2014. Drawing on the Aragon framework of organisation capacity we discuss the multiple accountabilities, daily routines, challenges and coping strategies among PHC facility managers. PHC in-charges perform complex and diverse roles in a difficult environment with relatively little formal preparation. Their key concerns are lack of job clarity and preparedness, the difficulty of balancing multidirectional accountability responsibilities amidst significant resource shortages, and remuneration anxieties. We show that day-to-day management in an environment of resource constraints and uncertainty requires PHC in-charges who are resilient, reflective, and continuously able to learn and adapt. We highlight the importance of leadership development including the building of critical soft skills such as relationship building.


ON A METHOD OF ISOLATING AND IDENTIFYING BACILLUS TYPHOSUS, BASED ON A STUDY OF BACILLUS TYPHOSUS AND MEMBERS OF THE COLON GROUP IN SEMI-SOLID CULTURE MEDIA.
Semi-solid culture media, and more especially media rendered semi-solid by temperatures of from 30 degrees to 40 degrees C., seem to have an important bearing in the differentiation of bacterial species, particularly those presenting various degrees of motility. In such media not only the effect of differences in consistence on the motility of an organism may be noted, but the effect produced by various chemicals and nutrient ingredients on the growth and motility may be readily observed. By systematically varying the constituents of such media it has been possible to produce a medium in which the behavior of Bacillus typhosus differentiates it from the various members of the colon group; and also to produce a medium in which the colonies of Bacillus typhosus assume a form which distinguishes them from the colonies of the colon bacilli in plate cultures. Bacillus typhosus alone of all the organisms investigated during these experiments has displayed both the power of giving rise to thread-forming colonies in the plating medium and that of the uniform clouding of the tube medium, hence these two characters may prove to be of great value in the identification of this organism. The practical application of the use of these media has led to the ready detection of Bacillus typhosus and its isolation from the stools of patients suffering from typhoid fever. No suspected water has been subjected to test, but from the investigation of artificially infected tap-water the media here described may be assumed to have an application in the detection of Bacillus typhosus in such waters.


O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells.
Metabolic disruptions that occur widely in cancers offer an attractive focus for generalized treatment strategies. The hexosamine biosynthetic pathway (HBP) senses metabolic status and produces an essential substrate for O-linked β-N-acetylglucosamine transferase (OGT), which glycosylates and thereby modulates the function of its target proteins. Here, we report that the HBP is activated in prostate cancer cells and that OGT is a central regulator of c-Myc stability in this setting. HBP genes were overexpressed in human prostate cancers and androgen regulated in cultured human cancer cell lines. Immunohistochemical analysis of human specimens (n = 1987) established that OGT is upregulated at the protein level and that its expression correlates with high Gleason score, pT and pN stages, and biochemical recurrence. RNA interference-mediated siliencing or pharmacologic inhibition of OGT was sufficient to decrease prostate cancer cell growth. Microarray profiling showed that the principal effects of OGT inhibition in prostate cancer cells were related to cell-cycle progression and DNA replication. In particular, c-MYC was identified as a candidate upstream regulator of OGT target genes and OGT inhibition elicited a dose-dependent decrease in the levels of c-MYC protein but not c-MYC mRNA in cell lines. Supporting this relationship, expression of c-MYC and OGT was tightly correlated in human prostate cancer samples (n = 1306). Our findings identify HBP as a modulator of prostate cancer growth and c-MYC as a key target of OGT function in prostate cancer cells.


Massive true thymic hyperplasia in a 3-month-old infant: case report and literature review.
True thymic hyperplasia (TTH) is characterized as a distinct increase in both size and weight of thymus, which retains normal microscopic and immunohistochemical appearances. Massive true thymic hyperplasia (MTTH) is an extremely rare but significant subtype of TTH in pediatric ages due to its potentially serious consequences. It was reported that the age of cases with MTTH was predominantly between 1 and 15 years, while those before 1 year rarely occurred. By presenting the diagnosis and treatment process of our case as well as reviewing the related literature, we aimed to analyze the clinical characteristics of MTTH for patients younger than 1 year. A 3-month-old male infant was admitted to our department with a chief complaint of gradually increasing polypnea over 9 days, whose preoperative imaging examination showed a large intrathoracic soft tissue shadow predominantly on the right side. The percutaneous fine-needle biopsy guided by ultrasonography was performed to identify its diagnosis. However, proliferating lymphocytes and Hassall`s corpuscles were seen microscopically in the biopsy tissues, which were immunohistochemically positive for CD3, CD19, CD20, CD99, TdT, PCK and Ki67 ( > 90%). Due to the aggravating symptoms, a second operation with total thymectomy was carried out successfully for this infant, which confirmed the diagnosis of TTH again by both morphological study and immunohistochemical staining from the surgical specimen. By reviewing the literature, there were only 10 cases with MTTH reported between 1975 and 2020 for children aged < 1 year of life, together with our present one. In MTTH patient`s sex had an obviously male predominance (70%). Nine out of 10 presented initial symptoms or signs related to respiratory system and 6 patients showed respiratory distress. All patients were successfully treated by surgical thymectomy without any postoperative complications. The prognosis of MTTH was very successful.


Modeling HIV infection and therapies in humanized mice.
The human immunodeficiency virus (HIV) type-1 is a human-specific virus. The lack of a widely available small-animal model has seriously hampered HIV research. In 2004, a new humanised mouse model was reported. It was based on the intrahepatic injection of human CD34+ cord blood cells into newborn, highly immunodeficient mice. These mice develop a lymphoid system of human origin and are highly susceptible to HIV infection and showed disseminated infection, persistent viraemia and characteristic helper CD4+ T-cell loss. Here, we will briefly review the various existing humanised mouse models and highlight their value to the study of HIV infection.


COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency.
Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.


Clinical research about airway pressure release ventilation for moderate to severe acute respiratory distress syndrome.
To evaluate clinical effects of airway pressure release ventilation (APRV) in patients suffering from moderate to severe acute respiratory distress syndrome (ARDS).e of a patient presented with significant high aminotransferase levels due to the first human R. aeschlimannii infection ever detected in Italy. The hypothesis of rickettsiosis was made on the basis of a comprehensive medical history and was confirmed by serological tests. Molecular analyses made on a sample of hepatic tissue revealed the presence of a rickettsial species never found before in human liver. From August 2012 to August 2014, fifty-two cases with moderate to severe ARDS were randomly divided into two groups. In the first group (APRV) the airway pressure release ventilation was used; the second group (SIMV) was ventilated using synchronized intermittent mandatory ventilation mode and positive end expiratory pressure (PEEP). Changes in oxygenation index, respiratory mechanics, extravascular lung water, functional residual capacity change and hemodynamics were recorded in both groups after mechanical ventilation. TNF-a and IL-10 levels in alveolar lavage were also measured. Acute physiology and chronic health evaluation (APACHE) II and Murray scores were evaluated. Pneumothorax and mediastinal emphysema during ventilation were also recorded. The probability of survival, the duration of ICU stay, days without organ failure and days without sedation were compared. Conditions in APRV were improved significantly. Oxygenation index was increased, airway peak pressure (Ppeak) was reduced, the lung dynamic compliance improved, extravascular lung water was relieved, functional residual capacity increased and Murray score was improved. In APRV group ventilation central venous pressure (CVP) and systemic circulation resistance index (SVRI) were reduced, but cardiac index (CI) increased, and at the same time lac and oxygen saturation of central venous blood (ScvO2) were improved. Free sedatives days were significantly reduced in APRV group while days without mechanical ventilation were increased and days in ICU were shortened significantly. TNF-α and IL-10 concentrations in the alveolar lavage, probability of survival and days without organ failure were similar in both groups. In patients suffering from moderate to severe ARDS, application of APRV improved lung function and hemodynamics. It also reduced the need for sedatives and the duration of mechanical ventilation as well as days in ICU.


Neural Patterns of the Implicit Association Test.
The Implicit Association Test (IAT) is a reaction time based categorization task that measures the differential associative strength between bipolar targets and evaluative attribute concepts as an approach to indexing implicit beliefs or biases. An open question exists as to what exactly the IAT measures, and here EEG (Electroencephalography) has been used to investigate the time course of ERPs (Event-related Potential) indices and implicated brain regions in the IAT. IAT-EEG research identifies a number of early (250-450 ms) negative ERPs indexing early-(pre-response) processing stages of the IAT. ERP activity in this time range is known to index processes related to cognitive control and semantic processing. A central focus of these efforts has been to use IAT-ERPs to delineate the implicit and explicit factors contributing to measured IAT effects. Increasing evidence indicates that cognitive control (and related top-down modulation of attention/perceptual processing) may be components in the effective measurement of IAT effects, as factors such as physical setting or task instruction can change an IAT measurement. In this study we further implicate the role of proactive cognitive control and top-down modulation of attention/perceptual processing in the IAT-EEG. We find statistically significant relationships between D-score (a reaction-time based measure of the IAT-effect) and early ERP-time windows, indicating where more rapid word categorizations driving the IAT effect are present, they are at least partly explainable by neural activity not significantly correlated with the IAT measurement itself. Using LORETA, we identify a number of brain regions driving these ERP-IAT relationships notably involving left-temporal, insular, cingulate, medial frontal and parietal cortex in time regions corresponding to the N2- and P3-related activity. The identified brain regions involved with reduced reaction times on congruent blocks coincide with those of previous studies.


Effects of integrated child development and nutrition interventions on child development and nutritional status.
We conducted a systematic review of studies that examined the effect of interventions combining a child development component with a nutrition one; in some cases the nutrition interventions also included health-promotion components. Only papers with both child development and nutrition outcomes and rated as moderate-to-good quality were included. Eleven efficacy and two nonrandomized trials, and eight program evaluations were identified. Only six trials examined interventions separately and combined. The trials showed nutritional interventions usually benefited nutritional status and sometimes benefited child development. Stimulation consistently benefited child development. There was no significant loss of any effect when interventions were combined, but there was little evidence of synergistic interaction between nutrition and stimulation on child development. Only three trials followed up the children after intervention. All at-scale program evaluations were combined interventions. Five benefited child development, but one did not, and two showed deficits. There was generally little benefit of at-scale programs to nutritional status. We found no rigorous evaluations of adding stimulation to health and nutrition services at scale and there is an urgent need for them. There is also a need to establish quality-control mechanisms for existing scaled-up programs and to determine their long-term effects. There is also a need to determine if there are any sustained benefits for the children after programs finish.


A Potential Role for Photobiomodulation Therapy in Disease Treatment and Prevention in the Era of COVID-19.
COVID-19 is an evolving pandemic that has far reaching global effects, with a combination of factors that makes the virus difficult to contain. The symptoms of infection can be devastating or at the least very debilitating for vulnerable individuals. It is clear that the elderly are at most risk of the adverse impacts of the virus, including hospitalization and death. Others at risk are those with comorbidities such as cardiovascular disease and metabolic conditions and those with a hyper-excitable immune response. Treatment options for those with acute responses to the virus are limited and there is an urgent need for potential strategies that can mitigate these severe effects. One potential avenue for treatment that has not been explored is the microbiome gut/lung axis. In addition to those severely affected by their acute reaction to the virus, there is also a need for treatment options for those that are slow to recover from the effects of the infection and also those who have been adversely affected by the measures put in place to arrest the spread of the virus. One potential treatment option is photobiomodulation (PBM) therapy. PBM has been shown over many years to be a safe, effective, non-invasive and easily deployed adjunctive treatment option for inflammatory conditions, pain, tissue healing and cellular energy. We have also recently demonstrated the effectiveness of PBM to alter the gut microbiome. PBM therapy is worthy of consideration as a potential treatment for those most vulnerable to COVID-19, such as the elderly and those with comorbidities. The treatment may potentially be advantageous for those infected with the virus, those who have a slow recovery from the effects of the virus and those who have been denied their normal exercise/rehabilitation programs due to the isolation restrictions that have been imposed to control the COVID-19 pandemic.


Plasmid-determined cytotoxicity in Yersinia pestis and Yersinia pseudotuberculosis.
Yersinia pestis KIM5 was found to be cytotoxic for the IC21 and P388D1 mouse macrophage cell lines, as well as for resident peritoneal macrophages from C57BL/6 mice. Affected cells phagocytosed KIM5 inefficiently, became spherical, detached readily from culture dishes, and retained 51Cr poorly. The cytotoxic effect was dependent on the presence of the 75-kilobase plasmid pCD1. Because this plasmid also encodes the low calcium response (LCR), three Mu d1 insertion mutants previously shown to be LCR- and of reduced virulence in mice were examined for cytotoxicity; all were found to be atoxic. The insertions in these mutants lie within three distinct LCR loci (lcrB, C, and D). Like LCR, cytotoxicity was expressed only at 37 degrees C. Unlike LCR, it was not influenced by Ca2+ concentration, indicating that the V and W antigens are probably not involved. Yersinia pseudotuberculosis was found to have a similar plasmid-dependent cytotoxicity. Thus, biological activity observed as cytotoxicity in vitro may well be a common feature contributing to virulence of the yersiniae.


Variation in Prenatal Diagnosis of Congenital Heart Disease in Infants.
Prenatal diagnosis allows improved perioperative outcomes for fetuses with certain forms of congenital heart disease (CHD). Variability in prenatal diagnosis has been demonstrated in other countries, leading to efforts to improve fetal imaging protocols and access to care, but has not been examined across the United States. The objective was to evaluate national variation in prenatal detection across geographic region and defect type in neonates and infants with CHD undergoing heart surgery. Cardiovascular operations performed in patients ≤6 months of age in the United States and included in the Society of Thoracic Surgeons Congenital Heart Surgery Database (2006-2012) were eligible for inclusion. Centers with >15% missing prenatal diagnosis data were excluded from the study. Prenatal diagnosis rates were compared across geographic location of residence and defect type using the χ(2) test. Overall, the study included 31,374 patients from 91 Society of Thoracic Surgeons Congenital Heart Surgery Database participating centers across the United States. Prenatal detection occurred in 34% and increased every year, from 26% (2006) to 42% (2012). There was significant geographic variation in rates of prenatal diagnosis across states (range 11.8%-53.4%, P < .0001). Significant variability by defect type was also observed, with higher rates for lesions identifiable on 4-chamber view than for those requiring outflow tract visualization (57% vs 32%, P < .0001). Rates of prenatal CHD detection in the United States remain low for patients undergoing surgical intervention, with significant variability between states and across defect type. Additional studies are needed to identify reasons for this variation and the potential impact on patient outcomes.


Association models for binding of molecules to nanostructures.
The interaction between nanoparticles and molecules plays a key role in determining the activity and performance of a given nanostructure. These interactions are pivotal for a variety of applications including drug delivery, surface manipulation for targeted therapies, and catalysis. However, to this day, gathering precise association parameters for the interaction of the molecules with nanostructures remains elusive and mostly imprecise. In this review, we present a critical discussion of the most commonly used techniques and models intended for determining the association of molecules with nanoparticles. Particular emphasis has been put on discussing the limitations and pitfalls related to determining association constants in this tutorial review.


Determinants of uterine rupture among cases of Adama city public and private hospitals, Oromia, Ethiopia: a case control study.
Ethiopia is among the ten world countries with highest maternal death rates that accounts for more than 59% of global maternal deaths. Uterine rupture is one of the dangerous obstetric problems with high potential of causing maternal and neonatal morbidity and mortality. The case fatality rate of uterine rupture is high and hence identifying factors associated with uterine rupture remains important to guide decision makers and practitioners. The study aimed to identify factors associated with uterine rupture among clients managed in Adama city public and private hospitals during January 2011 to December, 2015. Unmatched case control study design was employed. The sample size was determined using computer software considering the basic statistical assumptions and accordingly a total of 432 women, (144 with uterine rupture as cases and 288 with spontaneous vaginal delivery as controls) managed in all hospitals during the study period were included in the study. A data collection tool that contains available variables was designed and used to extract data from log books and client cards. Data were entered into EPI-Info-7 and exported to Stata-12 for cleaning and analysis. The study participants were characterized using descriptive statistics. The associations between uterine rupture and independent variables were modeled using binary logistic regression analysis. The association between independent variables and uterine rupture was estimated using odds ratio with 95% confidence intervals. The statistical significance of the association was declared at P-value < 0.05. The odds of having a uterine rupture were found to be more than six times higher among rural residents (AOR = 6.29; 95% CI: 3.39, 11.66) compared to urban. Other independent predictors include gravidity of five or more (AOR = 27.89; 95% CI: 8.42, 92.34), having a history of cesarean section scar (AOR = 9.94; 95% CI: 3.39, 11.66) and not having an antenatal care visit (AOR = 9.64; 95% CI: 4.37, 21.29). Rural residence, multigravidas, cesarean section scar and not having an antenatal care visit were independent predictors of uterine rupture in the current study. Therefore, improving access and strengthening essential obstetric care, antenatal and family planning services with complete packages are crucial interventions in the reduction of the odds of having uterine rupture. In addition, the strengthening of the referral system is mandatory for women residing in rural areas.


Phenotypic diversity of natural killer (NK) populations in patients with NK-type lymphoproliferative disease of granular lymphocytes.
Using monoclonal antibodies (MoAbs) termed GL183 and EB6, directed to a novel family of natural killer (NK) specific triggering molecules, four functional subsets of NK cells have been recently defined (GL183+EB6-; GL183+EB6+; GL183-EB6+; GL183-EB6-). In healthy individuals, all these subsets are represented in variable portion. The expression of EB6 and GL183 surface antigens has been analyzed in a series of 14 patients with lymphoproliferative disease of granular lymphocytes (LDGL) characterized by a chronic CD3-CD16+ lymphocytosis. Our data showed that in 11 of 14 cases, the proliferation was specifically sustained by one of the four possible subsets of granular lymphocytes (GLs) (seven cases: EB6-GL183-; three cases: EB6+GL183-; one case: EB6-GL183+). In the remaining three cases, a pattern was demonstrated that is consistent with that of healthy individuals (ie, the presence of all four subsets). When expressed on GL surfaces, in the majority of cases tested both EB6 and GL183 MoAbs behave as functional surface molecules as assessed in the redirected killing of P815 target cells. We also provided evidence that EB6+GL183+ proliferating cells show a definite (type 1) in vitro NK specificity as do their normal counterparts. The unique expansion of a defined subset of NK cells in most patients with LDGL suggests that the pathologic noxa leading to GL proliferation selectively acts on a specific subset of NK lymphocytes.


Pulmonary artery catheter versus pulse contour analysis: a prospective epidemiological study.
The choice of invasive systemic haemodynamic monitoring in critically ill patients remains controversial as no multicentre comparative clinical data exist. Accordingly, we sought to study and compare the features and outcomes of patients who receive haemodynamic monitoring with either the pulmonary artery catheter (PAC) or pulse contour cardiac output (PiCCO) technology. We conducted a prospective multicentre, multinational epidemiological study in a cohort of 331 critically ill patients who received haemodynamic monitoring by PAC or PiCCO according to physician preference in intensive care units (ICUs) of eight hospitals in four countries. We collected data on haemodynamics, demographic features, daily fluid balance, mechanical ventilation days, ICU days, hospital days, and hospital mortality. We statistically compared the two techniques. Three hundred and forty-two catheters (PiCCO 192 and PAC 150) were inserted in 331 patients. On direct comparison, patients with PAC were older (68 versus 64 years of age; p = 0.0037), were given inotropic drugs more frequently (37.3% versus 13%; p < 0.0001), and had a lower cardiac index (2.6 versus 3.2 litres/minute per square meter; p < 0.0001). Mean daily fluid balance was significantly greater during PiCCO monitoring (+659 versus +350 ml/day; p = 0.017) and mechanical ventilation-free days were fewer (12 for PiCCO versus 21 for PAC; p = 0.045). However, after multiple regression analysis, we found no significant effect of monitoring technique on mean daily fluid balance, mechanical ventilation-free days, ICU-free days, or hospital mortality. A secondary multiple logistic regression analysis for hospital mortality which included mean daily fluid balance showed that positive fluid balance was a significant predictor of hospital mortality (odds ratio = 1.0002 for each ml/day; p = 0.0073). On direct comparison, the use of PiCCO was associated with a greater positive fluid balance and fewer ventilator-free days. After correction for confounding factors, the choice of monitoring did not influence major outcomes, whereas a positive fluid balance was a significant independent predictor of outcome. Future studies may best be targeted at understanding the effect of pursuing different fluid balance regimens rather than monitoring techniques per se.


High resolution mapping of enhancer-promoter interactions.
RNA Polymerase II ChIA-PET data has revealed enhancers that are active in a profiled cell type and the genes that the enhancers regulate through chromatin interactions. The most commonly used computational method for analyzing ChIA-PET data, the ChIA-PET Tool, discovers interaction anchors at a spatial resolution that is insufficient to accurately identify individual enhancers. We introduce Germ, a computational method that estimates the likelihood that any two narrowly defined genomic locations are jointly occupied by RNA Polymerase II. Germ takes a blind deconvolution approach to simultaneously estimate the likelihood of RNA Polymerase II occupation as well as a model of the arrangement of read alignments relative to locations occupied by RNA Polymerase II. Both types of information are utilized to estimate the likelihood that RNA Polymerase II jointly occupies any two genomic locations. We apply Germ to RNA Polymerase II ChIA-PET data from embryonic stem cells to identify the genomic locations that are jointly occupied along with transcription start sites. We show that these genomic locations align more closely with features of active enhancers measured by ChIP-Seq than the locations identified using the ChIA-PET Tool. We also apply Germ to RNA Polymerase II ChIA-PET data from motor neuron progenitors. Based on the Germ results, we observe that a combination of cell type specific and cell type independent regulatory interactions are utilized by cells to regulate gene expression.


Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options.
The immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients initiating antiretroviral therapy (ART) results from restored immunity to specific infectious or non-infectious antigens. A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating therapy characterizes the syndrome. Potential mechanisms for the syndrome include a partial recovery of the immune system or exuberant host immunological responses to antigenic stimuli. The overall incidence of IRIS is unknown, but is dependent on the population studied and its underlying opportunistic infectious burden. The infectious pathogens most frequently implicated in the syndrome are mycobacteria, varicella zoster, herpesviruses, and cytomegalovirus (CMV). No single treatment option exists and depends on the underlying infectious agent and its clinical presentation. Prospective cohort studies addressing the optimal screening and treatment of opportunistic infections in patients eligible for ART are currently being conducted. These studies will provide evidence for the development of treatment guidelines in order to reduce the burden of IRIS. We review the available literature on the pathogenesis and epidemiology of IRIS, and present treatment options for the more common infectious manifestations of this diverse syndrome and for manifestations associated with a high morbidity.


Life-course observations of alcohol use among Navajo Indians: natural history or careers?
In this article, I describe changes in patterns of alcohol use and abuse among Navajo Indians from the mid-1960s to the late 1990s. The prevalence of alcohol dependence continues to be higher than in the general U.S. population, but remission is also common, as it was in the 1960s and previously. Men have substantially higher rates of alcohol dependence than women. The former engage in heavy drinking largely in response to the heavy drinking of those around them. The latter drink excessively largely as a response to psychiatric disorders, depression, and abuse by a partner or husband. As increasing numbers of people have moved to reservation and border towns, a youth culture has developed in which alcohol use is initiated by teenagers with their peers rather than, as in the past, with older kinsmen. Alcohol use has thus been freed from the constraints imposed by both isolation and family obligations.


Effect of Nigella sativa Seed Extract for Hypertension in Elderly: a Double-blind, Randomized Controlled Trial.
Nigella sativa (NS) seed extract shows diuretic activity, inhibits sympathetic nervous system overactivity and increases the production of Nitric Oxide in in vivo studies, thus it has a potential use as an adjuvant antihypertensive for elderly population. This study aimed to determine the effect of Nigella sativa seed extract to systolic blood pressure (SBP) and diastolic blood pressure (DBP) of elderly patients with hypertension. a double-blind, randomized controlled trial was conducted on elderly subjects with hypertension in three outpatient clinics in Cipto Mangunkusumo National Hospital Jakarta Indonesia from June to September 2011. Subjects were divided into intervention group given 300 mg Nigella sativa seed extract twice daily for 28 days and into another group which was given placebo. Blood pressure were measured on day 1 and 28. Intention to treat analysis using unpaired t-test to compare blood pressure after intervention between the two groups was performed. of a total of 85 patients, 76 subjects fulfilled the study criteria and were randomized into 2 groups, with 38 subjects in each group. Both groups were comparable in all important prognostic factors. The mean systolic blood pressure of the NS group was decreased from 160.4 (SD 15.7) mmHg to 145.8 (SD 19.8) mmHg, and from 160.9 (16.3) mmHg to 147.53 (SD 22.0) mmHg in the placebo group (p=0.36). The mean diastolic blood pressure in the NS group was decreased from 78.3 (SD 11.9) to 74.4 (SD 8.2) mmHg, and from 79.0 (SD 12.4) to 78.2 (SD 8.9) in the placebo group (p=0.35). Reported adverse events include dyspepsia in 6 subjects (15.7%), nausea in 3 subjects (7.8%), and constipation in 2 subjects (5.2%). No electrolyte abnormalities, liver and renal toxicities, or orthostatic hypotension were observed. although a trend towards a slight decrease in blood pressure was observed, Nigella sativa has not been proven to be effective in reducing blood pressure in elderly patients with hypertension.


Determining the potential benefits of yoga in chronic stroke care: a systematic review and meta-analysis.
Survivors of stroke have long-term physical and psychological consequences that impact their quality of life. Few interventions are available in the community to address these problems. Yoga, a type of mindfulness-based intervention, is shown to be effective in people with other chronic illnesses and may have the potential to address many of the problems reported by survivors of stroke. To date only narrative reviews have been published. We sought to perform, the first systematic review with meta-analyses of randomized controlled trials (RCTs) that investigated yoga for its potential benefit for chronic survivors of stroke. Ovid Medline, CINHAL plus, AMED, PubMed, PsychINFO, PeDro, Cochrane database, Sport Discuss, and Google Scholar were searched for papers published between January 1950 and August 2016. Reference lists of included papers, review articles and OpenGrey for Grey literature were also searched. We used a modified Cochrane tool to evaluate risk of bias. The methodological quality of RCTs was assessed using the GRADE approach, results were collated, and random effects meta-analyses performed where appropriate. The search yielded five eligible papers from four RCTs with small sample sizes (n = 17-47). Quality of RCTs was rated as low to moderate. Yoga is beneficial in reducing state anxiety symptoms and depression in the intervention group compared to the control group (mean differences for state anxiety 6.05, 95% CI:-0.02 to 12.12; p = 0.05 and standardized mean differences for depression: 0.50, 95% CI:-0.01 to 1.02; p = 0.05). Consistent but nonsignificant improvements were demonstrated for balance, trait anxiety, and overall quality of life. Yoga may be effective for ameliorating some of the long-term consequences of stroke. Large well-designed RCTs are needed to confirm these findings.


Efficacy of risedronate against hip fracture in patients with neurological diseases: a meta-analysis of randomized controlled trials.
Neurological diseases, including Alzheimer's disease, stroke, and Parkinson's disease have been reported to increase the risk for fractures. The purpose of the present study was to clarify the efficacy of risedronate against hip fracture in patients with neurological diseases. The literature was searched with PubMed from 1995 to the present, with respect to strictly conducted randomized controlled trials (RCTs) with narrow confidence intervals (CIs), and a meta-analysis was conducted. Four RCTs met the criteria; one RCT for Alzheimer's disease (n = 461, mean age = 78 years), two RCTs for stroke (n = 267, mean age = 76 years for men; n = 345, mean age = 71 years for women), and one RCT for Parkinson's disease (n = 223, mean age = 71 years). According to the results of RCTs, the relative risks (95% CI) for hip fracture with risedronate treatment compared with placebo treatment were 0.26 (0.10, 0.69) for Alzheimer's disease, 0.20 (0.04, 0.89) for stroke in men, 0.14 (0.02, 1.16) for stroke in women, and 0.34 (0.09, 1.21) for Parkinson's disease. Overall, the relative risk (95% CI) for hip fracture with risedronate treatment was 0.25 (0.13, 0.48), suggesting 75% of risk reduction rate with risedronate treatment in patients with one of the three neurological diseases (heterogeneity: 0.58, p = 0.9016 and overall effect: 17.36, p < 0.0001). No severe adverse events were reported in the risedronate and placebo groups. The results of a meta-analysis of strictly conducted RCTs suggest that there is efficacy against hip fracture and safety with risedronate treatment in patients with neurological diseases including Alzheimer's disease, stroke, and Parkinson's disease.


Identification of Ginkgo biloba as a novel activator of pregnane X receptor.
Pregnane X receptor (PXR; NR1I2) is a ligand-activated transcription factor that plays a role not only in drug metabolism and transport but also in various other biological processes. Ginkgo biloba is a herbal medicine commonly used to manage memory impairment. Treatment of primary cultures of rat hepatocytes with G. biloba extract increases the mRNA expression of CYP3A23, which is a target gene for rat PXR. The present study was conducted to test the hypothesis that G. biloba extract activates PXR. Treatment of mouse PXR (mPXR) or human PXR (hPXR)-transfected HepG2 cells with G. biloba extract at 200 microg/ml increased mPXR and hPXR activation by 3.2- and 9.5-fold, respectively. Dose-response analysis showed a log-linear increase in hPXR activation by the extract over the range of 200 to 800 microg/ml. To determine whether G. biloba extract induces hPXR target gene expression, cultured LS180 human colon adenocarcinoma cells were treated for 72 h with the extract. G. biloba extract at 200, 400, and 800 microg/ml increased CYP3A4 mRNA expression by 1.7-, 2.4-, and 2.5-fold, respectively. The same concentrations of the extract increased CYP3A5 (1.3-3.6-fold) and P-glycoprotein (ABCB) 1 (2.7-6.4-fold) mRNA expression. At concentrations (5 and 10 microM) that did not down-regulate PXR gene expression and were not cytotoxic, L-sulforaphane (an hPXR antagonist) decreased CYP3A4, CYP3A5, and ABCB1 gene expression in cells treated with G. biloba extract. In summary, G. biloba extract activated mPXR and hPXR in a cell-based reporter gene assay and induced CYP3A4, CYP3A5, and ABCB1 gene expression in hPXR-expressing LS180 cells.


Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis.
Context processing is a cognitive construct associated with activity in the middle frontal gyrus. Schizophrenia-related deficits in context processing tasks have been associated with prefrontal cortical dysfunction. This study evaluated whether prefrontal cortical dysfunction related to context processing occurred in first-episode, never-medicated schizophrenia patients, whether this dysfunction also occurred in patients with nonschizophrenia psychosis, and whether this dysfunction was related to psychotic symptom expression. A modified version of the AX continuous performance task was conducted during event-related functional magnetic resonance imaging in 18 never-medicated, first-episode schizophrenia patients, 12 never-medicated patients with first-episode nonschizophrenia psychosis, and 28 comparison participants without psychiatric disorder. In-scanner measures of errors and interference reaction time showed that the schizophrenia patients had a specific deficit in context processing. Trials with greater context processing demands corresponded to activity in the middle frontal gyrus (Brodmann's area 9) in the comparison subjects and in the patients with nonschizophrenia psychosis, but not in the schizophrenia patients. Individual differences in prefrontal cortical dysfunction were associated with context processing measures and disorganization symptoms. The schizophrenia patients also showed increased activity in the anterior (Brodmann's area 10) and inferior prefrontal cortices (Brodmann's area 45/46) when they were maintaining context over a delay. Prefrontal dysfunctions related to context processing were found only in schizophrenia patients early in the course of the illness, and these dysfunctions were related to disorganization symptoms. Instead of using context processing during a continuous performance task, schizophrenia patients may use an inefficient encoding and retrieval strategy.


8-Oxoguanosine and uracil repair of nuclear and mitochondrial DNA in red and white skeletal muscle of exercise-trained old rats.
Oxoguanine DNA glycosylase (OGG1) and uracil DNA glycosylase (UDG) are two of the most important repair enzymes that are involved in the base excision repair processes to eliminate oxidative damage from mammalian DNA, which accumulates with aging. Red and white skeletal muscle fibers have very different antioxidant enzyme activities and resistance to oxidative stress. In this paper, we demonstrate that the activity of OGG1 is significantly higher in the red type of skeletal muscle compared with white fibers from old rats. Exercise training resulted in increased OGG1 activity in the nuclei of red fibers and decreased activity in nuclei of white fibers and in the mitochondria of both red and white fibers. The activities of UDG were similar in both red and white muscle fibers. Exercise training appears to increase the activity of UDG in the nuclei and mitochondria. However, exercise training affects the activity of OGG1 in nuclei and mitochondria differently, suggesting different regulation of the enzymes. In contrast, UDG showed similar activities in nuclei and mitochondrial extracts of exercise-trained animals. These data provide evidence for differential regulation of UDG and OGG1 in maintaining fidelity of DNA in oxidatively stressed cells.


Diet-induced neuropeptide expression: feasibility of quantifying extended and highly charged endogenous peptide sequences by selected reaction monitoring.
Understanding regulation and action of endogenous peptides, especially neuropeptides, which serve as inter- and intracellular signal transmitters, is key in understanding a variety of functional processes, such as energy balance, memory, circadian rhythm, drug addiction, etc. Therefore, accurate and reproducible quantification of these bioactive endogenous compounds is highly relevant. The biosynthesis of endogenous peptides, involving multiple possible trimming and modification events, hinders the de novo prediction of the active peptide sequences, making MS-based measurements very valuable in determining the actual active compounds. Here, we report an extended selected reaction monitoring (SRM)-based strategy to reproducibly and quantitatively monitor the abundances of a set of 15 endogenously occurring peptides from Rattus norvegicus hypothalamus. We demonstrate that SRM can be extended toward reproducible detection and quantification of peptides, bearing characteristics very different from tryptic peptides. We show that long peptide sequences, producing precursors with up to five and MS2 fragment ions with up to three charges, can be targeted by SRM on a triple quadrupole instrument. Using this approach to quantify endogenous peptide levels in hypothalami of animals subjected to different diets revealed several significant changes, most notably the significant upregulation of VGF-derived signaling peptide AQEE-30 upon high caloric feeding.


Regression of intimal hyperplasia with restoration of endothelium-dependent relaxing factor-mediated relaxation in experimental vein grafts.
The reversibility of the morphologic and functional alterations that occur in veins transplanted into the arterial circulation was examined in this study. Common carotid vein bypass grafts (VG) were performed in 20 male New Zealand White rabbits. Ten VG and jugular veins (CV) were harvested after 14 days, and ten VG were reimplanted as venovenous bypass grafts (REV) and harvested after an additional 14 days. Vessels were taken for structural or isometric tension studies to norepinephrine, serotonin, and bradykinin and to acetylcholine and sodium nitroprusside after precontraction. There was a decrease in the thickness of the intima (p = 0.02) and the media (p = 0.002) in REV compared with VG. In REV, sensitivity to norepinephrine decreased (p = 0.0007) with a reduced maximal tension to norepinephrine (p = 0.02) and to serotonin (p = 0.0001). Bradykinin sensitivity increased in REV (p = 0.003 vs VG) and was greater than in CV. Only the precontracted CV and REV relaxed to acetylcholine. All tissues relaxed to sodium nitroprusside. This study suggests that intimal hyperplasia can be reversed with restoration of endothelium-dependent relaxing factor-mediated relaxation but that only a partial regression of the contractile abnormalities can be achieved.


Antiseizure medication use and medical resource utilization after resective epilepsy surgery in children in the United States: A contemporary nationwide cross-sectional cohort analysis.
Antiseizure drug (ASD) therapy can significantly impact quality of life for pediatric patients whose epilepsy remains refractory to medications and who experience neuropsychological side effects manifested by impaired cognitive and social development. Contemporary patterns of ASD reduction after pediatric epilepsy surgery across practice settings in the United States are sparsely reported outside of small series. We assessed timing and durability of ASD reduction after pediatric epilepsy surgery and associated effects on health care utilization. We performed a retrospective analysis of 376 pediatric patients who underwent resective epilepsy surgery between 2007 and 2016 in the United States using the Truven MarketScan database. Filled ASD prescriptions during the pre- and postoperative periods were compared. Univariate and multivariate analyses identified factors associated with achieving a stable discontinuation of or reduction in number of ASDs. Health care utilization and costs were systematically compared. One hundred seventy-one patients (45.5%) achieved a >90-day ASD-free period after surgery, and 84 (22.3%) additional patients achieved a stable reduction in number of ASDs. Achieving ASD freedom was more common in patients undergoing total hemispherectomy (n = 21, p = .002), and less common in patients with tuberous sclerosis (p = .003). A higher number of preoperative ASDs was associated with a greater likelihood of achieving ASD reduction postoperatively (hazard ratio [HR]: 1.85, 95% confidence interval [CI]: 1.50-2.28), but was not associated with a significant difference in the likelihood of achieving ASD freedom (0.83, 95% CI: 0.49-1.39). Achieving an ASD-free period was associated with fewer hospital readmissions within the first year after surgery. Patterns of ASD use and discontinuation after pediatric epilepsy surgery provide an unbiased surgical outcome endpoint extractable from administrative databases, where changes in seizure frequency are not captured. This quantitative measure can augment traditional surgical outcome scales, incorporating a significant clinical parameter associated with improved quality of life.


Blunt abdominal trauma in children.
This review will examine the current evidence regarding pediatric blunt abdominal trauma and the physical exam findings, laboratory values, and radiographic imaging associated with the diagnosis of intra-abdominal injuries (IAI), as well as review the current literature on pediatric hollow viscus injuries and emergency department disposition after diagnosis. The importance of the seat belt sign on physical examination and screening laboratory data remains controversial, although screening hepatic enzymes are recommended in the evaluation of nonaccidental trauma to identify occult abdominal organ injuries. Focused Assessment with Sonography for Trauma (FAST) has modest sensitivity for hemoperitoneum and IAI in the pediatric trauma patient. Patients with concern for undiagnosed IAI, including bowel injury, may be considered for hospital admission and serial abdominal exams without an increased risk of complications, if an exploratory laparotomy is not performed emergently. Although the FAST exam is not recommended as the sole screening tool to rule out IAI in hemodynamically stable trauma patients, it may be used in conjunction with the physical exam and laboratory findings to identify children at risk for IAI. Children with a normal physical exam and normal abdominal CT may not require routine hospitalization after blunt abdominal trauma.


Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.
The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.


Combined influences of chromatic aberration and scattering in depth-resolved two-photon fluorescence endospectroscopy.
The influence of chromatic aberration of an objective lens in two-photon fluorescence (TPF) endospectroscopy of scattering media has been systematically investigated through both experiments and numerical simulations. Experiments were carried out on a uniform 3D scattering gelatin phantom embedded with TiO(2) granules (to mimic tissue scattering) and fluorescein-tagged polystyrene beads. It was found that fluorescence spectral intensity and lineshape varied as a function of depth when measured with a gradient-index (GRIN) lens which has severe chromatic aberration. The spectral distortion caused by the chromatic aberration became diminishing as the imaging depth increased. Ray tracing analysis and Monte Carlo simulations were carried out to study the interplay of chromatic aberration and scattering in the depth-resolved TPF spectra. The simulation results suggest that the collected fluorescence signals from deeper layers included more out-of-focus photons that experienced a few or multiple scatterings, which diminish the influence of chromatic aberration on the measured TPF spectra. The simulated collection efficiencies of TPF at different wavelengths and depths can be used to properly recover the true depth-resolved TPF spectra of a relatively uniform scattering medium.


Physiological responses to ocean acidification and warming synergistically reduce condition of the common cockle Cerastoderma edule.
The combined effect of ocean acidification and warming on the common cockle Cerastoderma edule was investigated in a fully crossed laboratory experiment. Survival of the examined adult organisms remained high and was not affected by elevated temperature (+3 °C) or lowered pH (-0.3 units). However, the morphometric condition index of the cockles incubated under high pCO2 conditions (i.e. combined warming and acidification) was significantly reduced after six weeks of incubation. Respiration rates increased significantly under low pH, with highest rates measured under combined warm and low pH conditions. Calcification decreased significantly under low pH while clearance rates increased significantly under warm conditions and were generally lower in low pH treatments. The observed physiological responses suggest that the reduced food intake under hypercapnia is insufficient to support the higher energy requirements to compensate for the higher costs for basal maintenance and growth in future high pCO2 waters.


Do Users of Diverted Medical Cannabis Differ From Other Cannabis Users?
Policy discussions amidst recent changes in the legal status of cannabis for medical purposes have raised concerns regarding the diversion of medical cannabis to nonlicensed users. This study examined factors that predict frequency of use of diverted medical cannabis. Data were collected from an online convenience sample of 1,387 cannabis users in Israel. Linear regression was used to examine whether sociodemographic background, number of licensed acquaintances, patterns of use, and problematic cannabis use predicted frequency of use of diverted medical cannabis. In all, 70% of respondents reported using diverted medical cannabis at least once in their lifetime, but far fewer (30%) reported use 6 times or more. Reporting more acquaintances with a medical cannabis license, more cannabis use problems, higher cannabis use frequency, and more hours feeling "stoned" were all significantly related to more frequent use of diverted medical cannabis. This study suggests that diversion of medical cannabis exists among cannabis users in Israel and that use of diverted medical cannabis may be associated with adverse effects. Before direct intervention and policy recommendations can be developed, however, more evidence is needed about the extent of and how medical cannabis is diverted to the underground market and the potential detrimental effects of using this type of cannabis.


Associations of sedentary behavior bouts with community-dwelling older adults' physical function.
The study aim was to explore associations between sedentary behavior (SB) bouts and physical function in 1360 community-dwelling older adults (≥65 years old). SB was measured using an ActiGraph wGT3X + accelerometer for seven consecutive days at the dominant hip and processed accordingly. Various SB bout lengths were assessed including: 1- to 9-minutes; 10- to 29-minutes; 30- to 59-minutes; and ≥60-minutes, as well as maximum time spent in a SB bout. Total SB time was adjusted for within the SB bout variables used (percentage SB time in the SB bout length and number of SB bouts per total SB hour). Physical function was assessed using the 2-minute walk test (2MWT), 5-times sit-to-stand (chair stand) test, and unipedal stance test (UST). Hierarchical linear regression models were utilized. Covariates such as moderate-vigorous physical activity (MVPA), demographic and health characteristics were controlled for. Lower percentage time spent in ≥60-minute SB bouts was significantly (P < .05) associated with longer 2MWT distance while lower numbers of ≥60-minute SB bouts were associated with longer 2MWT distance, shorter chair stand time and longer UST time. There were mixed associations with physical function for 10- to 29-minute SB bouts. In a large cohort of European older adults, prolonged SB bouts lasting ≥60-minutes appear to be associated with reduced physical function after controlling for MVPA and numerous other important covariates. Besides reducing SB levels, these findings suggest there is a need to regularly interrupt prolonged SB to improve physical function in older adults.


Overlapping but distinct gene regulation profiles by glucocorticoids and progestins in human breast cancer cells.
Glucocorticoids and progestins bind to receptors that share many structural and functional similarities, including virtually identical DNA recognition specificity. Nonetheless, the two hormones mediate very distinct biological functions. For example, progestins are associated with the incidence and progression of breast cancer, whereas glucocorticoids are growth suppressive in mammary cancer cells. To understand the mechanisms that engender biological specificity, it is necessary to identify genes that are differentially regulated by the two receptors. Here we employ Affymetrix oligonucleotide arrays to compare glucocorticoid- and progestin-regulated gene expression in a human breast cancer cell line. This global analysis reveals that the two hormones regulate overlapping but distinct sets of genes, including 31 genes that are differentially regulated. Surprisingly, the set of differentially regulated genes was almost as large as the set of genes regulated by both hormones. Examination of the set of differentially regulated genes suggests mechanisms behind the distinct growth effects of the two hormones in breast cancer. The differential regulation of four genes representing different regulatory patterns was confirmed by RT-PCR and Northern blot analyses. Treatment with cycloheximide or RU486 indicates that the regulation is a primary, receptor-mediated event. Detailed analyses of genes identified in these studies will furnish a mechanistic understanding of differential regulation by glucocorticoids and progestins.


Epigenetic gene promoter methylation at birth is associated with child's later adiposity.
Fixed genomic variation explains only a small proportion of the risk of adiposity. In animal models, maternal diet alters offspring body composition, accompanied by epigenetic changes in metabolic control genes. Little is known about whether such processes operate in humans. Using Sequenom MassARRAY we measured the methylation status of 68 CpGs 5' from five candidate genes in umbilical cord tissue DNA from healthy neonates. Methylation varied greatly at particular CpGs: for 31 CpGs with median methylation ≥5% and a 5-95% range ≥10%, we related methylation status to maternal pregnancy diet and to child's adiposity at age 9 years. Replication was sought in a second independent cohort. In cohort 1, retinoid X receptor-α (RXRA) chr9:136355885+ and endothelial nitric oxide synthase (eNOS) chr7:150315553+ methylation had independent associations with sex-adjusted childhood fat mass (exponentiated regression coefficient [β] 17% per SD change in methylation [95% CI 4-31], P = 0.009, n = 64, and β = 20% [9-32], P < 0.001, n = 66, respectively) and %fat mass (β = 10% [1-19], P = 0.023, n = 64 and β =12% [4-20], P = 0.002, n = 66, respectively). Regression analyses including sex and neonatal epigenetic marks explained >25% of the variance in childhood adiposity. Higher methylation of RXRA chr9:136355885+, but not of eNOS chr7:150315553+, was associated with lower maternal carbohydrate intake in early pregnancy, previously linked with higher neonatal adiposity in this population. In cohort 2, cord eNOS chr7:150315553+ methylation showed no association with adiposity, but RXRA chr9:136355885+ methylation showed similar associations with fat mass and %fat mass (β = 6% [2-10] and β = 4% [1-7], respectively, both P = 0.002, n = 239). Our findings suggest a substantial component of metabolic disease risk has a prenatal developmental basis. Perinatal epigenetic analysis may have utility in identifying individual vulnerability to later obesity and metabolic disease.


Methods of solving aspheric singlets and cemented doublets with given primary aberrations.
Purely algebraic algorithms are proposed for solving aspheric singlets and cemented doublets with desired focal length and primary aberrations. Singlets can meet the focal length, spherical aberration and central coma; cemented doublets can even meet the longitudinal chromatic aberration. An aspheric surface can be defined by either a conic or a fourth-order aspheric coefficient. In some situations, conic surfaces must be adopted to satisfy the required aperture diameters. They may have one or multiple aspheric surfaces and the aberration equations indicate that these aspheric coefficients of different surfaces are linearly dependent. Four examples including a classical front-stop singlet landscape lens, a DVD-rewritable (DVD-RW) pickup head lens, a singlet with double conic surfaces, and a cemented doublet in a telescope system are demonstrated.


Understanding CD30 biology and therapeutic targeting: a historical perspective providing insight into future directions.
CD30 is a member of the tumor necrosis factor receptor superfamily. It is characteristically expressed in certain hematopoietic malignancies, including anaplastic large cell lymphoma and Hodgkin lymphoma, among others. The variable expression of CD30 on both normal and malignant lymphoid cells has focused research efforts on understanding the pathogenesis of CD30 upregulation, its contribution to lymphomagenesis through anti-apoptotic mechanisms, and its effect on cell survival. Given the restriction of CD30 to certain tumor types, the logical extension of this has been to attempt to exploit it as a therapeutic target. The efficacy of naked anti-CD30 antibodies in practice was, however, modest. Moreover, combinations with bacterial toxins and radioimmunoconjugates have also had limited success. The development of the antibody-drug compound brentuximab vedotin (BV), however, has rejuvenated interest in CD30 as a tumor target. Phase I and II clinical trials in Hodgkin lymphoma, peripheral T-cell lymphoma, cutaneous T cell lymphoma, and even CD30-expressing B-cell lymphomas, have shown the compound is well tolerated, but more importantly, able to deliver meaningful disease control even in patients with multiply relapsed or refractory disease. FDA approval has been granted for its use in relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma. A recent phase III trial of BV in cutaneous T-cell lymphoma has confirmed its superiority to standard of care therapies. In this manuscript, we explore the history of CD30 as a tumor marker and as a therapeutic target, both in the laboratory and in the clinic, with a view to understanding future avenues for further study.


SomatiCA: identifying, characterizing and quantifying somatic copy number aberrations from cancer genome sequencing data.
Whole genome sequencing of matched tumor-normal sample pairs is becoming routine in cancer research. However, analysis of somatic copy-number changes from sequencing data is still challenging because of insufficient sequencing coverage, unknown tumor sample purity and subclonal heterogeneity. Here we describe a computational framework, named SomatiCA, which explicitly accounts for tumor purity and subclonality in the analysis of somatic copy-number profiles. Taking read depths (RD) and lesser allele frequencies (LAF) as input, SomatiCA will output 1) admixture rate for each tumor sample, 2) somatic allelic copy-number for each genomic segment, 3) fraction of tumor cells with subclonal change in each somatic copy number aberration (SCNA), and 4) a list of substantial genomic aberration events including gain, loss and LOH. SomatiCA is available as a Bioconductor R package at http://www.bioconductor.org/packages/2.13/bioc/html/SomatiCA.html.


Evaluation of Immunohistochemical Profile of Breast Cancer for Prognostics and Therapeutic Use.
Breast cancer is leading cancer in women, and the incidence of breast cancer in India is on the rise. The most common histologic type of breast cancer is infiltrating ductal carcinoma. Prognostic and predictive factors are used in the management of breast cancer. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2/neu) are immunohistochemical markers of prognosis as well as predictors of response to therapy. The study was conducted to evaluate ER, PR, and HER2/neu expressions in invasive ductal carcinomas of the breast by immunohistochemistry, to explore the correlation of these markers to each other and to various clinicopathological parameters: age of the patient, histological grade, tumor size, and lymph node metastasis. This prospective study was conducted on 100 cases of infiltrating ductal carcinoma. Slides were prepared from blocks containing cancer tissue, and immunohistochemical staining was done for ER, PR, and HER2/neu expressions. Interpretation of expressions was done using Allred scoring system for ER/PR and the American Society of Clinical Oncology/College of American Pathologists guidelines for HER2/neu. Statistical analysis was performed to determine the statistical significance by applying Chi-square test. Majority of tumors were ER and PR positive and HER2/neu negative. ER and PR correlated significantly with age, tumor size, and tumor grade; whereas, HER2/neu correlated significantly with tumor size only. No association was seen with axillary lymph node metastasis. ER and PR expression correlated with each other, but none correlated with HER2/neu. As the majority of the tumors are ER, PR positive and since ER and PR correlate with each other as well as with age, tumor size, and grade. Therefore, routine assessment of hormone receptors is recommended for prognostic and therapeutic information in breast cancer cases.


Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.
Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.


The impact of diurnal variation of PSA on timing of measurement in prostate biopsy.
Prostate-specific antigen (PSA) synthesis is related to testosterone, which has a diurnal rhythm. PSA might have a diurnal variation and the timing of measurement could change the clinical practice for prostate biopsy. Male patients complaining of lower urinary tract symptoms (group 1) and diagnosed with prostate cancer (group 2) were recruited into the study. Morning fasting blood samples were withdrawn between 9.00 and 11.00 am for the determination of biochemical parameters, PSA (PSA1), total testosterone (T1), and estradiol (E1) levels. In the afternoon, between 15.00 and 15.30 pm, blood samples were again obtained from the same participants at the same day and the serum concentration of PSA (PSA2), total testosterone (T2), and estradiol (E2) were measured. A total of 160 and 30 patients were enrolled in groups 1 and 2, respectively. One hundred forty (87.5%) and 26 (86.6%) patients had a decrease in the PSA levels when measured in the afternoon. The Wilcoxon signed-rank test determined a statistically significant difference between the PSA levels measured in the morning and in the afternoon in each group. An analysis of covariance test revealed no statistically significant difference in PSA concentration between the groups after adjustment for baseline concentration (F(1.187) = 0.203, P = .653). There was a weak positive correlation between PSA1/PSA2 and T1/T2, rs (160) = 0.163, P = .034. An extra unit increase in PSA1 concentration leads to a 0.805 (95% confidence interval [CI], 0.781-0.830) and 0.828 (95% CI, 0.807-0.849) ng/mL increase in PSA2 concentration in groups 1 and 2, respectively, that is, patients with and without prostate cancer had a similar decrease in the PSA levels. When measured in the afternoon, 66.6% and 50% patients with a morning PSA level over 3 or 4 ng/mL had a PSA drop below these levels, respectively. PSA has a diurnal variation and the timing of measurement may alter the decision of the clinician for transrectal ultrasound prostate biopsy.


Effects of a combined oral contraceptive containing oestradiol valerate/dienogest on hormone withdrawal-associated symptoms: results from the multicentre, randomised, double-blind, active-controlled HARMONY II study.
The objective of this multicentre, randomised, double-blind study was to compare a combined oral contraceptive (COC) containing oestradiol valerate/dienogest (E2V/DNG) administered in a dynamic dosing regimen with a monophasic COC containing ethinyloestradiol/levonorgestrel (EE/LNG), with regard to their ability to reduce the frequency and intensity of headache and pelvic pain in women with hormone withdrawal-associated symptoms (HWAS). Women aged 18-50 years received E2V/DNG in an oestrogen step-down and progestin step-up regimen (26/2 regimen; n = 223) or EE 20 μg/LNG 100 μg (21/7 regimen; n = 218) over six cycles. Headache and pelvic pain were assessed using a visual analogue scale (VAS) during cycle days 22-28. Rescue medication use was also assessed. E2V/DNG was superior to EE/LNG with regard to reducing the frequency and intensity of headache and pelvic pain from baseline to cycle 6 (change from baseline in the average of the three highest VAS values [mean ± standard deviation]: 47.7 ± 29.4 vs 34.5 ± 25.7 mm, respectively; p < 0.0001). The use of rescue medication was also significantly reduced with E2V/DNG compared with EE/LNG (p < 0.05). E2V/DNG may be a good option for women who experience HWAS with traditional 21/7-day regimen COCs.


Using three-dimensional gait data for foot/ankle orthopaedic surgery.
We present the case of a forty year old male who sustained a torn carotid during strenuous physical activity. This was followed by a right hemispheric stroke due to a clot associated with the carotid. Upon recovery, the patient's gait was characterized as hemiparetic with a stiff-knee pattern, a fixed flexion deformity of the toe flexors, and a hindfoot varus. Based on clinical exams and radiographs, the surgical treatment plan was established and consisted of correction of the forefoot deformities, possible hamstrings lengthening, and tendon transfer of the posterior tibial tendon to the dorsolateral foot. To aid in surgical planning, a three-dimensional gait analysis was conducted using a state-of-the-art motion capture system. Data from this analysis provided insight into the pathomechanics of the patient's gait pattern. A forefoot driven hindfoot varus was evident from the presurgical data and the tendon transfer procedure was deemed unnecessary. A computer was used in the OR to provide surgeons with animations of the patient's gait and graphical results as needed. A second gait analysis was conducted 6 weeks post surgery, shortly after cast removal. Post-surgical gait data showed improved foot segment orientation and position. Motion capture data provides clinicians with detailed information on the multisegment kinematics of foot motion during gait, before and during surgery. Further, treatment effectiveness can be evaluated by repeating gait analyses after recovery.


Lifespan maturation and degeneration of human brain white matter.
Properties of human brain tissue change across the lifespan. Here we model these changes in the living human brain by combining quantitative magnetic resonance imaging (MRI) measurements of R1 (1/T1) with diffusion MRI and tractography (N=102, ages 7-85). The amount of R1 change during development differs between white-matter fascicles, but in each fascicle the rate of development and decline are mirror-symmetric; the rate of R1 development as the brain approaches maturity predicts the rate of R1 degeneration in aging. Quantitative measurements of macromolecule tissue volume (MTV) confirm that R1 is an accurate index of the growth of new brain tissue. In contrast to R1, diffusion development follows an asymmetric time-course with rapid childhood changes but a slow rate of decline in old age. Together, the time-courses of R1 and diffusion changes demonstrate that multiple biological processes drive changes in white-matter tissue properties over the lifespan.


An enzyme-coupled artificial photosynthesis system prepared from antenna protein-mimetic tyrosyl bolaamphiphile self-assembly.
An artificial photosynthesis system coupled with an enzyme was constructed using the nanospherical self-assembly of tyrosyl bolaamphiphiles, which worked as a host matrix exhibiting an antenna effect that allowed enhanced energy transfer to the ZnDPEG photosensitizer. The excited electrons from the photosensitizer were transferred to NAD+ to produce NADH, which subsequently initiated the conversion of an aldehyde to ethanol by alcohol dehydrogenase. Production of NADH and ethanol was enhanced by increasing the concentration of tyrosyl bolaamphiphiles. Spectroscopic investigations proved that the photosensitizer closely associated with the surface of the bolaamphiphile assembly through hydrogen bonds that allowed energy transfer between the host matrix and the photosensitizer. This study demonstrates that the self-assembly of bolaamphiphiles could be applicable to the construction of biomimetic energy systems exploiting biochemical activity.


PSEN1 p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer's Disease.
An in depth study of PSEN1 mutation p.Thr116Ile (c.335C>T) is presented from two Korean families with autosomal dominant inheritance. Clinical manifestation of our patients included memory loss, attention deficits, visuospatial dysfunction, agnosia, aphasia, apraxia, and personality changes, which occurred in their 30s. PSEN1 Thr116Ile was initially discovered in an Italian patient and two French families with early onset Alzheimer's disease (EOAD) with similar age of onset. To verify the possible pathogenic mechanisms of mutation, in silico predictions and 3D modeling were performed. Structure predictions revealed significant aberrations in first hydrophilic loop (HL-I loop). The hydrophobic isoleucine could alter the loop orientation through increased hydrophobic contacts with the surrounding amino acids. Mutation could destroy a possible hydrogen bond between tyrosine 115 and threonine 116, which may affect the loop conformation. HL-I was confirmed as a conservative region of PSEN1, which may be critical in PSEN1 functions. An additional pathogenic mutation, PSEN1 Thr116Asn, was also found for the same residue, where the patient presented young onset AD (YOND). Other mutations in HL-I loop, such as Tyr115His and Glu120Asp, were described in patients with YOND, supporting the critical role of HL-I loop in PSEN1 activity.


Assessment of dissociation in Bosnian treatment-seeking refugees in Denmark.
Dissociative experiences are common in traumatized individuals, and can sometimes be mistaken for psychosis. It is difficult to identify pathological dissociation in the treatment of traumatized refugees, because there is a lack of systematic clinical descriptions of dissociative phenomena in refugees. Furthermore, we are currently unaware of how dissociation measures perform in this clinical group. To describe the phenomenology of dissociative symptoms in Bosnian treatment-seeking refugees in Denmark. As a part of a larger study, dissociation was assessed systematically in 86 Bosnian treatment-seeking refugees using a semi-structured clinical interview (Structured Interview for Disorders of Extreme Stress-dissociation subscale; SIDES-D) and a self-report scale (Dissociative Experiences Scale; DES). The SIDES-D indicated twice as high prevalence of pathological dissociation as the DES. According to the DES, 30% of the refugees had pathological dissociation 15 years after their resettlement. On the SIDES-D, depersonalization and derealization experiences were the most common. Also, questions about depersonalization and derealization at times elicited reporting of visual and perceptual hallucinations, which were unrelated to traumatic re-experiencing. Questions about personality alteration elicited spontaneous reports of a phenomenon of "split" pre- and post-war identity in the refugee group. Whether this in fact is a dissociative phenomenon, characteristic of severe traumatization in adulthood, needs further examination. Knowledge of dissociative symptoms in traumatized refugees is important in clinical settings to prevent misclassification and to better target psychotherapeutic interventions. Much development in the measurement of dissociation in refugees is needed.


Selective lithium ion recognition in self-assembled columnar liquid crystals based on a lithium receptor.
Lithium is recognized as being significantly important due to its various applications in different areas especially in energy technology. In the present study, self-assembled nanostructured liquid-crystalline (LC) materials, that selectively bind lithium cations, have been developed for the first time. Wedge-shaped crown ether derivatives bearing dibenzo-14-crown-4 (DB14C4) or 12-crown-4 moieties are able to act as LC lithium-selective receptors. We have found that complexation of these receptors with lithium perchlorate induces liquid-crystalline columnar phases, while sodium perchlorate is immiscible with both receptors. Remarkably, a receptor consisting of DB14C4 as an effective lithium-selective ligand exhibits high selectivity for LiCl over NaCl, KCl, RbCl and CsCl. The lithium selectivity was demonstrated and investigated by 1H NMR, 1H COSY and FT-IR spectroscopic measurements. The preferred coordination number of four and the ideal cavity geometry of the DB14C4 moiety of the receptor are shown to be key factors for the high lithium selectivity. This new design of LC lithium-selective receptors opens unexplored paths for the development of methods to fabricate nanostructured materials for efficient selective lithium recognition.


An ontogenic study of the behavioral effects of chronic intermittent exposure to ayahuasca in mice.
Ayahuasca is a beverage obtained from decoctions of the Banisteriopsis caapi plus Psychotria viridis. In religious contexts, ayahuasca is used by different age groups. However, little is known of the effects of ayahuasca during ontogenic development, particularly with regard to the functional characteristics of the central nervous system. Animal models are useful for studying the ontogenic effects of ayahuasca because they allow exclusion of the behavioral influence associated with the ritualistic use. We investigated the effects of exposure to ayahuasca (1.5 mL/kg, orally, twice a week) on memory and anxiety in C57BL/6 mice, with the post-natal day (PND) being used as the ontogenic criterion for classification: childhood (PND21 to PND35), adolescence (PND35 to PND63), adulthood (PND90-PND118), childhood-adolescence (PND21 to PND63), childhood-adulthood (PND21 to PND118) and adolescence-adulthood (PND35 to PND118). One day after the last ayahuasca exposure, the mice were subjected to the Morris water maze (MWM), open field and elevated plus maze tasks (EPM). Ayahuasca did not affect locomotion in the open field or open arms exploration in the EPM, but increased the risk assessment behavior in the childhood group. Ayahuasca did not cause any change in acquisition of spatial reference memory in the MWM task, but decreased the time spent on the platform quadrant during the test session in the adolescence group. These results suggest that, in mice, exposure to ayahuasca in childhood and adolescence promoted anxiety and memory impairment, respectively. However, these behavioral changes were not long-lasting since they were not observed in the childhood-adulthood and adolescence-adulthood groups.