Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury.
Lung ischemia-reperfusion (I/R) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribute to the acute phase of lung I/R injury. However, the mechanism is unclear. AMs become activated and produce various cytokines and chemokines in many inflammatory responses, including transplantation. We hypothesize that AMs respond to I/R by producing key cytokines and chemokines and that depletion of AMs would reduce cytokine/chemokine expression and lung injury after I/R. To test this, using a buffer-perfused, isolated mouse lung model, we studied the impact of AM depletion by liposome-clodronate on I/R-induced lung dysfunction/injury and expression of cytokines/chemokines. I/R caused a significant increase in pulmonary artery pressure, wet-to-dry weight ratio, vascular permeability, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2 expression, as well as decreased pulmonary compliance, when compared with sham lungs. After AM depletion, the changes in each of these parameters between I/R and sham groups were significantly attenuated. Thus AM depletion protects the lungs from I/R-induced dysfunction and injury and significantly reduces cytokine/chemokine production. Protein expression of TNF-alpha and MCP-1 are positively correlated to I/R-induced lung injury, and AMs are a major producer/initiator of TNF-alpha, MCP-1, and MIP-2. We conclude that AMs are an essential player in the initiation of acute lung I/R injury.


Crosstalk between Two bZIP Signaling Pathways Orchestrates Salt-Induced Metabolic Reprogramming in Arabidopsis Roots.
Soil salinity increasingly causes crop losses worldwide. Although roots are the primary targets of salt stress, the signaling networks that facilitate metabolic reprogramming to induce stress tolerance are less understood than those in leaves. Here, a combination of transcriptomic and metabolic approaches was performed in salt-treated Arabidopsis thaliana roots, which revealed that the group S1 basic leucine zipper transcription factors bZIP1 and bZIP53 reprogram primary C- and N-metabolism. In particular, gluconeogenesis and amino acid catabolism are affected by these transcription factors. Importantly, bZIP1 expression reflects cellular stress and energy status in roots. In addition to the well-described abiotic stress response pathway initiated by the hormone abscisic acid (ABA) and executed by SnRK2 (Snf1-RELATED-PROTEIN-KINASE2) and AREB-like bZIP factors, we identify a structurally related ABA-independent signaling module consisting of SnRK1s and S1 bZIPs. Crosstalk between these signaling pathways recruits particular bZIP factor combinations to establish at least four distinct gene expression patterns. Understanding this signaling network provides a framework for securing future crop productivity.


Studies on mineralocorticoid 'escape' in cirrhosis.
1. The mineralocorticoid 9 alpha-fluorohydrocortisone was given to 12 patients with cirrhosis without ascites. In seven an 'escape' from its sodium-retaining effects was observed, the other five continuing to retain sodium. 2. Changes in plasma renin activity (PRA) and inulin clearance (Cinulin) were used in the assessment of possible changes in the 'effective' extracellular fluid volume. PRA fell and Cinulin increased to a similar extent in each of the two groups of patients. The findings do not support the concept that the failure to show the mineralocorticoid escape in some patients with cirrhosis is due to a failure of expansion of the effective extracellular fluid volume. 3. Sodium reabsorption in the different segments of the nephron as estimated by clearance techniques under conditions of maximal water diuresis showed that the greatest changes to account for both mineralocorticoid escape and sodium retention were in the part of the nephron beyond the diluting segment.


Laevistrombus Abbott 1960 (Gastropoda: Strombidae): Indian and southwest Pacific species.
Here we evaluate the taxonomy of the marine gastropod genus Laevistrombus Abbott, 1960 and determine that there are five extant species within this genus, three of which occur in the southwest Pacific. Comparative analyses of this complex have been problematic due to the lack of designated type material. Therefore, we present the type material for L. canarium Linnaeus, 1758; L. taeniatus Quoy Gaimard, 1834; and L. vanikorensis Quoy Gaimard, 1834. Current taxonomy has L. vanikorensis absorbed within the L. canarium complex. L. taeniatus is generally held to be a synonym of L. turturella Röding, 1789. We demonstrate that both L. taeniatus and L. vanikorensis are distinct species and reinstate both to species level. Our revision also notes the significant variability in early teleoconch structure within the geographic range of L. vanikorensis, and highlights the need for a greater revision of Laevistrombus, given the diversity in early teleoconch morphology present in southwest Pacific species.


Genetic contribution to variation in body configuration in Belgian nuclear families: a closer look at body lengths and circumferences.
The purpose of the current study was to evaluate the contribution of genetic factors on body configuration related phenotypes. The sample consisted of 119 Belgian nuclear families including 231 males and 229 females. Factor analysis with varimax rotation was carried out to analyse 13 length and circumference measures and the resulting two synthetic traits (LF and CF; linear and circumference factors, respectively) were used as summary variables. Univariate quantitative genetic analysis indicated that variation in anthropometric as well as in synthetic traits was significantly dependent on additive genetic effects, with heritabilities ranging from 0.55 to 0.88. Narrow sense heritability estimates were higher for measurements principally characterizing skeletal mass than in variables that also involve soft-tissues. Sex, age and their interactions explained 11-67% of the total phenotypic variance. This report also examined the covariations between pairs of anthropometric and synthetic traits (length measurements and LF vs. height; circumference measures and CF vs. weight and BMI; LF vs. CF). Significant genetic correlations among all the studied traits (except for middle finger length vs. height) confirmed the influence of pleiotropy on genetic determination of these phenotypes. Bivariate analysis showed that pleiotropic effects had a great influence in determining body traits variation within body length measurements, as well as between body circumferences and weight or BMI. In relation to the two synthetic traits, even the variation of body lengths and circumferences was highly determined by genetic factors, shared genetic influences were unlikely to explain much of the observed variation between LF and CF. The results of the present study allow us to conclude that in this population body configuration related traits are subject to a strong genetic control and that shared genes also contribute to this genetic structure.


Epileptic auras: phenomenology and neurophysiology.
This review discusses the phenomenology, neurophysiology, and localization of epileptic auras with particular emphasis on how auras can manifest as part of an epileptic network. Epileptic auras, as the first clinical symptom of a seizure, may lead us to infer the site of seizure onset. At the same time, auras can also be a result of activation or alteration in an epileptic network. They can be highly specific or ill-defined in symptomatology. They occur as a result of limited seizure activation, allowing access of the neural signal to the conscious brain. An understanding of epileptic auras offers a window into understanding fundamental brain functions, and helps the clinician at the bedside to make appropriate diagnostic and therapeutic choices.


Decontamination interventions for the reuse of surgical mask personal protective equipment: a systematic review.
The high demand for personal protective equipment during the novel coronavirus outbreak has prompted the need to develop strategies to conserve supply. Little is known regarding decontamination interventions to allow for surgical mask reuse. To identify and synthesize data from original research evaluating interventions to decontaminate surgical masks for the purpose of reuse. MEDLINE, Embase, CENTRAL, Global Health, the WHO COVID-19 database, Google Scholar, DisasterLit, preprint servers, and prominent journals from inception to April 8th, 2020, were searched for prospective original research on decontamination interventions for surgical masks. Citation screening was conducted independently in duplicate. Study characteristics, interventions, and outcomes were extracted from included studies by two independent reviewers. Outcomes of interest included impact of decontamination interventions on surgical mask performance and germicidal effects. Seven studies met eligibility criteria: one evaluated the effects of heat and chemical interventions applied after mask use on mask performance, and six evaluated interventions applied prior to mask use to enhance antimicrobial properties and/or mask performance. Mask performance and germicidal effects were evaluated with heterogeneous test conditions. Safety outcomes were infrequently evaluated. Mask performance was best preserved with dry heat decontamination. Good germicidal effects were observed in salt-, N-halamine-, and nanoparticle-coated masks. There is limited evidence on the safety or efficacy of surgical mask decontamination. Given the heterogeneous methods used in studies to date, we are unable to draw conclusions on the most efficacious and safe intervention for decontaminating surgical masks.


Opposite patterns of diurnal activity in the box jellyfish Tripedalia cystophora and Copula sivickisi.
Cubozoan medusae have a stereotypic set of 24 eyes, some of which are structurally similar to vertebrate and cephalopod eyes. Across the approximately 25 described species, this set of eyes varies surprisingly little, suggesting that they are involved in an equally stereotypic set of visual tasks. During the day Tripedalia cystophora is found at the edge of mangrove lagoons where it accumulates close to the surface in sun-lit patches between the prop roots. Copula sivickisi (formerly named Carybdea sivickisi) is associated with coral reefs and has been observed to be active at night. At least superficially, the eyes of the two species are close to identical. We studied the diurnal activity pattern of these two species both in the wild and under controlled conditions in laboratory experiments. Despite the very similar visual systems, we found that they display opposite patterns of diurnal activity. T. cystophora is active exclusively during the day, whereas C. sivickisi is actively swimming at night, when it forages and mates. At night T. cystophora is found on the muddy bottom of the mangrove lagoon. C. sivickisi spends the day attached to structures such as the underside of stones and coral skeletons. This species difference seems to have evolved to optimize foraging, since the patterns of activity follow those of the available prey items in their respective habitats.


Metabolite profiling of Panax notoginseng using UPLC-ESI-MS.
The metabolite profiling of different parts of Panax notoginseng was carried out using rapid ultra-performance liquid chromatography-electrospray ionization mass spectrometry (UPLC-ESI-MS) and multivariate statistical analysis. Principal component analysis (PCA) of the UPLC-ESI-MS data showed a clear separation of compositions among the flower buds, roots and rhizomes of P. notoginseng. The saponins accounting for such variations were identified through the corresponding loadings weights and were further verified by accurate mass, tandem mass and retention times of available standard saponins using UPLC quadrupole time-of-flight mass spectrometer (UPLC-QtofMS). Finally, the influential factors of different metabolic phenotypes of P. notoginseng was elucidated. The currently proposed UPLC-ESI-MS/MS analytical method coupled with multivariate statistical analysis can be further utilized to evaluate chemical components obtained from different parts of the plant and/or the plant of different geographical locations, thereby classifying the medicinal plant resources and potentially elucidating the mechanism of inherent phytochemical diversity.


Enhanced recovery in colorectal surgery: a multicentre study.
Major colorectal surgery usually requires a hospital stay of more than 12 days. Inadequate pain management, intestinal dysfunction and immobilisation are the main factors associated with delay in recovery. The present work assesses the short and medium term results achieved by an enhanced recovery program based on previously published protocols. This prospective study, performed at 12 Spanish hospitals in 2008 and 2009, involved 300 patients. All patients underwent elective colorectal resection for cancer following an enhanced recovery program. The main elements of this program were: preoperative advice, no colon preparation, provision of carbohydrate-rich drinks one day prior and on the morning of surgery, goal directed fluid administration, body temperature control during surgery, avoiding drainages and nasogastric tubes, early mobilisation, and the taking of oral fluids in the early postoperative period. Perioperative morbidity and mortality data were collected and the length of hospital stay and protocol compliance recorded. The median age of the patients was 68 years. Fifty-two % of the patients were women. The distribution of patients by ASA class was: I 10%, II 50% and III 40%. Sixty-four % of interventions were laparoscopic; 15% required conversion to laparotomy. The majority of patients underwent sigmoidectomy or right hemicolectomy. The overall compliance to protocol was approximately 65%, but varied widely in its different components. The median length of postoperative hospital stay was 6 days. Some 3% of patients were readmitted to hospital after discharge; some 7% required repeat surgery during their initial hospitalisation or after readmission. The most common complications were surgical (24%), followed by septic (11%) or other medical complications (10%). Three patients (1%) died during follow-up. Some 31% of patients suffered symptoms that delayed their discharge, the most common being vomiting or nausea (12%), dyspnoea (7%) and fever (5%). The following of this enhanced recovery program posed no risk to patients in terms of morbidity, mortality and shortened the length of their hospital stay. Overall compliance to protocol was 65%. The following of this program was of benefit to patients and reduces costs by shortening the length of hospital stay. The implantation of such programmes is therefore highly recommended.


Contextualizing Medicaid reimbursement rates for abortion procedures.
Low Medicaid reimbursement rates have been cited as a key threat to abortion clinic sustainability in the United States. This study examines differences between Medicaid and Medicare reimbursements for abortion and miscarriage management procedures under a fee-for-service (FFS) model. Using 2017 Medicaid and Medicare Physician fee schedules, we extracted reimbursement data for the two most commonly-billed abortion procedures and two miscarriage management procedures for 45 states and the District of Columbia (DC). We compared Medicaid and Medicare reimbursement rates for each procedure by state. Medicaid reimbursement rates for both procedures varied widely across the states. Medicaid rates for second-trimester abortion procedures had the widest range; $79-$626. Median Medicaid reimbursement rates were lower than median Medicare rates for first- and second-trimester abortion procedures. Median reimbursement rates for first-trimester induced abortion were lower than median reimbursement rates for miscarriage management for both Medicaid and Medicare. Our findings indicate that Medicaid reimbursement rates for abortion are low; the median patient cost for a first- and second-trimester abortion have been reported as $490 and $750, respectively. Median Medicaid reimbursement rates for a first- and second-trimester abortion covers approximately 37% and 41% of patient costs for a first- and second-trimester abortion. Further, while induced abortion procedures are similar to miscarriage management procedures, Medicaid and Medicare reimbursement rates are lower for first- and second-trimester abortion procedures. Ensuring reimbursement rates are closely aligned with procedural costs bolsters provider willingness to accept Medicaid. Data that highlights the potential impact of fee-for-service reimbursement rates on healthcare provision and ultimately patient access can help inform healthcare policies. This is especially important as more states consider expanding Medicaid coverage of abortion.


Curve-based multivariate distance matrix regression analysis: application to genetic association analyses involving repeated measures.
Most, if not all, human phenotypes exhibit a temporal, dosage-dependent, or age effect. Despite this fact, it is rare that data are collected over time or in sequence in relevant studies of the determinants of these phenotypes. The costs and organizational sophistication necessary to collect repeated measurements or longitudinal data for a given phenotype are clearly impediments to this, but greater efforts in this area are needed if insights into human phenotypic expression are to be obtained. Appropriate data analysis methods for genetic association studies involving repeated or longitudinal measures are also needed. We consider the use of longitudinal profiles obtained from fitted functions on repeated data collections from a set of individuals whose similarities are contrasted between sets of individuals with different genotypes to test hypotheses about genetic influences on time-dependent phenotype expression. The proposed approach can accommodate uncertainty of the fitted functions, as well as weighting factors across the time points, and is easily extended to a wide variety of complex analysis settings. We showcase the proposed approach with data from a clinical study investigating human blood vessel response to tyramine. We also compare the proposed approach with standard analytic procedures and investigate its robustness and power via simulation studies. The proposed approach is found to be quite flexible and performs either as well or better than traditional statistical methods.


Biphasic pattern in the effect of severe measles infection; the difference between additive and multiplicative scale.
Infection with measles virus (MeV) causes immunosuppression and increased susceptibility to other infectious diseases. Only few studies reported a duration of immunosuppression, with varying results. We investigated the effect of immunosuppression on the incidence of hospital admissions for infectious diseases in Vietnamese children. We used retrospective data (2005 to 2015; N = 4419) from the two pediatric hospitals in Ho Chi Minh City, Vietnam. We compared the age-specific incidence of hospital admission for infectious diseases before and after hospitalization for measles. We fitted a Poisson regression model that included gender, current age, and time since measles to obtain a multiplicative effect measure. Estimates were transformed to the additive scale. We observed two phases in the incidence of hospital admission after measles. The first phase started with a fourfold increased rate of admissions during the first month after measles, dropping to a level quite comparable to children of the same age before measles. In the second phase, lasting until at least 6 years after measles, the admission rate decreased further, with values up to 20 times lower than in children of the same age before measles. However, on the additive scale the effect size in the second phase was much smaller than in the first phase. The first phase highlights the public health benefits of measles vaccination by preventing measles and immune amnesia. The beneficial second phase is interesting, but its strength strongly depends on the scale. It suggests a complicated interaction between MeV infection and the host immunity.


Early versus late removal of the laryngeal mask airway (LMA) for general anaesthesia.
The laryngeal mask airway (LMA) is a safe and effective modality to maintain the airway for general anaesthesia during surgical procedures. The LMA is removed at the end of surgery and anaesthesia, when the patient maintains an adequate respiratory rate and depth. This removal of the LMA can be done either when the patient is deep under anaesthesia (early removal) or only after the patient has regained consciousness (late removal). It is not clear which of these techniques is superior. The objective of this review was to compare the safety of LMA removal in the deep plane of anaesthesia (early removal) versus removal in the awake state (late removal) for participants undergoing general anaesthesia. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 8); MEDLINE (1966 to August 2014); EMBASE (1980 to August 2014); LILACS (1982 to August 2014); CINAHL (WebSPIRS; 1984 to August 2014); and ISI Web of Science (1984 to August 2014). We searched for ongoing trials through various trial registration websites. In addition, we searched conference proceedings and reference lists of relevant articles. We included randomized controlled trials (RCTs) on adults and children undergoing elective general anaesthesia using the LMA, that compared early removal of the LMA (defined as removal of the LMA in the deep plane of anaesthesia) versus late removal of the LMA (defined as removal of the LMA after the patient is awake). Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We used a random-effects model to generate forest plots from the data. We identified a total of 9188 citations and included 15 RCTs conducted on 2242 participants in this review. All trials used the LMA Classic in American Society of Anesthesiologists (ASA) physical status I or II for patients undergoing elective general anaesthesia. Children were enrolled in 11 trials and adults in five trials. None of the trials were of high methodological quality. Eight of the 15 studies had adequate generation of random sequence, whereas only one trial had adequate concealment of random sequence. Three trials had blinded the outcome assessor. Thus, the majority of the studies appeared to have a high risk of bias in the study design.Using the GRADE approach, we found low quality evidence that the risk of laryngospasm was similar with early removal of the LMA (3.3%) versus late removal (2.7%): risk ratio (RR) 1.23, 95% confidence interval (CI) 0.74 to 2.03; 11 trials, 1615 participants. The quality of evidence was very low that the risk of coughing was less after early removal (13.9%) than late removal (19.4%): RR 0.52, 95% CI 0.29 to 0.94; 11 trials, 1430 participants. The quality of evidence for the risk of desaturation was also very low; there was no difference between early removal (7.9%) and late removal (10.1%): RR 0.68, 95% CI 0.4 to 1.16; 13 trials, 2037 participants. We found low quality evidence that the risk of airway obstruction was higher with early removal (15.6%) compared to late removal of the LMA (4.6%): RR 2.69, 95% CI 1.32 to 5.5; eight trials, 1313 participants. This systematic review suggests that current best evidence comparing early versus late removal of the LMA in participants undergoing general anaesthesia does not demonstrate superiority of either intervention. However, the quality of evidence available is either low or very low. There is a paucity of well designed RCTs and a need for large scale RCTs to demonstrate whether early removal or late removal of the LMA is better after general anaesthesia.


Apps and wearables in the monitoring of mental health disorders.
Recent advances in smartphone technology have revealed new opportunities for the diagnosis, monitoring and provision of mental health care. Such digital approaches have the potential to enhance our understanding of the course of mental disorder, enable early diagnosis and generate new treatment targets. However, issues relating to mobile phone ownership, misuse of clinical data, commercial devices and the ethics of such approaches need to be overcome if smartphones are to be routinely used in mental health care. This article reviews the potential as well as the challenges posed by the use of such technologies in mental health settings.


Adolescents' and Young Adults' Naïve Understandings of the Economic Crisis.
Over the last decade, Financial Literacy (FL) and interventions aimed at improving it, that is Financial Education (FE), have been the focus of increased attention from economists, governments, and international organizations such as the world Bank and OECD, but much less by scholars in the fields of Learning and Instruction. We examined open-ended written answers on the causes of the economic crisis that started in 2007-2008, as given by 381 Italian secondary school and university students, and 268 Swiss Italian-speaking secondary school students. Most Italian students mentioned internal political causes (i.e., corrupt politicians or inefficiency of the government), whereas Swiss students mentioned banks more often. International factors were rarely mentioned by either group, and explanations were generally very poor, listing a few causes without making connections between them. These findings indicate the need for economics education aimed at making people more knowledgeable of the workings of the economic system and the effects of financial systems on the real economy.


Water-pipe (narghile) smoking: an emerging health risk behavior.
Narghile, or water-pipe smoking (WPS), has been practiced extensively for approximately 400 years. It is common in the Arabian Peninsula, Turkey, India, Pakistan, and other countries. In recent years, there has been a revival of WPS, notably among youth. Most US health professionals are unfamiliar with the practice and health consequences of WPS. Therefore, this trend presents a new challenge for adolescent health care providers. The composition of the tobacco used in WPS is variable and not well standardized. Studies that have examined narghile smokers and the aerosol of narghile smoke have reported high concentrations of carbon monoxide, nicotine, "tar," and heavy metals. These concentrations were as high or higher than those among cigarette smokers. The few scientific data regarding the adverse health consequences of WPS point to dangers that are similar to those associated with cigarette smoking: malignancy, impaired pulmonary function, low birth weight, and others. Additional dangers not encountered with cigarette smoking are infectious diseases resulting from pipe sharing and the frequent addition of alcohol or psychoactive drugs to the tobacco. Public health strategies for controlling the emerging epidemic of WPS include carrying out epidemiologic and toxicologic research; implementation of laws to limit acquisition and use; and health education, targeting adolescents in particular.


Correlation detection and resonance in neural systems with distributed noise sources.
We investigated the resonance behavior in model neurons receiving a large number of random synaptic inputs, whose distributed nature permits one to introduce correlations between them and investigate its effect on cellular responsiveness. A change in the strength of this background led to enhanced responsiveness, consistent with stochastic resonance. Altering the correlation revealed a type of resonance behavior in which the neuron is sensitive to statistical properties rather than the strength of the noise. Remarkably, the neuron could detect weak correlations among the distributed inputs within millisecond time scales.


Deficits in eye movements following frontal eye-field and superior colliculus ablations.
1. This study investigated the effects of frontal eye-field and superior colliculus ablations on fixation patterns and saccadic eye movements. Monkeys were trained to pick apple pieces out of a multiple-slotted apple board while their heads were fixed. Eye movement records were obtained using predominantly the implanted search-coil method. 2. Both unilateral and bilateral frontal eye-field lesions produced only temporary deficits in eye movements. Following surgery monkeys tended to neglect the contralateral peripheral visual field and made fewer saccades to peripheral targets. Recovery was virtually completed in 2-4 wk. 3. Superior colliculus ablation reduced fixation accuracy, saccade frequency, and saccade velocity. These deficits showed little recovery with time. 4. Paired frontal eye-field and superior colliculus lesions produced dramatic deficits in visually triggered eye movements. Animals could no longer fixate their eyes on visual targets with any degree of accuracy. The range of eye movements was greatly reduced, as was the frequency and velocity of saccades. These deficits showed little recovery with time. 5. These results suggest that visually triggered saccadic eye movements are controlled by two parallel channels, one involving the superior colliculus and the other the frontal eye field.


PaWFE: Fast Signal Feature Extraction Using Parallel Time Windows.
Motivation: Hand amputations can dramatically affect the quality of life of a person. Researchers are developing surface electromyography and machine learning solutions to control dexterous and robotic prosthetic hands, however long computational times can slow down this process. Objective: This paper aims at creating a fast signal feature extraction algorithm that can extract widely used features and allow researchers to easily add new ones. Methods: PaWFE (Parallel Window Feature Extractor) extracts the signal features from several time windows in parallel. The MATLAB code is publicly available and supports several time domain and frequency features. The code was tested and benchmarked using 1,2,4,8,16,32, and 48 threads on a server with four Xeon E7- 4820 and 128 GB RAM using the first 5 datasets of the Ninapro database, that are recorded with different acquisition setups. Results: The parallel time window analysis approach allows to reduce the computational time up to 20 times when using 32 cores, showing a very good scalability. Signal features can be extracted in few seconds from an entire data acquisition and in <100 ms from a single time window, easily reducing of up to over 15 times the feature extraction procedure in comparison to traditional approaches. The code allows users to easily add new signal feature extraction scripts, that can be added to the code and on the Ninapro website upon request. Significance: The code allows researchers in machine learning and biosignals data analysis to easily and quickly test modern machine learning approaches on big datasets and it can be used as a resource for real time data analysis too.


The default mode network in healthy aging and Alzheimer's disease.
In the past decade, a "default mode network" (DMN) has been highlighted in neuroimaging studies as a set of brain regions showing increased activity in task-free state compared to cognitively demanding task, and synchronized activity at rest. Changes within this network have been described in healthy aging as well as in Alzheimer's disease (AD) and populations at risk for AD, that is, amnestic Mild Cognitive Impairment (aMCI) patients and APOE-ε4 carriers. This is of particular interest in the context of early diagnosis and more generally for our understanding of the physiopathological mechanisms of AD. This paper gives an overview of the anatomical and physiological characteristics of this network as well as its relationships with cognition, before focusing on changes in the DMN over normal aging and Alzheimer's disease. While perturbations of the DMN have been consistently reported, especially within the posterior cingulate, further studies are needed to understand their clinical implication.


Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.
Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.


Anthocyanins: targeting of signaling networks in cancer cells.
It is becoming progressively more understandable that phytochemicals derived from edible plants have shown potential in modelling their interactions with their target proteins. Rapidly accumulating in-vitro and in- vivo evidence indicates that anthocyanins have anticancer activity in rodent models of cancer. More intriguingly, evaluation of bilberry anthocyanins as chemopreventive agents in twenty-five colorectal cancer patients has opened new window of opportunity in translating the findings from laboratory to clinic. Confluence of information suggests that anthocyanins treated cancer cells reveal up-regulation of tumor suppressor genes. There is a successive increase in the research-work in nutrigenomics and evidence has started to shed light on intracellular-signaling cascades as common molecular targets for anthocyanins. In this review we bring to limelight how anthocyanins induced apoptosis in cancer cells via activation of extrinsic and intrinsic pathways.


An aerosol particle containing enriched uranium encountered in the remote upper troposphere.
We describe a submicron aerosol particle sampled at an altitude of 7 km near the Aleutian Islands that contained a small percentage of enriched uranium oxide. 235U was 3.1 ± 0.5% of 238U. During twenty years of aircraft sampling of millions of particles in the global atmosphere, we have rarely encountered a particle with a similarly high content of 238U and never a particle with enriched 235U. The bulk of the particle consisted of material consistent with combustion of heavy fuel oil. Analysis of wind trajectories and particle dispersion model results show that the particle could have originated from a variety of areas across Asia. The source of such a particle is unclear, and the particle is described here in case it indicates a novel source where enriched uranium was dispersed.


Glycemic index and glycemic load of selected Chinese traditional foods.
To determine the glycemic index (GI) and glycemic load (GL) values of Chinese traditional foods in Hong Kong. Fifteen healthy subjects (8 males and 7 females) volunteered to consume either glucose or one of 23 test foods after 10-14 h overnight fast. The blood glucose concentrations were analyzed immediately before, 15, 30, 45, 60, 90 and 120 min after food consumption using capillary blood samples. The GI value of each test food was calculated by expressing the incremental area under the blood glucose response curve (IAUC) value for the test food as a percentage of each subject's average IAUC value for the glucose. The GL value of each test food was calculated as the GI value of the food multiplied by the amount of the available carbohydrate in a usual portion size, divided by 100. Among all the 23 Chinese traditional foods tested, 6 of them belonged to low GI foods (Tuna Fish Bun, Egg Tart, Green Bean Dessert, Chinese Herbal Jelly, Fried Rice Vermicelli in Singapore-style, and Spring Roll), 10 of them belonged to moderate GI foods (Baked Barbecued Pork Puff, Fried Fritter, "Mai-Lai" Cake, "Pineapple" Bun, Fried Rice Noodles with Sliced Beef, Barbecue Pork Bun, Moon Cakes, Glutinous Rice Ball, Instant Sweet Milky Bun, and Salted Meat Rice Dumpling), the others belonged to high GI foods (Fried Rice in Yangzhou-Style, Sticky Rice Wrapped in Lotus Leaf, Steamed Glutinous Rice Roll, Jam and Peanut Butter Toast, Plain Steamed Vermicelli Roll, Red Bean Dessert, and Frozen Sweet Milky Bun). The GI and GL values for these Chinese traditional foods will provide some valuable information to both researchers and public on their food preference.


Association of Bisphenol A and Its Substitutes, Bisphenol F and Bisphenol S, with Obesity in United States Children and Adolescents.
Bisphenol F (BPF) and bisphenol S (BPS) are increasingly used as substitutes for bisphenol A (BPA), an environmental obesogen. However, health effects of BPF and BPS remain unclear. In this study, we evaluated the associations of BPA, BPF, and BPS with obesity in children and adolescents. We used data from the U.S. National Health and Nutrition Examination Survey 2013 to 2014, a nationally representative study. We included 745 participants aged 6 to 17 years old. General obesity was defined based on the 2000 Centers for Disease Control and Prevention body mass index-for-age growth charts for the United States. Abdominal obesity was defined as waist-to-height ratio ≥0.5. After adjustment for demographic, socioeconomic and lifestyle factors, and urinary creatinine levels, the odds ratio of general obesity comparing the highest with lowest quartile of urinary bisphenol levels was 1.74 (95% confidence interval [CI], 0.92 to 3.31) for BPA, 1.54 (95% CI, 1.02 to 2.32) for BPF, and 1.36 (95% CI, 0.53 to 3.51) for BPS. Moreover, the associations were stronger in boys than in girls for BPA and BPF. Similar results were observed for abdominal obesity. This study for the first time showed that exposure to BPF, a commonly used substitute for BPA, was positively associated with higher risk of obesity in children and adolescents. The association of BPA and BPF with general and abdominal obesity was primarily observed in boys, suggesting a possible sex difference. Further investigations on the underlying mechanisms are needed.


Flexible updating of dynamic knowledge structures.
Schemas are knowledge structures that allow us to make efficient judgments about the world without the cost of memorizing every detail of previous experiences. It has long been known that schemas can enhance long-term memory for related information. The usefulness of schemas, however, critically depends on their adaptability: how flexibly a schema can be updated according to changing environmental conditions. Prior consolidation of a schema supports new learning of schema-consistent information. Yet, the effect of consolidation on inconsistent information, and how schemas may be subsequently updated, are not well understood. It is difficult to track the dynamic updating of knowledge structures with traditional memory measures. Here, using a continuous-report paradigm, we were able to show that schematization increases incrementally with consolidation and that the strength with which schemas are initially established predicts schema-guided responding in a later test. Critically, schema updating in response to inconsistent information was more pronounced in a group which was given time to consolidate compared to a group that was not given time to consolidate. Importantly, the later group reverted back to the no longer relevant schema, indicating that systematic bias towards old information, rather than increased forgetting, underlies reduced memory for schema-inconsistent information.


Prenatal acetaminophen affects maternal immune and endocrine adaptation to pregnancy, induces placental damage, and impairs fetal development in mice.
Acetaminophen (APAP; ie, Paracetamol or Tylenol) is generally self-medicated to treat fever or pain and recommended to pregnant women by their physicians. Recent epidemiological studies reveal an association between prenatal APAP use and an increased risk for asthma. Our aim was to identify the effects of APAP in pregnancy using a mouse model. Allogeneically mated C57Bl/6J females were injected i.p. with 50 or 250 mg/kg APAP or phosphate-buffered saline on gestation day 12.5; nonpregnant females served as controls. Tissue samples were obtained 1 or 4 days after injection. APAP-induced liver toxicity was mirrored by significantly increased plasma alanine aminotransferase levels. In uterus-draining lymph nodes of pregnant dams, the frequencies of mature dendritic cells and regulatory T cells significantly increased on 250 mg/kg APAP. Plasma progesterone levels significantly decreased in dams injected with APAP, accompanied by a morphologically altered placenta. Although overall litter sizes and number of fetal loss remained unaltered, a reduced fetal weight and a lower frequency of hematopoietic stem cells in the fetal liver were observed on APAP treatment. Our data provide strong evidence that prenatal APAP interferes with maternal immune and endocrine adaptation to pregnancy, affects placental function, and impairs fetal maturation and immune development. The latter may have long-lasting consequences on children's immunity and account for the increased risk for asthma observed in humans.


Seroconversion following hepatitis B vaccination in children with chronic kidney disease.
Seroconversion following hepatitis B vaccination is low in children with chronic kidney disease (CKD). This study aimed to assess the seroconversion and persistence of protective immunity following hepatitis B vaccination in children with CKD. This prospective observational study was conducted in a tertiary pediatric nephrology centre to assess the seroconversion and maintenance of antibody titers (>10 mIU/mL) at one year following hepatitis B vaccination (10 μg at 0, 1, and 2 months) in children with CKD Stages II to V. Those who did not seroconvert after the schedule were re-vaccinated, and antibody titers were checked. Categorical data were expressed as proportions and analyzed using the Chi-square test. Pearson's correlation test was used to determine the correlation of antibody titers with other continuous variables. Seroconversion was observed in 72% (n = 26/36) after vaccination. Only 60% (n = 6/10) had seroconversion after the second course of vaccination. Only 60% of children (n = 12/20) who seroconverted had protective antibody titers at one year. Seroconversion following three doses of hepatitis B vaccine is low in children with CKD. Antibody titers should be monitored periodically as the protective immunity wanes rapidly.


"When I go to bed hungry and sleep, I'm not hungry": Children and parents' experiences of food insecurity.
Evidence demonstrates food insecurity has a detrimental impact on a range of outcomes for children, but little research has been conducted in the UK, and children have rarely been asked to describe their experiences directly. We examined the experiences of food insecure families living in South London. Our mixed-methods approach comprised a survey of parents (n = 72) and one-to-one semi-structured interviews with children aged 5-11 years (n = 19). The majority of parents (86%) described their food security during the preceding year as very low. Most reported they had often or sometimes had insufficient food, and almost all had worried about running out of food. Two thirds of parents had gone hungry. Most parents reported they had been unable to afford a nutritionally balanced diet for their children, and just under half reported that their children had gone hungry. Four themes emerged from the interviews with children: sources of food; security of food, nutritional quality of food, and experiences of hunger. Children's descriptions of insufficient food being available indicate that parents are not always able to shield them from the impact of food insecurity. The lack of school-meals and after-school clubs serving food made weekends particularly problematic for some children. A notable consequence of food insecurity appears to be reliance on low-cost takeaway food, likely to be nutritionally poor.


Comparison of Illumina versus Nanopore 16S rRNA Gene Sequencing of the Human Nasal Microbiota.
Illumina and nanopore sequencing technologies are powerful tools that can be used to determine the bacterial composition of complex microbial communities. In this study, we compared nasal microbiota results at genus level using both Illumina and nanopore 16S rRNA gene sequencing. We also monitored the progression of nanopore sequencing in the accurate identification of species, using pure, single species cultures, and evaluated the performance of the nanopore EPI2ME 16S data analysis pipeline. Fifty-nine nasal swabs were sequenced using Illumina MiSeq and Oxford Nanopore 16S rRNA gene sequencing technologies. In addition, five pure cultures of relevant bacterial species were sequenced with the nanopore sequencing technology. The Illumina MiSeq sequence data were processed using bioinformatics modules present in the Mothur software package. Albacore and Guppy base calling, a workflow in nanopore EPI2ME (Oxford Nanopore Technologies-ONT, Oxford, UK) and an in-house developed bioinformatics script were used to analyze the nanopore data. At genus level, similar bacterial diversity profiles were found, and five main and established genera were identified by both platforms. However, probably due to mismatching of the nanopore sequence primers, the nanopore sequencing platform identified Corynebacterium in much lower abundance compared to Illumina sequencing. Further, when using default settings in the EPI2ME workflow, almost all sequence reads that seem to belong to the bacterial genus Dolosigranulum and a considerable part to the genus Haemophilus were only identified at family level. Nanopore sequencing of single species cultures demonstrated at least 88% accurate identification of the species at genus and species level for 4/5 strains tested, including improvements in accurate sequence read identification when the basecaller Guppy and Albacore, and when flowcell versions R9.4 (Oxford Nanopore Technologies-ONT, Oxford, UK) and R9.2 (Oxford Nanopore Technologies-ONT, Oxford, UK) were compared. In conclusion, the current study shows that the nanopore sequencing platform is comparable with the Illumina platform in detection bacterial genera of the nasal microbiota, but the nanopore platform does have problems in detecting bacteria within the genus Corynebacterium. Although advances are being made, thorough validation of the nanopore platform is still recommendable.


Evaluation of publicly financed and privately delivered model of emergency referral services for maternal and child health care in India.
Emergency referral services (ERS) are being strengthened in India to improve access for institutional delivery. We evaluated a publicly financed and privately delivered model of ERS in Punjab state, India, to assess its extent and pattern of utilization, impact on institutional delivery, quality and unit cost. Data for almost 0.4 million calls received from April 2012 to March 2013 was analysed to assess the extent and pattern of utilization. Segmented linear regression was used to analyse month-wise data on number of institutional deliveries in public sector health facilities from 2008 to 2013. We inspected ambulances in 2 districts against the Basic Life Support (BLS) standards. Timeliness of ERS was assessed for determining quality. Finally, we computed economic cost of implementing ERS from a health system perspective. On an average, an ambulance transported 3-4 patients per day. Poor and those farther away from the health facility had a higher likelihood of using the ambulance. Although the ERS had an abrupt positive effect on increasing the institutional deliveries in the unadjusted model, there was no effect on institutional delivery after adjustment for autocorrelation. Cost of operating the ambulance service was INR 1361 (USD 22.7) per patient transported or INR 21 (USD 0.35) per km travelled. Emergency referral services in Punjab did not result in a significant change in public sector institutional deliveries. This could be due to high baseline coverage of institutional delivery and low barriers to physical access. Choice of interventions for reduction in Maternal Mortality Ratio (MMR) should be context-specific to have high value for resources spent. The ERS in Punjab needs improvement in terms of quality and reduction of cost to health system.


Visual gravity influences arm movement planning.
When submitted to a visuomotor rotation, subjects show rapid adaptation of visually guided arm reaching movements, indicated by a progressive reduction in reaching errors. In this study, we wanted to make a step forward by investigating to what extent this adaptation also implies changes into the motor plan. Up to now, classical visuomotor rotation paradigms have been performed on the horizontal plane, where the reaching motor plan in general requires the same kinematics (i.e., straight path and symmetric velocity profile). To overcome this limitation, we considered vertical and horizontal movement directions requiring specific velocity profiles. This way, a change in the motor plan due to the visuomotor conflict would be measurable in terms of a modification in the velocity profile of the reaching movement. Ten subjects performed horizontal and vertical reaching movements while observing a rotated visual feedback of their motion. We found that adaptation to a visuomotor rotation produces a significant change in the motor plan, i.e., changes to the symmetry of velocity profiles. This suggests that the central nervous system takes into account the visual information to plan a future motion, even if this causes the adoption of nonoptimal motor plans in terms of energy consumption. However, the influence of vision on arm movement planning is not fixed, but rather changes as a function of the visual orientation of the movement. Indeed, a clear influence on motion planning can be observed only when the movement is visually presented as oriented along the vertical direction. Thus vision contributes differently to the planning of arm pointing movements depending on motion orientation in space.


Prevalence of gestational diabetes mellitus among James Bay Cree women in northern Quebec.
The prevalence of gestational diabetes mellitus has been reported to vary widely in aboriginal populations. Most of the data have come from the United States. To help determine the extent of gestational diabetes in Canada's aboriginal population, the authors assessed the prevalence in a population of Cree women in northern Quebec. A cross-sectional study was conducted using the National Diabetes Data Group (NDDG) criteria. Information was obtained from patient charts on pregnancies between January 1995 and December 1996 among women residing in 9 Cree communities in the eastern James Bay region of northern Quebec. Women who were not Cree, had pre-existing diabetes, had spontaneous abortion or were receiving glucocorticoid treatment were excluded. Data on 654 pregnancies that met the inclusion criteria were available. Results of the screening oral glucose challenge test were available for 579 of the pregnancies; the remaining 75 were excluded. The mean gestational age at screening was 28.3 (standard deviation 2.6) weeks. The prevalence of gestational diabetes was 12.8% (74/579) (95% confidence interval [CI] 10.1%-15.5%). The prevalence in the inland communities was twice as high as that in the coastal communities (18.0% v. 9.3%, p = 0.002). Women with gestational diabetes or impaired glucose tolerance tended to be older, have had more pregnancies, weigh more before pregnancy and have heavier babies than those with a normal glycemic status. The prevalence of gestational diabetes among James Bay Cree women in northern Quebec is twice as high as that among women in the general North American population and the second highest reported in an aboriginal group worldwide.


Left main coronary artery stenosis: factors predicting cardiac events in patients awaiting coronary surgery.
Although most patients with left main coronary artery stenosis undergo urgent coronary artery bypass grafting, limited information is available regarding the risk factors that might lead to cardiac events between angiographic diagnosis and surgery. We retrospectively reviewed 1,731 cases of coronary artery bypass grafting at our institution, 97 of which were performed in patients with significant (> or = 50%) left main coronary artery stenosis. These patients were placed in 1 of 2 groups: eventful waiting or uneventful waiting. We analyzed multiple preoperative variables, and the incidence of serious cardiac events (death, myocardial infarction, unstable angina, left ventricular failure, and life-threatening ventricular arrhythmias) during the waiting period between angiography and surgery Four patients (4.1%) experienced serious cardiac events while awaiting surgery (1 had non-ST-elevation myocardial infarction; 3 had life-threatening ventricular arrhythmias); none died. All the events occurred more than 24 hours after cardiac catheterization. Of the preoperative variables analyzed (acute coronary syndrome, age, history of diabetes, hypertension, hyperlipidemia, smoking, renal failure, severity of left main stenosis, right coronary artery involvement, ejection fraction, and use of intra-aortic balloon pump), only acute coronary syndrome predicted the incidence of preoperative cardiac events (P=0.001). The occurrence of severe cardiac events while patients await coronary artery bypass grafting is rare. Carefully selected patients with severe left main coronary artery stenosis can safely await surgery. Concomitant acute coronary syndrome and severe left main coronary artery stenosis indicate a high risk for cardiac events. Therefore, in patients with these conditions, emergency coronary artery bypass may be preferable.


Allogeneic cardiosphere-derived cells for the treatment of heart failure with reduced ejection fraction: the Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells (DYNAMIC) trial.
The DYNAMIC trial assessed the safety and explored the efficacy of multivessel intracoronary infusion of allogeneic cardiosphere-derived cells (CDCs) in patients with heart failure and reduced ejection fraction (HFrEF). Here we report the results of the DYNAMIC trial. We enrolled 14 patients with EF ≤35% and NYHA Class III-IV despite maximal medical and device-based therapy in this single-centre, open-label trial. Intracoronary catheterisation delivered four escalating doses (totalling 37.5-75 million cells) by sequential non-occlusive technique to all three major coronary arteries. The primary safety endpoint was a composite of post-infusion TIMI flow, ventricular tachycardia/fibrillation, sudden death, major adverse cardiac events or acute myocarditis within 72 hours. Twelve patients were male and EF averaged 23.0% (±4.5%). No primary safety endpoints were observed. Two patients died of HFrEF progression nine and 12 months following infusion. Compared to baseline, there was an improvement in EF (26.8% vs 22.9%, p=0.023) and left ventricular end-systolic volume (139.5 vs 177.8 cm3, p=0.03) at six months. Quality of life (QoL) scores and NYHA class (p=0.006) improved at six months. At 12 months, the improvement in EF and QoL remained significant. Global intracoronary infusion of allogeneic CDCs is safe and feasible. The efficacy of allogeneic CDCs in HFrEF needs to be tested in larger randomised trials.


Evolving applications of light therapy.
The psychiatric intervention, light therapy, grew from an intensive 25-year research focus on seasonal affective disorder (SAD). Dosing and timing strategies have been honed to optimize the antidepressant effect, and efficacy relative to placebo has provided the evidence base for widespread implementation. A persistent question has been whether the model system for SAD has wider utility for psychiatric disturbance, even beyond depression. The circadian phase-shifting capacity of timed light exposure is universal, and chronobiological factors are at play across the disease spectrum. Recent promising initiatives extend to light treatment for nonseasonal major depressive disorder and bipolar depression, including drug- and electroconvulsive therapy-resistant cases. With light therapy, patients with antepartum depression may find an alternative to medication during pregnancy. Cognitive improvement under light therapy has been noted in adult attention deficit hyperactivity disorder. Motor function in Parkinson's disease has improved in parallel with the antidepressant effect of light therapy. The rest-activity disturbance of elderly dementia has been partially allayed under light therapy. In a new initiative, three major chronotherapeutic inventions-light therapy, sleep deprivation (wake therapy) and sleep time displacement (sleep phase advance therapy) are being combined to snap hospitalized patients out of deep depression and maintain long-term improvement.


Granulomatous and lymphocytic interstitial lung disease: a spectrum of pulmonary histopathologic lesions in common variable immunodeficiency--histologic and immunohistochemical analyses of 16 cases.
Common variable immunodeficiency is a primary immunodeficiency of unknown etiology characterized by low serum immunoglobulin G, a decreased ability to make specific antibodies, and variable T-cell defects. Approximately 10-30% of patients with common variable immunodeficiency develop clinical evidence of a diffuse parenchymal lung disease with a constellation of histopathologic findings termed granulomatous and lymphocytic interstitial lung disease. In this study, we characterized the histologic and immunohistochemical features in a series of 16 cases diagnosed by open lung biopsy. Peribronchiolar and interstitial lymphocytic infiltration, granulomatous inflammation, and organizing pneumonia were consistent features; interstitial fibrosis with architectural remodeling was also found in a subgroup of patients. By immunohistochemistry, a predominance of CD4+ T lymphocytes with variable numbers of CD8+ T cells and B cells was present, with a striking absence of FOXP3-positive T-regulatory cells. This heretofore unrecognized immunohistochemical finding needs further investigation for a potential role in the pathogenesis of the condition. The presence of interstitial fibrosis with or without architectural remodeling in a subset of patients also needs additional study, for effect on prognosis.


Novel Survivin Inhibitor for Suppressing Pancreatic Cancer Cells Growth via Downregulating Sp1 and Sp3 Transcription Factors.
Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. The IC50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G2/M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.


Microfluidic cell sorting: a review of the advances in the separation of cells from debulking to rare cell isolation.
Accurate and high throughput cell sorting is a critical enabling technology in molecular and cellular biology, biotechnology, and medicine. While conventional methods can provide high efficiency sorting in short timescales, advances in microfluidics have enabled the realization of miniaturized devices offering similar capabilities that exploit a variety of physical principles. We classify these technologies as either active or passive. Active systems generally use external fields (e.g., acoustic, electric, magnetic, and optical) to impose forces to displace cells for sorting, whereas passive systems use inertial forces, filters, and adhesion mechanisms to purify cell populations. Cell sorting on microchips provides numerous advantages over conventional methods by reducing the size of necessary equipment, eliminating potentially biohazardous aerosols, and simplifying the complex protocols commonly associated with cell sorting. Additionally, microchip devices are well suited for parallelization, enabling complete lab-on-a-chip devices for cellular isolation, analysis, and experimental processing. In this review, we examine the breadth of microfluidic cell sorting technologies, while focusing on those that offer the greatest potential for translation into clinical and industrial practice and that offer multiple, useful functions. We organize these sorting technologies by the type of cell preparation required (i.e., fluorescent label-based sorting, bead-based sorting, and label-free sorting) as well as by the physical principles underlying each sorting mechanism.


[Three years of AIDS. Experience of the Curry Cabral Hospital with HIV infections (1985-1988)].
The AA. present a retrospective study on their experience with HIV positive patients, followed on the Infectious Diseases Department of the Hospital Curry Cabral, in Lisbon. This study was done in 90 patients seen since 1985 till March 1988. From the 90 patients, 81 were HIV--1 positive, 6 HIV--2 and 3 HIV1 + HIV2 positives. It is presented their distribution by sex (Male = 97.8%), age (mean--36.5 years), risk groups (homosexuals--64.4%, heterosexuals--21.1%, IVDA--7.7%, blood-related--5.6%), and their Walter Reed and CDC classifications. It is emphasised the increasing incidence of infected people along the years and an unexpected high rate of heterosexual males infected. It is also pointed the incidence of Kaposi (22%), Pneumocystis carinii pneumonia (55.6%), and Criptococosis (13.9%) in the WR6 group. The mortality rate was 31.3% for WR5 and 63.9% for WR6. We calculate some Relative Risks for clinical situations matched with risk groups and immunological status (meaning the T Helper lymphocitic count), and measured their statistical significance with the chi-square test. Besides the immunodeficiency, it was mentioned the associated lymphadenopathy and dermatological lesions, the HIV encephalopathy and the constitutional symptoms of the wasting syndrome.


Can bone apposition predict the retention force of a femoral stem? An experimental weight-bearing hip-implant model in goats.
The increasing incidence of prosthesis revision surgery in the Western world has led to an increased focus on the capacity for stem removal. We previously reported on a femoral stem implanted in goats with an approximate 15% reduction in retention force by drilling longitudinally orientated grooves on the side of the stem. In this current study, we aimed to histologically evaluate the bony apposition towards this stem and correlate this apposition with the pullout force. We analyzed the femora of 22 goats after stem removal. All stems remained in place for 6 months, and the goats were allowed regular loading of the hip during this time. For histological evaluation, all femora were immersed in EDTA and decalcified until sufficiently soft for standard technique preparation. We evaluated bone apposition, the presence of foreign particle debris and other factors. The apposition was evaluated with a scoring system based on semi-quantitative bone apposition in four quadrants. Kappa statistics were calculated for the score. We correlated the retention force with the amount of bone apposition. The stem drilling was the only significant factor influencing the retention force (p = 0.020). The bone apposition Kappa score comparing poor and good apposition scores was fair (κ = 0.4, 95% CI 0.00-0.88). Signs of foreign body reaction were noted in 5 of 22 goats. Based on the current findings in an experimental goat model, it appears that the effect of drilling tissue/bone out of the longitudinal grooves has a more significant impact on the retention force required to remove the stem than the amount of bone apposition outside the stem grooves. This observation may be further explored in the research of stem designs that are potentially easier to remove.


Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels.
Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10(-12)) and SNP rs13144478 (P = 6.19 × 10(-18)), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10(-7)). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03-1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.


Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation.
The α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors (AMPAR) subunits can be posttranscriptionally modified by alternative splicing forming flip and flop isoforms. We determined if an ischemia-like insult to retinal ganglion cells (RGCs) increases AMPAR susceptibility to s-AMPA-mediated excitotoxicity through changes in posttranscriptional modified isoforms. Purified neonatal rat RGCs were subjected to either glucose deprivation (GD) or oxygen/glucose deprivation (OGD) conditions followed by treatment with either 100 μM s-AMPA or Kainic acid. A live-dead assay and caspase 3 assay was used to assess cell viability and apoptotic changes, respectively. We used JC-1 dye and dihydroethidium to measure mitochondria depolarization and reactive oxygen species (ROS), respectively. Calcium imaging with fura-2AM was used to determine intracellular calcium, while the fluorescently-labeled probe, Nanoprobe1, was used to detect calcium-permeable AMPARs. Quantitative PCR (qPCR) analysis was done to determine RNA editing sites AMPAR isoforms. Glucose deprivation, as well as an OGD insult followed by AMPAR stimulation, produced a significant increase in RGC death. Retinal ganglion cell death was independent of caspase 3/7 activity, but was accompanied by increased mitochondrial depolarization and increased ROS production. This was associated with an elevated intracellular Ca(2+) and calcium permeable-AMPARs. The mRNA expression of GLUA2 and GLUA3 flop isoform decreased significantly, while no appreciable changes were found in the corresponding flip isoforms. There were no changes in the Q/R editing of GLUA2, while R/G editing of GLUA2 flop declined under these conditions. Following oxidative injury, RGCs become more susceptible to AMPAR-mediated excitotoxicity. RNA editing and changes in alternative spliced flip and flop isoforms of AMPAR subunits may contribute to increased RGC death.


Stable isotopes reveal links between human food inputs and urban ant diets.
The amount of energy consumed within an average city block is an order of magnitude higher than that consumed in any other ecosystem over a similar area. This is driven by human food inputs, but the consequence of these resources for urban animal populations is poorly understood. We investigated the role of human foods in ant diets across an urbanization gradient in Manhattan using carbon and nitrogen stable isotopes. We found that some-but not all-ant species living in Manhattan's most urbanized habitats had δ(13)C signatures associated with processed human foods. In particular, pavement ants (Tetramorium sp. E) had increased levels of δ(13)C similar to δ(13)C levels in human fast foods. The magnitude of this effect was positively correlated with urbanization. By contrast, we detected no differences in δ(15)N, suggesting Tetramorium feeds at the same trophic level despite shifting to human foods. This pattern persisted across the broader ant community; species in traffic islands used human resources more than park species. Our results demonstrate that the degree urban ants exploit human resources changes across the city and among species, and this variation could play a key role in community structure and ecosystem processes where human and animal food webs intersect.


Echocardiographic findings in patients with Wegener granulomatosis.
To describe the spectrum and clinical implications of echocardiographic findings associated with Wegener granulomatosis. We retrospectively reviewed the clinical records and echocardiographic data of consecutive patients with confirmed Wegener granulomatosis referred to the echocardiography laboratory during the 21-year period from 1976 through 1997. Of the 85 patients Identified as having confirmed Wegener granulomatosis, 73 (86%) were found to have echocardiographic abnormalities. In 26 (36%) of these 73 patients, lesions appeared directly related to Wegener granulomatosis. We found regional wall motion abnormalities in 17 (65%) of these 26 patients. Left ventricular systolic dysfunction with decreased ejection fraction was found in 13 patients (50%) and pericardial effusion in 5 patients (19%). Other findings Included valvulitis, left ventricular aneurysm, and a large intracardlac mass. A significantly increased mortality rate was observed among patients who had cardiac involvement of Wegener granulomatosis found by echocardiography. We found a high frequency of echocardiographic abnormalities that appear to be related to Wegener granulomatosis and associated with Increased mortality. Because cardiac involvement in Wegener granulomatosis often is silent and associated with Increased morbidity and worse prognosis, echocardlographic screening of patients with active Wegener granulomatosis may be of clinical value.


An aphid effector promotes barley susceptibility through suppression of defence gene expression.
Aphids secrete diverse repertoires of effectors into their hosts to promote the infestation process. While 'omics' approaches facilitated the identification and comparison of effector repertoires from a number of aphid species, the functional characterization of these proteins has been limited to dicot (model) plants. The bird cherry-oat aphid Rhopalosiphum padi is a pest of cereal crops, including barley. Here, we extend efforts to characterize aphid effectors with regard to their role in promoting susceptibility to the R. padi-barley interaction. We selected three R. padi effectors based on sequence similarity to previously characterized Myzus persicae effectors and assessed their subcellular localization, expression, and role in promoting plant susceptibility. Expression of R. padi effectors RpC002 and Rp1 in transgenic barley lines enhanced plant susceptibility to R. padi but not M. persicae, for which barley is a poor host. Characterization of Rp1 transgenic barley lines revealed reduced gene expression of plant hormone signalling genes relevant to plant-aphid interactions, indicating that this effector enhances susceptibility by suppressing plant defences in barley. Our data suggest that some aphid effectors specifically function when expressed in host species, and feature activities that benefit their corresponding aphid species.


Towards Real-Time Heartbeat Classification: Evaluation of Nonlinear Morphological Features and Voting Method.
Abnormal heart rhythms are one of the significant health concerns worldwide. The current state-of-the-art to recognize and classify abnormal heartbeats is manually performed by visual inspection by an expert practitioner. This is not just a tedious task; it is also error prone and, because it is performed, post-recordings may add unnecessary delay to the care. The real key to the fight to cardiac diseases is real-time detection that triggers prompt action. The biggest hurdle to real-time detection is represented by the rare occurrences of abnormal heartbeats and even more are some rare typologies that are not fully represented in signal datasets; the latter is what makes it difficult for doctors and algorithms to recognize them. This work presents an automated heartbeat classification based on nonlinear morphological features and a voting scheme suitable for rare heartbeat morphologies. Although the algorithm is designed and tested on a computer, it is intended ultimately to run on a portable i.e., field-programmable gate array (FPGA) devices. Our algorithm tested on Massachusetts Institute of Technology- Beth Israel Hospital(MIT-BIH) database as per Association for the Advancement of Medical Instrumentation(AAMI) recommendations. The simulation results show the superiority of the proposed method, especially in predicting minority groups: the fusion and unknown classes with 90.4% and 100%.


Interdomain allosteric regulation of Polo kinase by Aurora B and Map205 is required for cytokinesis.
Drosophila melanogaster Polo and its human orthologue Polo-like kinase 1 fulfill essential roles during cell division. Members of the Polo-like kinase (Plk) family contain an N-terminal kinase domain (KD) and a C-terminal Polo-Box domain (PBD), which mediates protein interactions. How Plks are regulated in cytokinesis is poorly understood. Here we show that phosphorylation of Polo by Aurora B is required for cytokinesis. This phosphorylation in the activation loop of the KD promotes the dissociation of Polo from the PBD-bound microtubule-associated protein Map205, which acts as an allosteric inhibitor of Polo kinase activity. This mechanism allows the release of active Polo from microtubules of the central spindle and its recruitment to the site of cytokinesis. Failure in Polo phosphorylation results in both early and late cytokinesis defects. Importantly, the antagonistic regulation of Polo by Aurora B and Map205 in cytokinesis reveals that interdomain allosteric mechanisms can play important roles in controlling the cellular functions of Plks.


Computer program to predict likelihood of finding and HLA-matched donor: methodology, validation, and application.
Approximately 65% of the patients requiring bone marrow transplantation do not have an HLA-A, -B, -DR identical sibling and therefore need to find a phenotypically matched unrelated donor. As of June 30, 1996, the National Marrow Donor Program maintains a registry of 2.31 million volunteer donors, 35% of whom are fully typed for HLA-A, -B, -DR loci. Because a majority of the donors has not been DR typed, a patient who does not find a complete match at the time of the preliminary search may elect to prospectively DR type A, B matched and A, B one-antigen mismatched donors. An efficient strategy is therefore needed for determining the likelihood that an appropriate donor exists and for deciding which of the donors that have not yet been DR typed should be tested for DR matching with the candidate. We developed a mathematical algorithm and computer program to facilitate the search for a suitable donor by donor race and phenotype. The program provides information on the likelihood of 1) finding at least one HLA-A, -B, -DR phenotypically matched donor, 2) the likelihood of finding at least one DR match among m A, B matched donors who have not yet been DR typed, and 3) the likelihood of an A, B one antigen mismatched donor of a specific phenotype being a DR match with the patient. The mathematical models underlying the program are based on basic population genetics theory and utilize HLA-A, -B, DR haplotype frequencies derived from the NMDP registry. The results of the validation study show that the prediction is highly accurate at the level of broad antigens. The algorithm and program have the potential to assist patients and physicians in optimizing their decisions regarding clinical management and resource allocation on the process of searching for a suitable unrelated bone marrow donor.


Factors Affecting Pycnidium Production of Diaporthe citri on Detached Citrus Twigs.
Melanose, caused by Diaporthe citri, produces black-to-reddish brown lesions on twigs, leaves, and fruit of citrus and reduces the external quality of fruit destined for the fresh market. Inoculum for infection is produced primarily in pycnidia formed on dead twigs, and conidia are dispersed by rainwater. In laboratory studies, the effect of moisture, temperature, twig size, and melanose severity on pycnidium production on detached twigs was investigated. Pycnidium production was greatest when twigs were soaked for 3 to 4 h on alternate days three times per week and the temperature was 28°C. Production was greatest on twigs 3 to 5 mm in diameter and less on thinner or thicker twigs. Pycnidium production was related linearly to melanose severity on the twigs, and almost no pycnidia were produced on asymptomatic twigs. In the field, pycnidium production was greatest on detached, melanose-affected twigs placed in the canopy monthly during January to April than it was on twigs placed in the canopy during other months. The largest number of pycnidia was produced from May to August when fruit is most susceptible. The number of pycnidia produced was related significantly to degree-days above 20°C and weakly related to cumulative rainfall. Knowledge of inoculum production peaks may assist in timing of pruning and fungicide sprays.


Recellularized Native Kidney Scaffolds as a Novel Tool in Nephrotoxicity Screening.
Drug-induced kidney injury in medicinal compound development accounts for over 20% of clinical trial failures and involves damage to different nephron segments, mostly the proximal tubule. Yet, currently applied cell models fail to reliably predict nephrotoxicity; neither are such models easy to establish. Here, we developed a novel three-dimensional (3D) nephrotoxicity platform on the basis of decellularized rat kidney scaffolds (DS) recellularized with conditionally immortalized human renal proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1). A 5-day SDS-based decellularization protocol was used to generate DS, of which 100-μm slices were cut and used for cell seeding. After 8 days of culturing, recellularized scaffolds (RS) demonstrated 3D-tubule formation along with tubular epithelial characteristics, including drug transporter function. Exposure of RS to cisplatin (CDDP), tenofovir (TFV), or cyclosporin A (CsA) as prototypical nephrotoxic drugs revealed concentration-dependent reduction in cell viability, as assessed by PrestoBlue and Live/Dead staining assays. This was most probably attributable to specific uptake of CDDP by the organic cation transporter 2 (OCT2), TFV through organic anion transporter 1 (OAT1), and CsA competing for P-glycoprotein-mediated efflux. Compared with 2D cultures, RS showed an increased sensitivity to cisplatin and tenofovir toxicity after 24-hour exposure (9 and 2.2 fold, respectively). In conclusion, we developed a physiologically relevant 3D nephrotoxicity screening platform that could be a novel tool in drug development.


Adaptation of swallowing hyo-laryngeal kinematics is distinct in oral vs. pharyngeal sensory processing.
Before a bolus is pushed into the pharynx, oral sensory processing is critical for planning movements of the subsequent pharyngeal swallow, including hyoid bone and laryngeal (hyo-laryngeal) kinematics. However, oral and pharyngeal sensory processing for hyo-laryngeal kinematics is not fully understood. In 11 healthy adults, we examined changes in kinematics with sensory adaptation, sensitivity shifting, with oropharyngeal swallows vs. pharyngeal swallows (no oral processing), and with various bolus volumes and tastes. Only pharyngeal swallows showed sensory adaptation (gradual changes in kinematics with repeated exposure to the same bolus). Conversely, only oropharyngeal swallows distinguished volume differences, whereas pharyngeal swallows did not. No taste effects were observed for either swallow type. The hyo-laryngeal kinematics were very similar between oropharyngeal swallows and pharyngeal swallows with a comparable bolus. Sensitivity shifting (changing sensory threshold for a small bolus when it immediately follows several very large boluses) was not observed in pharyngeal or oropharyngeal swallowing. These findings indicate that once oral sensory processing has set a motor program for a specific kind of bolus (i.e., 5 ml water), hyo-laryngeal movements are already highly standardized and optimized, showing no shifting or adaptation regardless of repeated exposure (sensory adaptation) or previous sensory experiences (sensitivity shifting). Also, the oral cavity is highly specialized for differentiating certain properties of a bolus (volume) that might require a specific motor plan to ensure swallowing safety, whereas the pharyngeal cavity does not make the same distinctions. Pharyngeal sensory processing might not be able to adjust motor plans created by the oral cavity once the swallow has already been triggered.


Comparative functional study of clonal insulin-secreting cells cultured in five commercially available tissue culture media.
The electrofusion-derived rat insulin-secreting cell line BRIN-BD11 was cultured in five different commercially available media to determine the optimum medium for the in vitro maintenance of such clonal cell lines. Cells were cultured in RPMI-1640, DMEM, McCOY'S, F-12K, or MEM culture medium supplemented with 10% (v/v) fetal bovine serum and antibiotics (100 U/ml penicillin and 0.1 g/L streptomycin). Insulin secretion studies performed after 10 days revealed RPMI-1640 to be the best performing medium in terms of insulin secretory responsiveness to a range of stimuli including glucose, L-alanine, L-arginine, carbachol, and glibenclamide. Insulin release was significantly decreased (p < 0.01 to p < 0.05) in all other media compared to RPMI-1640. Only the cells cultured in RPMI-1640 and DMEM showed a significant glucose-induced insulin secretory response (p < 0.01 and p < 0.05). McCOY'S gave the next best result followed by F-12K and MEM. After the 10-day culture period, the highest insulin content was found in cells cultured in RPMI-1640 and DMEM with significantly lower levels of insulin in cells cultured in McCOY'S, F-12K, and MEM (p < 0.01 to p < 0.001). RPMI-1640 was used for further studies to investigate the effects of 5.6-16.7 mmol/L glucose in culture on the secretory responsiveness of BRIN-BD11 cells. Significant responses to a number of nonglucidic secretagogues were seen following culture at 5.6 and 16.7 mmol/L glucose, although responsiveness was less than after culture with 11.1 mmol/L glucose. At 16.7 mmol/L glucose culture, glucose-stimulated insulin release was abolished.


Bacterial ammonia causes significant plant growth inhibition.
Many and complex plant-bacteria inter-relationships are found in the rhizosphere, since plants release a variety of photosynthetic exudates from their roots and rhizobacteria produce multifaceted specialized compounds including rich mixtures of volatiles, e.g., the bouquet of Serratia odorifera 4Rx13 is composed of up to 100 volatile organic and inorganic compounds. Here we show that when growing on peptone-rich nutrient medium S. odorifera 4Rx13 and six other rhizobacteria emit high levels of ammonia, which during co-cultivation in compartmented Petri dishes caused alkalization of the neighboring plant medium and subsequently reduced the growth of A. thaliana. It is argued that in nature high-protein resource degradations (carcasses, whey, manure and compost) are also accompanied by bacterial ammonia emission which alters the pH of the rhizosphere and thereby influences organismal diversity and plant-microbe interactions. Consequently, bacterial ammonia emission may be more relevant for plant colonization and growth development than previously thought.


From neurons to neuron neighborhoods: the rewiring of the cerebellar cortex in essential tremor.
Remarkably little has been written on the biology of essential tremor (ET), despite its high prevalence. The olivary model, first proposed in the 1970s, is the traditional disease model for ET; however, the model is problematic for a number of reasons. Recently, intensive tissue-based studies have identified a series of structural changes in the brains of most ET cases, and nearly all of the observed changes are located in the cerebellar cortex. These studies suggest that Purkinje cells are central to the pathogenesis of ET and may thus provide a focus for the development of novel therapeutic strategies. Arising from these studies, a new model of ET proposes that the population of Purkinje cells represents the site of the initial molecular/cellular events leading to ET. Furthermore, a number of secondary changes/remodeling observed in the molecular and granular layers (i.e., in the Purkinje cell "neighborhood") are likely to be of additional mechanistic importance. On a physiological level, the presence of remodeling indicates the likely formation of aberrant synapses and the creation of new/abnormal cortical circuits in ET. Specific efforts need to be devoted to understanding the cascade of biochemical and cellular events occurring in the Purkinje cell layer in ET and its neuron neighborhood, as well as the physiological effects of secondary remodeling/rewiring that are likely to be occurring in this brain region in ET.


Data-Driven Modeling for Precision Medicine in Pediatric Acute Liver Failure.
Absence of early outcome biomarkers for Pediatric Acute Liver Failure (PALF) hinders medical and liver transplant decisions. We sought to define dynamic interactions among circulating inflammatory mediators to gain insights into PALF outcome sub-groups. Serum samples from 101 participants in the PALF study, collected over the first 7 days following enrollment, were assayed for 27 inflammatory mediators. Outcomes (Spontaneous survivors [S, n=61], Non-survivors [NS, n=12], and liver transplant patients [LTx, n=28]) were assessed at 21 days post-enrollment. Dynamic interrelations among mediators were defined using data-driven algorithms. Dynamic Bayesian Network inference identified a common network motif with HMGB1 as a central node in all patient sub-groups. The networks in S and LTx were similar, and differed from NS. Dynamic Network Analysis suggested similar dynamic connectivity in S and LTx, but a more highly-interconnected network in NS that increased with time. A Dynamic Robustness Index calculated to quantify how inflammatory network connectivity changes as a function of correlation stringency differentiated all three patient sub-groups. Our results suggest that increasing inflammatory network connectivity is associated with non-survival in PALF, and may ultimately lead to better patient outcome stratification.


Alcohol and Drug Use Among Postoperative Bariatric Patients: A Systematic Review of the Emerging Research and Its Implications.
Emerging research suggests that some bariatric surgery patients are at a heightened risk for developing substance use problems, especially alcohol use problems. An exhaustive literature review was conducted in January 2015 to investigate all articles published that included data on postoperative alcohol use, alcohol use disorders, and illicit drug use among bariatric surgery patients. Twenty-three studies reported on alcohol and/or substance use among bariatric patients. Six studies longitudinally assessed alcohol use behaviors; 3 of these studies found an increase in alcohol use following surgery. Six studies were cross-sectional, and 2 studies assessed medical records. Five studies investigated the prevalence of admissions to substance abuse treatment, and 3 studies combined alcohol and drug use data in a single index. Six studies reported on illicit drug use and reported low-postoperative use. The studies' samples were primarily non-Hispanic white females in their upper 40s, and only 11 of the 23 studies utilized validated assessment instruments. Studies employing longitudinal designs and large sample sizes indicate that bariatric patients who had the gastric bypass procedure are at an elevated risk for alcohol use problems postoperatively. Research also indicates that bariatric surgery patients might be overrepresented in substance abuse treatment facilities. Risk factors for problematic postoperative alcohol use include regular or problematic alcohol use presurgery, male gender, younger age, tobacco use, and symptoms of attention deficient and hyperactivity disorder. As a whole, however, studies indicate bariatric surgery patients demonstrate a low prevalence of problematic alcohol use, and studies about gastric bypass patients are not entirely conclusive. Prospective, longitudinal studies are needed, utilizing standardized and validated alcohol assessment instruments that follow postoperative bariatric patients well beyond 2 years, and account for types of bariatric procedure. Finally, study samples with greater racial/ethnic diversity and wider age ranges are needed.


Plasma Cathepsin S and Cathepsin S/Cystatin C Ratios Are Potential Biomarkers for COPD.
Purpose. This study aimed to examine whether plasma levels of cathepsin S or its inhibitor, cystatin C, may serve as biomarkers for COPD. Patients and Methods. We measured anthropometrics and performed pulmonary function tests and chest CT scans on 94 patients with COPD and 31 subjects with productive cough but no airflow obstruction ("at risk"; AR). In these subjects and in 52 healthy nonsmokers (NS) and 66 healthy smokers (HS) we measured plasma concentrations of cathepsin S and cystatin C using an ELISA. Data were analyzed using simple and logistic regression and receiver operating characteristic analyses. Results. Cathepsin S and cystatin C plasma levels were significantly higher in the COPD and AR groups than in the NS and HS groups (p < 0.01). Among the COPD patients and AR subjects, plasma cathepsin S levels and cathepsin S/cystatin C ratios, but not cystatin C levels, were negatively related to severe airflow limitation (% FEV1 predicted < 50%; p = 0.005) and severe emphysema as assessed by low attenuation area (LAA) score on chest CT scans (LAA ≥ 8.0; p = 0.001). Conclusion. Plasma cathepsin S and cathepsin S/cystatin C ratios may serve as potential biomarkers for COPD.


Change in Pericardial Fat Volume and Cardiovascular Risk Factors in a General Population of Japanese Men.
Pericardial fat volume (PFV), defined as the volume of ectopic fat in and around the heart, is associated with the atherosclerotic process in coronary arteries. The magnitude of change in PFV over time and the factors affecting this change in a general population, however, have not been investigated. Methods and Results: Cardiac computed tomography (CT) was carried out at baseline and at follow-up in 623 Japanese men aged 40-79 years without a history of cardiovascular disease who were selected randomly in Kusatsu (Shiga, Japan). PFV was measured on cardiac CT in a qualified laboratory. Age, heart rate, triglycerides, and obesity measurements (weight, body mass index, and waist circumference) were significantly and positively associated with PFV at baseline. Over an average interval of 4.7 years, median PFV increased significantly from 64.1 cm3 (IQR, 47.2-90.0 cm3) to 73.6 cm3 (IQR, 53.3-98.1 cm3; P<0.001). Current smoking and heart rate were significantly and independently associated with changes in PFV (B=3.336, P<0.001 and B=6.409, P=0.003, respectively). PFV increased significantly over time in a population-based observational study of Japanese men. PFV change was significantly and independently associated with smoking status and heart rate, suggesting that quitting smoking might help reduce PFV, which could be expected to decrease the risk of coronary artery disease.


Role of brain death and the dead-donor rule in the ethics of organ transplantation.
The "dead-donor rule" requires patients to be declared dead before the removal of life-sustaining organs for transplantation. The concept of brain death was developed, in part, to allow patients with devastating neurologic injury to be declared dead before the occurrence of cardiopulmonary arrest. Brain death is essential to current practices of organ retrieval because it legitimates organ removal from bodies that continue to have circulation and respiration, thereby avoiding ischemic injury to the organs. The concept of brain death has long been recognized, however, to be plagued with serious inconsistencies and contradictions. Indeed, the concept fails to correspond to any coherent biological or philosophical understanding of death. We review the evidence and arguments that expose these problems and present an alternative ethical framework to guide the procurement of transplantable organs. This alternative is based not on brain death and the dead-donor rule, but on the ethical principles of nonmaleficence (the duty not to harm, or primum non nocere) and respect for persons. We propose that individuals who desire to donate their organs and who are either neurologically devastated or imminently dying should be allowed to donate their organs, without first being declared dead. Advantages of this approach are that (unlike the dead-donor rule) it focuses on the most salient ethical issues at stake, and (unlike the concept of brain death) it avoids conceptual confusion and inconsistencies. Finally, we point out parallel developments, both domestically and abroad, that reflect both implicit and explicit support for our proposal.


Effects of active treatment discontinuation in patients with a CD4+ T-cell nadir greater than 350 cells/mm3: 48-week Treatment Interruption in Early Starters Netherlands Study (TRIESTAN).
To evaluate the safety and efficacy of discontinuing highly active antiretroviral therapy (HAART) in HIV-1-positive patients who initiated HAART at a CD4+ T-cell count >350 cells/mm. Eligible patients were identified from the Dutch AIDS Therapy Evaluation, The Netherlands (ATHENA) national observational cohort. Interruption or continuation of HAART was offered to all. Of 71 patients enrolled, 46 (64%) interrupted HAART (STOP group) and 25 (36%) continued HAART (control group). The median CD4+ T-cell nadirs at the start of HAART were 469 (interquartile range [IQR]: 430-720) cells/mm3 and 510 (IQR: 440-637) cells/mm3, respectively. At week 48, the median plasma HIV RNA level in the STOP group had stabilized at approximately pre-HAART values (4.55 log10, IQR: 4.2-4.9 copies/mL), but the CD4+ T-cell count still exceeded the pre-HAART count (563 cells/mm3, IQR: 450-710 cells/mm3). Only 5 patients (11%) had reinitiated HAART after 48 weeks, all for personal reasons. No Centers for Disease Control and Prevention category events or death occurred after interruption. In 6 (13%) of 46 patients, mild symptoms of acute retroviral rebound syndrome (ARVS) were identified. No improvement was observed in mental or physical health scores. In 37% of patients, nonnucleoside reverse transcriptase inhibitor drug concentrations were still detectable 1 week after stopping. Although HAART can safely be interrupted in patients with a high CD4 T-cell nadir, no improvement in quality of life was established. Patients can experience ARVS, the risk for development of resistance after treatment interruption is realistic, and there is a potential hazard of HIV transmission to sexual partners. We would not actively advise stopping treatment in patients who started treatment too early according to current guidelines.