Processing demands upon cognitive, linguistic, and articulatory functions promote grey matter plasticity in the adult multilingual brain: Insights from simultaneous interpreters.
Until now, considerable effort has been made to determine structural brain characteristics related to exceptional multilingual skills. However, at least one important question has not yet been satisfactorily addressed in the previous literature, namely whether and to which extent the processing demands upon cognitive, linguistic, and articulatory functions may promote grey matter plasticity in the adult multilingual brain. Based on the premise that simultaneous interpretation is a highly demanding linguistic task that places strong demands on executive and articulatory functions, here we compared grey matter volumes between professional simultaneous interpreters (SI) and multilingual control subjects. Thereby, we focused on a specific set of a-priori defined bilateral brain regions that have previously been shown to support neurocognitional aspects of language control and linguistic functions in the multilingual brain. These regions are the cingulate gyrus, caudate nucleus, frontal operculum (pars triangularis and opercularis), inferior parietal lobe (IPL) (supramarginal and angular gyrus), and the insula. As a main result, we found reduced grey matter volumes in professional SI, compared to multilingual controls, in the left middle-anterior cingulate gyrus, bilateral pars triangularis, left pars opercularis, bilateral middle part of the insula, and in the left supramarginal gyrus (SMG). Interestingly, grey matter volume in left pars triangularis, right pars opercularis, middle-anterior cingulate gyrus, and in the bilateral caudate nucleus was negatively correlated with the cumulative number of interpreting hours. Hence, we provide first evidence for an expertise-related grey matter architecture that may reflect a composite of brain characteristics that were still present before interpreting training and training-related changes.


Expression of membrane currents in rat diencephalic neurons in serum-free culture.
The whole-cell gigaseal voltage clamp technique has been used to investigate the timing of expression and type of voltage-dependent ionic currents in dissociated primary cultures of fetal rat (E17) diencephalic neurons grown in a serum-free defined medium. The expression of membrane currents varied among cells at any particular time in culture. Despite this variability, certain characteristics of the appearance of ionic currents emerge from this study. These are: (i) the earliest appearing membrane current is a voltage-dependent outward current carried by K+. In some cells, it is the classical delayed rectifier current, whereas in others it is the transient outward current (IA). (ii) The earliest appearing inward current is carried by Na+. In some cells the channels are first expressed in the neurites and then in or near the cell body. The early neuritic Na+ channels are blocked by cobalt or cadmium as well as by tetrodotoxin (TTX). In others, the early Na+ channels appear in or near the cell body and are only blocked by TTX. (iii) With additional time in culture, a majority of cells exhibit a Ca2+ current at the time of Na+ channel appearance in or near the cell body as well as a transient Ca2+-dependent outward current. The Ca2+ current is only a small fraction of the total inward current. These inward currents show the classical pharmacologic profile. The complex pattern of expression of ionic current may reflect multiple populations of neurons with different developmental sequences resulting from differences in cell age and lineage.


Current use of inotropes in circulatory shock.
Treatment decisions on critically ill patients with circulatory shock lack consensus. In an international survey, we aimed to evaluate the indications, current practice, and therapeutic goals of inotrope therapy in the treatment of patients with circulatory shock. From November 2016 to April 2017, an anonymous web-based survey on the use of cardiovascular drugs was accessible to members of the European Society of Intensive Care Medicine (ESICM). A total of 14 questions focused on the profile of respondents, the triggering factors, first-line choice, dosing, timing, targets, additional treatment strategy, and suggested effect of inotropes. In addition, a group of 42 international ESICM experts was asked to formulate recommendations for the use of inotropes based on 11 questions. A total of 839 physicians from 82 countries responded. Dobutamine was the first-line inotrope in critically ill patients with acute heart failure for 84% of respondents. Two-thirds of respondents (66%) stated to use inotropes when there were persistent clinical signs of hypoperfusion or persistent hyperlactatemia despite a supposed adequate use of fluids and vasopressors, with (44%) or without (22%) the context of low left ventricular ejection fraction. Nearly half (44%) of respondents stated an adequate cardiac output as target for inotropic treatment. The experts agreed on 11 strong recommendations, all of which were based on excellent (> 90%) or good (81-90%) agreement. Recommendations include the indications for inotropes (septic and cardiogenic shock), the choice of drugs (dobutamine, not dopamine), the triggers (low cardiac output and clinical signs of hypoperfusion) and targets (adequate cardiac output) and stopping criteria (adverse effects and clinical improvement). Inotrope use in critically ill patients is quite heterogeneous as self-reported by individual caregivers. Eleven strong recommendations on the indications, choice, triggers and targets for the use of inotropes are given by international experts. Future studies should focus on consistent indications for inotrope use and implementation into a guideline for circulatory shock that encompasses individualized targets and outcomes.


Temperature dependence of phonon properties in CVD MoS2 nanostructures - a statistical approach.
In this paper, we report the results of Raman measurements on various molybdenum disulfide (MoS2) nanostructures grown by the chemical vapor deposition (CVD) method on a typical Si/SiO2 substrate. The phonon properties investigated include the positions, widths, and intensities of the E2g and A1g modes and the derivative of the mode positions with respect to the temperature in the 300-460 K range. Our results give new insight into changes in phonon energies in response to different disturbances and show that changes induced by the temperature are similar to the changes induced by stress, making these two factors hardly resolvable in the ħωA1g-ħωE2g coordinate system. We prove that all our samples are weakly coupled to the substrate; thus, the presented results almost purely illustrate the effect of the temperature and thickness. The much stronger coupling to the substrate, however, can explain the high variation in the data reported in the literature. The statistical approach applied makes our results highly reliable and allows proper uncertainty assessment of the obtained results, which is helpful when comparing our results to the results reported by other authors.


Studies on the syngeneic mixed lymphocyte reaction. III. Development of a monoclonal antibody with specificity for autoreactive T cells.
Monoclonal antibodies with specificity for autoreactive murine T cells have been developed. These antibodies inhibit proliferative response of splenic T cells activated by syngeneic spleen cells. These antibodies have no effect on the proliferative response of T cells activated by allogeneic spleen cells or PHA. The number of splenic T cells that react with these monoclonal antibodies is comparable in several normal mouse strains.


Metformin does not improve survival in patients with hepatocellular carcinoma.
To assess whether metformin, which has a chemopreventive effect in chronic liver disease, has any chemotherapeutic effect in hepatocellular carcinoma. This was a retrospective study of 701 patients with newly diagnosed hepatocellular carcinoma (HCC) seen between January 2005 and June 2011 at Mayo Clinic, Rochester, Minnesota. This patient cohort was a part of the global HCC BRIDGE study, which is a large longitudinal study of HCC determining the real-world experience of HCC characteristics, management and patient outcomes. We defined significant metformin exposure as continuation of this agent at least 90 d beyond diagnosis of HCC, and compared survival of diabetic patients on metformin to diabetic patients not on metformin and non-diabetics. Our cohort was 72.9% male, with a mean ± SD age of 62.6 ± 12.3 years. The most common etiologies of liver disease were hepatitis C (34%), alcoholic liver disease (29%), fatty liver disease (15%) and hepatitis B (9%). By univariate analysis, using diabetics not on metformin as the reference group, diabetic patients with HCC on metformin had no survival advantage, with a HR (95%CI) of 1.0 (0.8-1.3). Non-diabetic HCC patients also did not appear to have a survival advantage as compared to diabetic HCC patients not on metformin, as demonstrated by a HR (95%CI) of 1.1 (0.7-1.7). Diabetics on metformin beyond 90 d after HCC diagnosis had a longer median survival at 34.2 mo, as compared to 25.5 mo among diabetic patients who were not on metformin or had discontinued metformin within 90 d after HCC diagnosis. This finding was likely due to potential survival bias among those who lived long enough to receive metformin. Although the literature suggests a chemotherapeutic effect in other malignancies, our study demonstrates no survival benefit to the use of metformin in diabetic patients with HCC.


Broadband calibration-free cavity-enhanced complex refractive index spectroscopy using a frequency comb.
We present broadband cavity-enhanced complex refractive index spectroscopy (CE-CRIS), a technique for calibration-free determination of the complex refractive index of entire molecular bands via direct measurement of transmission modes of a Fabry-Perot cavity filled with the sample. The measurement of the cavity transmission spectrum is done using an optical frequency comb and a mechanical Fourier transform spectrometer with sub-nominal resolution. Molecular absorption and dispersion spectra (corresponding to the imaginary and real parts of the refractive index) are obtained from the cavity mode broadening and shift retrieved from fits of Lorentzian profiles to the individual cavity modes. This method is calibration-free because the mode broadening and shift are independent of the cavity parameters such as the length and mirror reflectivity. In this first demonstration of broadband CE-CRIS we measure simultaneously the absorption and dispersion spectra of three combination bands of CO2 in the range between 1525 nm and 1620 nm and achieve good agreement with theoretical models. This opens up for precision spectroscopy of the complex refractive index of several molecular bands simultaneously.


[Does geometry of the lumbosacral inclination have an effect on the etiology of isolated osteochondrosis of L5/S1?].
Men and women with isolated osteochondrosis L5/S1 (excluding transitional anomalies) were compared against a corresponding group of healthy volunteers to see whether there is any geometric or statistical evidence that might constitute predisposing factors for isolated osteochondrosis L5/S1. Arithmetic means, variances, standard deviations, and correlation coefficients were calculated for all the characteristics determined for the two groups. Multiple linear discriminant analysis was used to try to reproduce any classifications our groupings of the characteristic bearers on the basis of their characteristics. It was found that the position of the sacrum in the pelvis and the extent of lumbar lordosis play a major role. To detect a predisposition for isolated osteochondrosis L5/S1, it is thus necessary to evaluate: the position of the sacrum with regard to the pelvis and the degree of lumbar lordosis-excluding that of the fifth lumbar vertebra-in the angle system. This evaluation can be performed by measuring the dorsal inclination of the sacrum (the delta angle) and the Albrecht inclination.


Genetic resistance to experimental infection with Mycobacterium bovis in red deer (Cervus elaphus).
Tuberculosis (Tb) caused by Mycobacterium bovis is a worldwide threat to livestock and humans. One control strategy is to breed livestock that are more resistant to Mycobacterium bovis. In a 3-year heritability study 6 farmed red deer stags were selected from 39 on the basis of their differing responses to experimental challenge via the tonsillar sac with approximately 500 CFU of M. bovis. Two stags remained uninfected, two were moderately affected, and two developed serious spreading Tb. Seventy offspring, bred from these six stags by artificial insemination using stored semen, were similarly challenged with M. bovis. The offspring showed patterns of response to M. bovis challenge similar to those of their sires, providing evidence for a strong genetic basis to resistance to Tb, with an estimated heritability of 0.48 (standard error, 0.096; P < 0. 01). This is the first time the heritability of Tb resistance in domestic livestock has been measured. The breeding of selection lines of resistant and susceptible deer will provide an ideal model to study the mechanisms of Tb resistance in a ruminant and could provide an additional strategy for reducing the number and severity of outbreaks of Tb in farmed deer herds. Laboratory studies to identify genetic and immunological markers for resistance to Tb are under way. Preliminary studies showed no associations between NRAMP or DRB genes and resistance to Tb in deer. Patterns of immune responses seen in resistant animals suggest that both innate and acquired pathways of immunity are necessary to produce the resistant phenotype.


Tramadol and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects, but decreased analgesic effects, in genetically deficient serotonin transporter (SERT) mice.
The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wild-type (+/+), heterozygous (+/-) and knockout (-/-) mice. Comparisons were made with SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviours in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT-/- mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT-/- mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT+/- mice.


Long-term outcome of cutaneous melanoma patients treated with boron neutron capture therapy (BNCT).
Our aim was to assess the long-term clinical outcome of boron neutron capture therapy (BNCT) using 10B-para-boronophenylalanine (BPA) as the boron delivery agent for cutaneous melanoma. Eight patients (eight lesions) were treated between October 2003 and April 2014. Their ages ranged from 48 to 86 years at the time of treatment. All of the targets were primary lesions and they were located on the sole or face. No patient had evidence of regional lymph node involvement, distant metastases or an active secondary cancer. The clinical stage was cT1-2N0M0 and performance scores were <2. BNCT was carried out at the Kyoto University Research Reactor (KUR). The patients were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin dose. Eight patients were evaluated and six showed a complete response (CR), while two patients had a partial response (PR). Of the two patients with a PR, one has remained a PR with brown spots persisting for 7.5 years following BNCT. The tumor in the other patient recurred after 6 years at the site of persisting brown macula. The overall control rate (CR + PR without recurrence) for the cohort was 88% (7/8). There have never been any adverse events >Grade 2 for the long follow-up period. Our results suggest that BNCT may be a promising treatment modality in the management of early stage cutaneous melanoma when wide local excision is not feasible.


Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients.
The use of extracorporeal membrane oxygenation (ECMO) for severe acute respiratory failure (ARF) in adults is growing rapidly given recent advances in technology, even though there is controversy regarding the evidence justifying its use. Because ECMO is a complex, high-risk, and costly modality, at present it should be conducted in centers with sufficient experience, volume, and expertise to ensure it is used safely. This position paper represents the consensus opinion of an international group of physicians and associated health-care workers who have expertise in therapeutic modalities used in the treatment of patients with severe ARF, with a focus on ECMO. The aim of this paper is to provide physicians, ECMO center directors and coordinators, hospital directors, health-care organizations, and regional, national, and international policy makers a description of the optimal approach to organizing ECMO programs for ARF in adult patients. Importantly, this will help ensure that ECMO is delivered safely and proficiently, such that future observational and randomized clinical trials assessing this technique may be performed by experienced centers under homogeneous and optimal conditions. Given the need for further evidence, we encourage restraint in the widespread use of ECMO until we have a better appreciation for both the potential clinical applications and the optimal techniques for performing ECMO.


Molecular basis of lipoprotein lipase deficiency in two Austrian families with type I hyperlipoproteinemia.
To determine the molecular basis for type I hyperlipoproteinemia in two Austrian families, the lipoprotein lipase (LPL) gene of two patients exhibiting LPL deficiency was analyzed by Southern blotting and by direct genomic sequencing of DNA amplified by polymerase chain reaction (PCR). All exons of the LPL gene except part of the noncoding region of exon 10, all splice donor and acceptor sites, as well as 430 basepairs of the 5'-region including the promotor were sequenced. A homozygous substitution of adenine for guanine in the fifth exon at cDNA position 818 of the LPL gene was found in both patients. Our sequencing strategy largely ruled out a linkage disequilibrium of the identified nucleotide change with another defect potentially causing the clinical phenotype. The base change described abolishes a normally present AvaII restriction site allowing the identification of carriers of the mutant allele by AvaII digestion of PCR fragments of exon 5; three members of the two families were homozygous for this mutation and ten members were heterozygous. The activity of LPL in postheparin plasma was almost completely absent in homozygotes and about half normal in heterozygotes. The loss of activity was related to LPL protein structure. This mutation alters the amino acid sequence at residue 188 from Gly to Glu. The conformational preferences of the protein chain around position 188 were calculated with the use of a knowledge-based computerized method. The most probable conformation is a beta-turn formed by residues 189-192. The mutation seems to destabilize the beta-turn and/or a yet larger domain critical for substrate alignment.


ZraP is a periplasmic molecular chaperone and a repressor of the zinc-responsive two-component regulator ZraSR.
The bacterial envelope is the interface with the surrounding environment and is consequently subjected to a barrage of noxious agents including a range of compounds with antimicrobial activity. The ESR (envelope stress response) pathways of enteric bacteria are critical for maintenance of the envelope against these antimicrobial agents. In the present study, we demonstrate that the periplasmic protein ZraP contributes to envelope homoeostasis and assign both chaperone and regulatory function to ZraP from Salmonella Typhimurium. The ZraP chaperone mechanism is catalytic and independent of ATP; the chaperone activity is dependent on the presence of zinc, which is shown to be responsible for the stabilization of an oligomeric ZraP complex. Furthermore, ZraP can act to repress the two-component regulatory system ZraSR, which itself is responsive to zinc concentrations. Through structural homology, ZraP is a member of the bacterial CpxP family of periplasmic proteins, which also consists of CpxP and Spy. We demonstrate environmental co-expression of the CpxP family and identify an important role for these proteins in Salmonella's defence against the cationic antimicrobial peptide polymyxin B.


The retirement system in transition: the 2007 Retirement Confidence Survey.
WORKERS SLOW TO SEE OR ADAPT TO A CHANGING U.S. RETIREMENT SYSTEM: The 17th annual wave of the Retirement Confidence Survey (RCS) suggests that American workers may be slow to recognize how the U.S. retirement system is changing, and those who are aware of these changes may not be adapting to them in ways that are likely to secure them a comfortable retirement. HALF OF WORKERS LESS CONFIDENT ABOUT PENSION BENEFITS: The RCS finds pension-plan changes by employers have left nearly half of workers less confident about the benefits they will receive from a traditional pension plan, but that those experiencing a decline in retirement benefits often fail to react constructively. Moreover, although Americans will rely increasingly on 401(k) retirement savings plans and other personal savings and investments to fund their retirement security, data suggest that many may not follow professional investment advice when it is offered to them. MANY WORKERS COUNTING ON BENEFITS THAT WON'T BE THERE: Many workers are counting on employer-provided benefits in retirement that are increasingly unavailable. Only 41 percent of workers indicate they or their spouse currently have a defined benefit pension plan, yet 62 percent say they are expecting to receive income from such a plan in retirement. Likewise, workers are as likely to expect as retirees are to receive retiree health insurance through an employer, even though the number of employers offering this benefit to future retirees is declining. MANY WORKERS UNLIKELY TO HEED INVESTMENT ADVICE EVEN IF THEY GET IT: More than half of workers indicate they would be likely to take advantage of professional investment advice offered by companies that manage employer-sponsored retirement plans. However, two-thirds of these workers say they would probably implement only some of the recommendations they receive and 1 in 10 think they would implement none of them. AMERICANS OVERESTIMATE LONG-TERM CARE COVERAGE: One-quarter of workers and more than one-third of retirees report they have long-term care insurance (separate from health insurance, Medicare, and Medicaid) to help pay for care they might need in a nursing home, assisted living facility, or at home. But only 10 percent of Americans age 65 and older are estimated to have had private long-term care insurance in 2002, suggesting that many are counting on coverage they do not actually have. MOST SAVINGS LEVELS ARE MODEST: Almost half of workers saving for retirement report total savings and investments (not including the value of their primary residence or any defined benefit plans) of less than $25,000. The majority of workers who have not put money aside for retirement have little in savings at all: Seven in 10 of these workers say their assets total less than $10,000. CONTINUED IGNORANCE ABOUT SOCIAL SECURITY COVERAGE: Despite the longstanding increase in the eligibility age for Social Security, only a small minority of workers are aware of the age at which they can receive full retirement benefits from Social Security without a reduction for early retirement.


Analysis of Warburg's impedance and its equivalent electric circuits.
The derivation of Warburg's impedance is revisited and critically analyzed. We show that the original derivation where the electric current is assumed to be due only to the diffusion of ions, as proposed by Warburg, raises some fundamental questions. The roles of the drift current, in the absence of which the equilibrium is never reached in the dc case, and of the displacement current, which is important even in the low frequency region where the Warburg's impedance appears, are discussed. Finally, the utility of models based on equivalent electric circuits, ladder networks, or transmission lines in the analysis of impedance spectroscopy data is investigated.


Engaging physicians in change: results of a safety net quality improvement program to reduce overuse.
Identifying, understanding, and addressing clinical variation is a useful tool to promote appropriate care while helping control health care costs. Although accurate, relevant, and useful data are important in the process, successfully engaging physicians to change behavior is often the most significant challenge. Using a commercially available variation analysis process, a California Medicaid managed care plan identified significant network practice pattern variation. A team of panel practitioners then developed a strategy to reduce overuse of 5 identified behaviors. The intervention was evaluated using a pre-post comparison of the panel's use of the 5 behaviors. During the preintervention period, narcotics, muscle relaxants, magnetic resonance imaging (MRI), and spinal injections increased between 8% and 18% per month. Postintervention, the trends reversed. The differences were statistically significant (P<.0001) for muscle relaxant use, narcotic use, overall MRI use, and spinal injections. Peer comparison data and respectful feedback was associated with significant change in patterns of overuse.


Melanopsin and the Non-visual Photochemistry in the Inner Retina of Vertebrates.
Melanopsin (Opn4), a member of the G-protein-coupled receptor family, is a vitamin A-based opsin in the vertebrate retina that has been shown to be involved in the synchronization of circadian rhythms, pupillary light reflexes, melatonin suppression and other light-regulated tasks. In nonmammalian vertebrates there are two Opn4 genes, Opn4m and Opn4x, the mammalian and Xenopus orthologs respectively. Opn4x is only expressed in nonmammalian vertebrates including reptiles, fish and birds, while Opn4m is found in a subset of retinal ganglion cells (RGCs), the intrinsically photosensitive (ip) RGCs of the inner retina of both mammals and nonmammalian vertebrates. All opsins described utilize retinaldehyde as chromophore, photoisomerized from 11-cis- to all-trans-retinal upon light exposure. Visual retinal photoreceptor cones and rods, responsible for day and night vision respectively, recycle retinoids through a process called the visual cycle that involves the retinal pigment epithelium or glial Müller cells. Although Opn4 has been characterized as a bistable photopigment, little is known about the mechanism/s involved in its chromophore regeneration. In this review, we will attempt to shed light on the visual cycle taking place in the inner retina and discuss the state of the art in the nonvisual photochemistry of vertebrates.


Contribution of diet to the composition of the human gut microbiota.
In the human gut, millions of bacteria contribute to the microbiota, whose composition is specific for every individual. Although we are just at the very beginning of understanding the microbiota concept, we already know that the composition of the microbiota has a profound impact on human health. A key factor in determining gut microbiota composition is diet. Preliminary evidence suggests that dietary patterns are associated with distinct combinations of bacteria in the intestine, also called enterotypes. Western diets result in significantly different microbiota compositions than traditional diets. It is currently unknown which food constituents specifically promote growth and functionality of beneficial bacteria in the intestine. The aim of this review is to summarize the recently published evidence from human in vivo studies on the gut microbiota-modulating effects of diet. It includes sections on dietary patterns (e.g. Western diet), whole foods, food constituents, as wells as food-associated microbes and their influence on the composition of human gut microbiota. The conclusions highlight the problems faced by scientists in this fast-developing field of research, and the need for high-quality, large-scale human dietary intervention studies.


Gender differences among hardcore smokers: an analysis of the tobacco use supplement of the current population survey.
Despite significant declines in smoking rates in the United States, a substantial percentage of adults continue to smoke. Improved understanding of current smokers and their contact with sources of cessation support future tobacco control efforts. Recent evidence suggests that hardcore smokers, established smokers without a history of quit attempts, have less contact with cessation support. Although gender is among the major factors that influence smoking cessation, no research is available on gender differences among hardcore smokers. Demographic, environmental, and smoking-related characteristics of female hardcore smokers and male hardcore smokers and other female smokers were examined. Data from 17,777 smokers from the 2003 Current Population Survey Tobacco Use Supplement were analyzed. Compared with female hardcore smokers, male hardcore smokers were more likely to have contact with smoking restrictions at work (OR = 1.69) and at home (OR = 1.45). Compared with female hardcore smokers, female other smokers were more likely to have seen a healthcare provider during the past year who advised them to quit smoking (OR = 1.39) and more likely to have smoking restrictions at work (OR = 1.25) and at home (OR = 2.32)). Measures of nicotine dependence suggested that female hardcore smokers were less dependent than male hardcore smokers but more dependent than other female smokers. The sociodemographic and healthcare access variations in tobacco use identified in our analyses have significant public health implications and underscore the vital need for clinical and scientific advances in tobacco use prevention and control efforts.


Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway).
To investigate whether prognosis of breast-, colon- and prostate cancer may be related to vitamin D(3), induced from solar ultra-violet (UV) radiation, through studies on geographical and seasonal variations in UV radiation. This study includes 115,096 cases of breast-, colon- or prostate cancer, diagnosed between 1964 and 1992. Among these, 45,667 deaths due to the cancer were registered. On the basis of a north-south gradient in solar UV radiation and geographical climatic differences, Norway was divided into eight residential regions. According to seasonal variations in UV radiation, four periods of diagnosis during the year were used. Case fatality according to residential region and to season of diagnosis was estimated using Cox regression. The effects of occupational sun exposure, childbearing pattern and educational level were also evaluated. No geographic variation in case fatality was observed for the three cancer types studied. A significant variation in prognosis by season of diagnosis was observed. Diagnoses during summer and fall, the seasons with the highest level of vitamin D(3), revealed the lowest risk of cancer death. The results suggest that a high level of vitamin D(3) at the time of diagnosis, and thus, during cancer treatment, may improve prognosis of the three cancer types studied.


Opiate receptors and cardiovascular control in conscious SHR and WKY rats.
This study examined the cardiovascular, respiratory, and sympathetic effects of selective mu and delta opioid agonists microinjected into the hypothalamic nucleus preopticus medialis (POM) of conscious SHR and WKY rats. The mu receptor agonist D-Ala2-MePhe4-Gly5-ol-enkephalin (DAGO) at a dose of 0.6 or 6.0 nanomoles (Nmol) increased the blood pressure and heart rate in WKY rats. In SHR rats, the lower dose of DAGO similarly had a pressor effect whereas the higher dose was depressor; heart rat was increased only by the 6.0 nmol dose in these animals. In both SHR and WKY rats, this opioid caused respiratory acidosis and elevation of plasma norepinephrine (NE) and epinephrine (E); plasma vasopressin was reduced by the higher dose of DAGO. All of these effects of the mu agonist were reversed by the opiate receptor antagonist naloxone (0.5 mg/kg, i.a.). The delta opiate-receptor agonist D-Ala2-D-leu5-eukephalin at a dose of 6.0 or 20.0 nmol increased blood pressure and heart rate in both SHR and WKY rats without affecting respiratory variables. Plasma NE and EPI were elevated at the peak of the pressor period. These studies suggest that the anteroventral hypothalamic region may be an important site in central autonomic regulation by opioid peptides. The mu-receptor agonist was more potent than the delta agonist in eliciting cardiovascular and respiratory effects and associated sympatho-adrenomedullary activation.(ABSTRACT TRUNCATED AT 250 WORDS)


Immunogenicity of New Primary Immunization Schedules With Inactivated Poliovirus Vaccine and Bivalent Oral Polio Vaccine for the Polio Endgame: A Review.
In May 2016, countries using oral polio vaccine for routine immunization switched from trivalent oral poliovirus vaccine (tOPV) to bivalent type 1 and 3 OPV (bOPV). This was done in order to reduce risks from type 2 vaccine-derived polioviruses (VDPV2) and vaccine-associated paralytic poliomyelitis (VAPP) and to introduce ≥1 dose of inactivated poliovirus vaccine (IPV) to mitigate post-switch loss of type 2 immunity. We conducted a literature review of studies that assessed humoral and intestinal immunogenicity induced by the newly recommended schedules. Differences in seroconversion rates were closely associated with both timing of first IPV administration and number of doses administered. All studies demonstrated high levels of immunity for types 1 and 3 regardless of immunization schedule. When administered late in the primary series, a second dose of IPV closed the humoral immunity gap against polio type 2 associated with a single dose. IPV doses and administration schedules appear to have limited impact on type 2 excretion following challenge.


Evidence-Based Causal Chains for Linking Health, Development, and Conservation Actions.
Sustainability challenges for nature and people are complex and interconnected, such that effective solutions require approaches and a common theory of change that bridge disparate disciplines and sectors. Causal chains offer promising approaches to achieving an integrated understanding of how actions affect ecosystems, the goods and services they provide, and ultimately, human well-being. Although causal chains and their variants are common tools across disciplines, their use remains highly inconsistent, limiting their ability to support and create a shared evidence base for joint actions. In this article, we present the foundational concepts and guidance of causal chains linking disciplines and sectors that do not often intersect to elucidate the effects of actions on ecosystems and society. We further discuss considerations for establishing and implementing causal chains, including nonlinearity, trade-offs and synergies, heterogeneity, scale, and confounding factors. Finally, we highlight the science, practice, and policy implications of causal chains to address real-world linked human-nature challenges.


Community hospital and medical school cooperation in continuing medical education.
To determine the extent and trends of cooperation in continuing medical education (CME) between community teaching hospitals and medical schools in the United States. A questionnaire was sent in September 1992 to the directors of CME at 276 teaching hospital members of the Association for Hospital Medical Education (AHME). The survey was designed to answer two questions: (1) What is the extent of cooperation between hospital CME providers and medical schools? (2) In the next three years will community hospitals seek competitive or collaborative relationships in CME with medical schools? By late April 1993, 216 (78%) of the questionnaires had been returned. Of these, 177 (64% of the sample) were analyzed. Of the responding hospitals, 91 (52%) cooperated with 92 medical schools in CME; 75 (45%) of the hospitals planned to increase cooperation. Only ten (11%) of the hospitals described their current CME relationship with a medical school as "competitive in most areas"; 23 (14%) expected to increase competition in the next three years. Forty-one (24%) of the respondents were part of a community hospital CME consortium; only 20 (16%) of the other institutions expected to participate in a consortium in the next three years. Hospital size and membership in the Association of American Medical Colleges' Council of Teaching Hospitals were generally correlated with current and future competition in CME with a medical school and likely participation in a community CME consortium. The majority of teaching hospital members of the AHME perceived that they would have cooperative relationships in CME with affiliated medical schools in the three years following the survey. These collaborative relationships should provide an important basis for the further planning and development of medical education consortia.


An Evolutionarily Conserved Abscisic Acid Signaling Pathway Regulates Dormancy in the Liverwort Marchantia polymorpha.
Dormancy is a key process allowing land plants to adapt to changing conditions in the terrestrial habitat, allowing the cessation of growth in response to environmental or physiological cues, entrance into a temporary quiescent state, and subsequent reactivation of growth in more favorable environmental conditions [1-3]. Dormancy may be induced seasonally, sporadically (e.g., in response to drought), or developmentally (e.g., seeds and apical dominance). Asexual propagules, known as gemmae, derived via clonal reproduction in bryophytes, are often dormant until displaced from the parent plant. In the liverwort Marchantia polymorpha, gemmae are produced within specialized receptacles, gemma cups, located on the dorsal side of the vegetative thallus [4]. Mature gemmae are detached from the parent plant but may remain in the cup, with gemma growth suppressed as long as the gemmae remain in the gemma cup and the parental plant is alive [5]. Following dispersal of gemmae from gemma cups by rain, the gemmae germinate in the presence of light and moisture, producing clonal offspring [6]. In land plants, the plant hormone abscisic acid (ABA) regulates many aspects of dormancy and water balance [7]. Here, we demonstrate that ABA plays a central role in the control of gemma dormancy as transgenic M. polymorpha gemmae with reduced sensitivity to ABA fail to establish and/or maintain dormancy. Thus, the common ancestor of land plants used the ABA signaling module to regulate germination of progeny in response to environmental cues, with both gemmae and seeds being derived structures co-opting an ancestral response system.


Epigallocatechin-3-gallate (EGCG): chemical and biomedical perspectives.
The compound (-)-epigallocatechin-3-gallate (EGCG) is the major catechin found in green tea [Camellia sinensis L. Ktze. (Theaceae)]. This polyphenolic compound and several related catechins are believed to be responsible for the health benefits associated with the consumption of green tea. The potential health benefits ascribed to green tea and EGCG include antioxidant effects, cancer chemoprevention, improving cardiovascular health, enhancing weight loss, protecting the skin from the damage caused by ionizing radiation, and others. The compound EGCG has been shown to regulate dozens of disease-specific molecular targets. Many of these molecular targets are only affected by concentrations of EGCG that are far above the levels achieved by either drinking green tea or consuming moderate doses of green tea extract-based dietary supplements. In spite of this, well-designed double-blinded controlled clinical studies have recently demonstrated the efficacy of green tea extracts and purified EGCG products in patients. Therefore, this review highlights results from what the authors believe to be some of the most clinically significant recent studies and describes current developments in the stereoselective total synthesis of EGCG.


Histopathologic and clinical subtypes of autoimmune pancreatitis: the Honolulu consensus document.
Autoimmune pancreatitis (AIP) has been extensively reported from Japan, Europe, and the United States. Whereas the descriptions of AIP from Japan have predominantly been based on the presence of a distinct clinical phenotype, reports from Europe and the United States describe at least 2 histopathologic patterns in patients' condition currently diagnosed as AIP, viz, lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct centric pancreatitis (IDCP) or granulocyte epithelial lesion (GEL)-positive pancreatitis. Although the 2 entities share common histopathologic features (periductal lymphoplasmacytic infiltration and peculiar periductal fibrosis), expert pathologists can accurately distinguish them based on other unique histopathologic features. Clinically, the 2 entities have similar clinical presentation (obstructive jaundice/pancreatic mass and a dramatic response to steroids) but differ significantly in their demography, serological characteristics, other organ involvement, and disease relapse. While LPSP is associated with elevation in titers of nonspecific autoantibodies and serum IgG4 levels, IDCP does not have definitive serological autoimmune markers. All experts agreed that the clinical phenotypes associated with LPSP and IDCP should be nosologically distinguished; however, their terminology was debated. Whereas most experts agreed that the entities should be referred to as type 1 and type 2 AIP, respectively, others had concerns regarding use of the term "autoimmune" to describe IDCP.


Characterization of SB-705498, a potent and selective vanilloid receptor-1 (VR1/TRPV1) antagonist that inhibits the capsaicin-, acid-, and heat-mediated activation of the receptor.
Vanilloid receptor-1 (TRPV1) is a nonselective cation channel, predominantly expressed by sensory neurons, which plays a key role in the detection of noxious painful stimuli such as capsaicin, acid, and heat. TRPV1 antagonists may represent novel therapeutic agents for the treatment of a range of conditions including chronic pain, migraine, and gastrointestinal disorders. Here we describe the in vitro pharmacology of N-(2-bromophenyl)-N'-[((R)-1-(5-trifluoromethyl-2-pyridyl)pyrrolidin-3-yl)]urea (SB-705498), a novel TRPV1 antagonist identified by lead optimization of N-(2-bromophenyl)-N'-[2-[ethyl(3-methylphenyl)amino]ethyl]urea (SB-452533), which has now entered clinical trials. Using a Ca(2+)-based fluorometric imaging plate reader (FLIPR) assay, SB-705498 was shown to be a potent competitive antagonist of the capsaicin-mediated activation of the human TRPV1 receptor (pK(i) = 7.6) with activity at rat (pK(i) = 7.5) and guinea pig (pK(i) = 7.3) orthologs. Whole-cell patch-clamp electrophysiology was used to confirm and extend these findings, demonstrating that SB-705498 can potently inhibit the multiple modes of receptor activation that may be relevant to the pathophysiological role of TRPV1 in vivo: SB-705498 caused rapid and reversible inhibition of the capsaicin (IC(50) = 3 nM)-, acid (pH 5.3)-, or heat (50 degrees C; IC(50) = 6 nM)-mediated activation of human TRPV1 (at -70 mV). Interestingly, SB-705498 also showed a degree of voltage dependence, suggesting an effective enhancement of antagonist action at negative potentials such as those that might be encountered in neurons in vivo. The selectivity of SB-705498 was defined by broad receptor profiling and other cellular assays in which it showed little or no activity versus a wide range of ion channels, receptors, and enzymes. SB-705498 therefore represents a potent and selective multimodal TRPV1 antagonist, a pharmacological profile that has contributed to its definition as a suitable drug candidate for clinical development.


Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.
A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease.


Context-dependent bidirectional regulation of the MutS homolog 2 by transforming growth factor β contributes to chemoresistance in breast cancer cells.
The TGF-β, a tumor suppressive cytokine in normal cells, is abused in cancer to promote the malignancy. In this study, we reported that TGF-β downregulated the mutS homolog 2 (MSH2), a central component of the DNA mismatch repair (MMR) system, in HER2-transformed MCF10A mammary epithelial cells and in breast cancer (BC) cells. This was mediated by a TGF-β-induced micro RNA (miRNA), miR-21, which targeted the 3' untranslated region of MSH2 mRNA and downregulated its expression. A negative correlation between the expression of TGF-β1 and MSH2 was also detected in primary breast tumors. In contrast, TGF-β upregulated MSH2 in nontransformed cells through Smad-mediated, p53-dependent promoter activation, which was absent in BC cells with impaired p53 function. Although this upregulating mechanism also existed in MCF10A/HER2 and p53-proficient BC cells, both basal and TGF-β-induced MSH2 promoter activities were significantly lower than those in MCF10A. Moreover, the basal and TGF-β-induced miR-21 levels were markedly higher in transformed cells, suggesting that the preset levels of miR-21 and MSH2 promoter activity, which is affected by the p53 status, determine the outputs of the bidirectional regulation of MSH2 by TGF-β in a certain cellular context. We further found that by downregulating MSH2, TGF-β contributed to resistance to DNA-damaging chemotherapy agents in cancer cells. Our results indicated a regulatory antagonism between promoter activation and miRNA-mediated posttranscriptional inhibition underlying a dual effect of TGF-β on the DNA repair machinery, which may influence the genomic stability in a context-dependent manner and contribute to chemoresistance in cancer.


Improved Physical Activity Screening Enhances Intervention Effectiveness in Ethnic Minority Women: A Longitudinal Study.
This study identified inconsistencies in physical activity (PA) reported at screening and baseline of a 6-month health promotion intervention and explored how these inconsistencies influenced intervention effectiveness in African American and Hispanic women. Participants completed a telephone screener to determine eligibility for a PA intervention. Inactive participants (≤90 minutes of PA/week) were invited to a baseline assessment, where they completed the International Physical Activity Questionnaire, measuring work, transportation, gardening/housework, and leisure-time PA. Women returned after 6 months to complete an identical post-intervention assessment. Despite being screened as inactive, baseline Questionnaire data indicated that 85.0% of participants (N = 274, M age = 44.6 years, M body mass index = 34.8 kg/m2) were active (>90 minutes of PA/week). Women who reported any work-related PA were 20.9 times more likely to be active at baseline than those who did not (p < .001). Participants who were inactive at both screening and baseline reported greater increases in domestic and gardening PA and total PA from baseline to postintervention (ps < .05). Overweight/obese ethnic minority women may misreport being physically inactive during screening if specific questions about type of PA are not included. Post hoc analyses controlling for screening inaccuracies may improve effectiveness of PA interventions and help intervention programs reach women who may benefit the most.


Newborn screening of neuromuscular diseases.
Neuromuscular diseases represent an heterogenous group of more than 400 diseases, with a very broad phenotypic spectrum. Given their rarity and complexity, neuromuscular diseases are often diagnosed with a very significant delay after which irreversible muscle damage may limit the efficacy of treatments when available. In this context, neonatal screening could constitute a solution for early detection and treatment. A systematic review of the literature in PubMed up to May 1, 2021, was conducted according to PRISMA guidelines, including classical neuromuscular diseases and diseases with a clear peripheral nervous system involvement (including central nervous system disease with severe neuropathy). We found seven diseases for which newborn screening data were reported: spinal muscular atrophy (9), Duchenne muscular dystrophy (9), Pompe disease (8), X-linked adrenoleukodystrophy (5), Krabbe disease (4), myotonic dystrophy type 1 (1), metachromatic leukodystrophy (1). The future of newborn screening for neuromuscular disorders pass through a global technological switch, from a biochemical to a genetic-based approach. The rapid development of therapy also requires the possibility to quickly adapt the list of treated conditions, to allow innovative therapies to achieve their best efficacy.


Phototherapy with combination of super-pulsed laser and light-emitting diodes is beneficial in improvement of muscular performance (strength and muscular endurance), dyspnea, and fatigue sensation in patients with chronic obstructive pulmonary disease.
Phototherapy is an electrophysical intervention being considered for the retardation of peripheral muscular fatigue usually observed in chronic obstructive pulmonary disease (COPD). The objective of this study was to evaluate the acute effects of combination of super-pulsed laser and light-emitting diodes phototherapy on isokinetic performance in patients with COPD. Thirteen patients performed muscular endurance tests in an isokinetic dynamometer. The maximum voluntary isometric contraction (MVIC), peak torque (PT), and total work (TW) of the non-dominant lower limb were measured in two visits. The application of phototherapy or placebo (PL) was conducted randomly in six locations of femoral quadriceps muscle by using a cluster of 12 diodes (4 of 905 nm super-pulsed lasers, 0.3125 mW each; 4 of 875 nm LEDs, 17.5 mW each; and 4 of 640 nm LEDs, 15 mW each, manufactured by Multi Radiance Medical™). We found statistically significant increases for PT (174.7 ± 35.7 N · m vs. 155.8 ± 23.3 N · m, p = 0.003) and TW after application of phototherapy when compared to placebo (778.0 ± 221.1 J vs. 696.3 ± 146.8 J, p = 0.005). Significant differences were also found for MVIC (104.8 ± 26.0 N · m vs. 87.2 ± 24.0 N · m, p = 0.000), sensation of dyspnea (1 [0-4] vs. 3 [0-6], p = 0.003), and fatigue in the lower limbs (2 [0-5] vs. 5 [0.5-9], p = 0.002) in favor of phototherapy. We conclude that the combination of super-pulsed lasers and LEDs administered to the femoral quadriceps muscle of patients with COPD increased the PT by 20.2% and the TW by 12%. Phototherapy with a combination of super-pulsed lasers and LEDs prior to exercise also led to decreased sensation of dyspnea and fatigue in the lower limbs in patients with COPD.


Fatty Acid-Mediated Stromal Reprogramming of Pancreatic Stellate Cells Induces Inflammation and Fibrosis That Fuels Pancreatic Cancer.
Pancreatic ductal adenocarcinoma is one of the deadliest diseases worldwide. Fatty acids (FAs) have properties that affect both cancer cells and tumor environment. We assessed the effects of FAs on malignant characteristics in a pancreatic cancer and pancreatic stellate cell (PSC) coculture model. This study aimed to clarify the FA signature of PSC-derived inflammation and fibrosis in vitro and in a clinicopathological analysis. The in vitro model involved coculture of the human pancreatic cancer cell lines PANC-1 and MIA PaCa-2 with human PSCs. Clinical histological samples were analyzed to characterize the surgical margins of samples from patients who received distal pancreatectomies. The pancreatic cancer cells took up lipids from the culture media. Saturated and unsaturated FAs were required to induce inflammatory responses in human PSCs, and the cocultures showed fibrotic changes. Clinical samples from pancreatic ductal adenocarcinoma patients had more fatty and fibrotic changes in the normal tissue in the surgical margins than samples from noncancer patients. Inflammation and fibrosis levels were increased in pancreatic cancer specimens, supporting the in vitro observations and suggesting that PSCs contribute to pancreatic carcinogenesis. Pancreatic stellate cells thus represent a potential therapeutic target for suppressing stromal changes in pancreatic cancer.


Indoor mold, toxigenic fungi, and Stachybotrys chartarum: infectious disease perspective.
Damp buildings often have a moldy smell or obvious mold growth; some molds are human pathogens. This has caused concern regarding health effects of moldy indoor environments and has resulted in many studies of moisture- and mold-damaged buildings. Recently, there have been reports of severe illness as a result of indoor mold exposure, particularly due to Stachybotrys chartarum. While many authors describe a direct relationship between fungal contamination and illness, close examination of the literature reveals a confusing picture. Here, we review the evidence regarding indoor mold exposure and mycotoxicosis, with an emphasis on S. chartarum. We also examine possible end-organ effects, including pulmonary, immunologic, neurologic, and oncologic disorders. We discuss the Cleveland infant idiopathic pulmonary hemorrhage reports in detail, since they provided important impetus for concerns about Stachybotrys. Some valid concerns exist regarding the relationship between indoor mold exposure and human disease. Review of the literature reveals certain fungus-disease associations in humans, including ergotism (Claviceps species), alimentary toxic aleukia (Fusarium), and liver disease (Aspergillys). While many papers suggest a similar relationship between Stachybotrys and human disease, the studies nearly uniformly suffer from significant methodological flaws, making their findings inconclusive. As a result, we have not found well-substantiated supportive evidence of serious illness due to Stachybotrys exposure in the contemporary environment. To address issues of indoor mold-related illness, there is an urgent need for studies using objective markers of illness, relevant animal models, proper epidemiologic techniques, and examination of confounding factors.


An audit of the quality of care of traumatic brain injury at a busy regional hospital in South Africa.
Access to care by a dedicated neurosurgical unit is limited in the developing world, and the vast majority of patients who sustain a head injury are managed by general surgeons. Prevention of secondary brain injury is paramount. While the principles of management are relatively straightforward, delivering this care may be difficult. This audit looks at the spectrum of head injuries presenting to a busy regional hospital and attempts to measure the quality of care offered to these patients. The audit includes three separate sections. The first is a prospective audit of all patients with a traumatic brain injury presenting to the Accident and Emergency (AE) department at Edendale Hospital, Pietermaritzburg, over a 2-month period. The next two sub-audits consist of a random review of referral letters and AE clerking notes to assess the quality of care received by these patients. A total of 25 referral letters and 28 AE inpatient notes were randomly chosen for review and compared with agreed standardised markers for quality of care. Over the 2 months October and November 2007, 150 patients with a head injury were seen in the AE department. Of these 117 were male. A total of 76 were discharged home after investigation with a head injury warning chart, 49 were admitted to the general wards, 11 were admitted to the surgical intensive care unit, 10 were referred to the neurosurgical centre in Durban, and 4 died in the AE department. Of the 10 who needed advanced neurosurgical care, 3 required urgent burr-holes before referral. One of these patients died. All the remaining 9 patients who were transferred to the neurosurgery unit survived. The referral letters and AE clerking notes revealed major deficits. Traumatic brain injury is a common problem. Only a small subset of patients require specialised neurosurgical care. Although many patients with intracranial injury can tolerate the delay associated with transfer, some cases are acute and urgent intervention by non-neurosurgeons is needed. Prevention of secondary brain injury is poorly understood and not prioritised. This situation needs to be improved. The introduction of formalised standard referral and management sheets may help to improve care.


Hate to Burst Your Balloon: Successful REBOA Use Takes More Than a Course.
Resuscitative endovascular balloon occlusion of the aorta (REBOA) is emerging as a viable intervention for hemorrhagic shock. Training surgeons to place the device is only part of the process. We hypothesize that implementation challenges extend beyond surgical skills training and initial REBOA use should not be expected to mirror published success. All REBOA placements from January 2016 to February 2017 at a level 1 trauma center were reviewed for opportunities for improvement. From September 2016 to February 2017, all patients meeting highest trauma activation criteria were reviewed against our REBOA algorithm to identify patients meeting criteria for REBOA placement but not undergoing the procedure. REBOA was introduced at our institution in September 2015, with the first placement in January 2016. Trauma surgery, emergency department, and operating room staff underwent training. Nine patients had REBOA placed with six survivors. One patient underwent an unsuccessful REBOA attempt and died. Four patients had complications from REBOA. Eight additional patients met indications but did not undergo REBOA. Successful REBOA use requires more than teaching surgeons indications and techniques. For a successful REBOA program, system factors must be addressed. System processes must ensure equipment and procedures are standardized and familiar to all involved. Complications should be expected.


Microplastics: an emerging threat to food security and human health.
Microplastic presence in seafood and foodstuff have been documented globally in recent studies. Consequently, human exposure to microplastics through the ingestion of contaminated food is inevitable and pose a risk to food security and human health. In this review, microplastics and related xenobiotics are defined, global evidence of microplastic pollution in seafood is reviewed, the impacts to commercial marine species and food security are discussed, and the current knowledge of its direct effects on human health is reviewed. In addition, limited information regarding food security and scientific gaps are identified. Although microplastics in the marine environment and its effects on marine organisms have been well documented, more research is needed to completely understand the implications of microplastics over food security and human health. Further research must focus on monitoring and eliminating microplastics along the food supply chain and determining the extent to which food security is affected by microplastic pollution.


Hybrid cricket auditory behavior: evidence for genetic coupling in animal communication.
Male field crickets produce species-specific and stereotyped calling songs. Conspecific females are attracted to the call. Reciprocal F1 hybrid females prefer the calls of sibling hybrids to reciprocal hybrids. Discrimination is probably based on temporal pattern and not carrier frequency of the call. The results imply that production of song by males and its detection by females have a common genetic basis.


Adaptive latitudinal variation in Common Blackbird Turdus merula nest characteristics.
Nest construction is taxonomically widespread, yet our understanding of adaptive intraspecific variation in nest design remains poor. Nest characteristics are expected to vary adaptively in response to predictable variation in spring temperatures over large spatial scales, yet such variation in nest design remains largely overlooked, particularly amongst open-cup-nesting birds. Here, we systematically examined the effects of latitudinal variation in spring temperatures and precipitation on the morphology, volume, composition, and insulatory properties of open-cup-nesting Common Blackbirds' Turdus merula nests to test the hypothesis that birds living in cooler environments at more northerly latitudes would build better insulated nests than conspecifics living in warmer environments at more southerly latitudes. As spring temperatures increased with decreasing latitude, the external diameter of nests decreased. However, as nest wall thickness also decreased, there was no variation in the diameter of the internal nest cups. Only the mass of dry grasses within nests decreased with warmer temperatures at lower latitudes. The insulatory properties of nests declined with warmer temperatures at lower latitudes and nests containing greater amounts of dry grasses had higher insulatory properties. The insulatory properties of nests decreased with warmer temperatures at lower latitudes, via changes in morphology (wall thickness) and composition (dry grasses). Meanwhile, spring precipitation did not vary with latitude, and none of the nest characteristics varied with spring precipitation. This suggests that Common Blackbirds nesting at higher latitudes were building nests with thicker walls in order to counteract the cooler temperatures. We have provided evidence that the nest construction behavior of open-cup-nesting birds systematically varies in response to large-scale spatial variation in spring temperatures.


Republished: Society for Neuroscience in Anesthesiology and Critical Care expert consensus statement: Anesthetic management of endovascular treatment for acute ischemic stroke.
Literature on the anesthetic management of endovascular treatment of acute ischemic stroke (AIS) is limited. Anesthetic management during these procedures is still mostly dependent on individual or institutional preferences. Thus, the Society of Neuroscience in Anesthesiology and Critical Care (SNACC) created a task force to provide expert consensus recommendations on anesthetic management of endovascular treatment of AIS. The task force conducted a systematic literature review (up to August 2012). Because of the limited number of research articles relating to this subject, the task force solicited opinions from experts in this area. The task force created a draft consensus statement based on the available data. Classes of recommendations and levels of evidence were assigned to articles specifically addressing anesthetic management during endovascular treatment of stroke using the standard American Heart Association evidence rating scheme. The draft consensus statement was reviewed by the Task Force, SNACC Executive Committee and representatives of Society of NeuroInterventional Surgery (SNIS) and Neurocritical Care Society (NCS) reaching consensus on the final document. For this consensus statement the anesthetic management of endovascular treatment of AIS was subdivided into 12 topics. Each topic includes a summary of available data followed by recommendations. This consensus statement is intended for use by individuals involved in the care of patients with acute ischemic stroke, such as anesthesiologists, interventional neuroradiologists, neurologists, neurointensivists and neurosurgeons.


Open-label, multicenter study of self-administered icatibant for attacks of hereditary angioedema.
Historically, treatment for hereditary angioedema (HAE) attacks has been administered by healthcare professionals (HCPs). Patient self-administration could reduce delays between symptom onset and treatment, and attack burden. The primary objective was to assess the safety of self-administered icatibant in patients with HAE type I or II. Secondary objectives included patient convenience and clinical efficacy of self-administration. In this phase IIIb, open-label, multicenter study, adult patients were trained to self-administer a single 30-mg icatibant subcutaneous injection to treat their next attack. Icatibant-naïve patients were treated by an HCP prior to self-administration. Evaluations included adverse event (AE) reporting, a validated questionnaire for convenience, and visual analog scale for efficacy. A total of 151 patients were enrolled; 104 had an attack requiring treatment during the study, and 97 patients (19 naïve) were included in the self-administration cohort. Recurrence or worsening of HAE symptoms (22 of 97) was the most commonly reported AE; rescue medications including icatibant (N = 3) and C1-inhibitor concentrate (N = 6) were used in 13 cases. Overall, 89 of 97 patients used a single injection of icatibant. No serious AEs or hospitalizations were reported. Most patients (91.7%) found self-administration preferable to administration in the clinic. The median time to symptom relief (3.8 h) was comparable with results from controlled trials of icatibant. With appropriate training, patients were successfully able to recognize HAE attacks and decide when to self-administer icatibant. This, coupled with the patient-reported high degree of satisfaction, convenience and ease of use supports the adoption of icatibant self-administration in clinical practice.


Knee-specific quality-of-life instruments: which ones measure symptoms and disabilities most important to patients?
Knee-specific quality-of-life instruments are commonly used outcome measures. However, they have not been compared for their ability to detect symptoms and disabilities important to patients. Cohort study (diagnosis); Level of evidence, 1. Subjective portions of 11 knee-specific instruments were consolidated. The frequency and importance of each item were assessed. One hundred fifty-three patients with anterior cruciate ligament ruptures, isolated meniscal tears, or osteoarthritis were polled. Instruments were ranked according to the number of items with high mean importance, high frequency importance product, and low mean importance, and according to the number endorsed by at least 51% of patients. For anterior cruciate ligament tears, the Mohtadi quality-of-life instrument scored highest in 3 categories. For meniscal tears, the Western Ontario Meniscal Evaluation Tool scored highly in all 4 categories. For osteoarthritis, the Western Ontario and McMaster Universities Osteoarthritis Index scored highly in 4 categories. Of the general knee instruments, the International Knee Documentation Committee Standard Evaluation Form and the Knee Injury and Osteoarthritis Outcome Score scored favorably. The Mohtadi quality-of-life instrument, Western Ontario Meniscal Evaluation Tool, and Western Ontario and McMaster Universities Osteoarthritis Index-disease-specific instruments-contain many items important to patients. Of general knee instruments studied, the International Knee Documentation Committee Standard Evaluation Form and the Knee Injury and Osteoarthritis Outcome Score contain the most items important to patients. This study guides clinicians and researchers in selecting instruments that ensure that the patient's perspective is considered for outcome studies involving 3 common knee disorders.


Does Compensatory Anterior Pelvic Tilt Decrease After Bilateral Periacetabular Osteotomy?
The kinetic link among the lumbar spine, pelvic tilt, and the hip has been hypothesized, but this relationship requires further study in acetabular dysplasia. Anecdotal reports suggest that patients may compensate for acetabular dysplasia with an involuntary increase in anterior pelvic tilt; it is not known if this relationship is affected by acetabular reorientation. (1) Does compensatory pelvic tilt decrease on preoperatively obtained standing AP pelvis radiographs compared with those obtained at a minimum of 6 months after bilateral periacetabular osteotomy (PAO)? (2) Does a modified surrogate measurement of pelvic tilt, the pubic symphysis to sacroiliac (PS-SI) index, correlate with a physical synthetic bones model in which pelvic tilt can be directly measured? (3) Can the PS-SI index demonstrate high interrater reliability? We assessed the surgical records of one surgeon, who participates in the longitudinally maintained Academic Network of Conservational Hip Outcomes Research (ANCHOR) registry, for patients who had undergone the second side of a staged bilateral PAO between 2007 and 2016; there were 113 such patients. Of those, 70 (62%) were lost to followup within 6 months of the second PAO or did not have adequate imaging studies, and another three (3%) were excluded for prespecified reasons, leaving 40 (35%) for evaluation in this retrospective study. Standing preoperative and most recent postoperative AP pelvis radiographs were used to measure the Tönnis angle, anterior wall index, posterior wall index, lateral center-edge angle, pubis symphysis-to-sacrococcygeal junction distance, and the PS-SI index. The most recent radiographs were obtained at a mean of 16 ± 6 months after the second PAO. We chose 6 months as the minimum because at this time point, the majority of patients have reached their maximum clinical improvement and are no longer limited by postoperative muscle dysfunction. Statistical analysis was performed using the intraclass correlation coefficient (ICC) for interrater reliability and paired t-tests for assessing change in measurements from pre- to postoperative. Additionally, a model was created using a physical synthetic bones model in which pelvic tilt could be directly measured. This model was secured through bilateral acetabuli on a mount and rotated through 5° increases in pelvic tilt. AP pelvis radiographs were obtained at each point, the PS-SI index was measured, and a regression analysis performed to evaluate for trend. Overall, 37 of 40 patients (93%) had a decrease in pelvic tilt, as measured by the PS-SI index. The mean amount of pelvic tilt as measured by the PS-SI index decreased after surgery when comparing the preoperative with latest radiographs on this parameter (97 ± 14 mm versus 89 ± 13 mm, mean difference 8 ± 9 mm; 95% confidence interval, -11 to -5; range 17 increase to 24 decrease, p < 0.001). A linear relationship between pelvic tilt and PS-SI index (PS-SI index = 5.0° + 3.6° tilt, R = 0.99) was identified in the synthetic bones validation model. Finally, the interrater reliability was found to be excellent for the PS-SI index preoperatively (ICC = 0.986) and postoperatively (ICC = 0.988). We found a modest reduction in anterior pelvic tilt after bilateral PAO. This finding suggests that acetabular reorientation affects pelvic position. In clinical practice, patients with acetabular dysplasia may compensate with dynamic and reversible changes in pelvic tilt. The PS-SI index is a reproducible tool to measure the height of the pelvic inlet as an assessment of pelvic tilt. In the future, clinical studies should evaluate the clinical implications of these radiographic findings, including the assessment of back pain, which although multifactorial may be influenced by pelvic tilt. Level III, therapeutic study.


A review of evidence-based strategies to treat obesity in adults.
Obesity, with its comorbidities, is a major public health problem. Population-based surveys estimate 2 of every 3 U.S. adults are overweight or obese. Despite billions of dollars spent annually on weight loss attempts, recidivism is high and long-term results are disappointing. In simplest terms, weight loss and maintenance depend on energy balance, and a combination of increased energy expenditure by exercise and decreased energy intake through caloric restriction is the mainstay of behavioral interventions. Many individuals successfully lose 5%-10% of body weight through behavioral approaches and thereby significantly improve health. Similar success occurs with some weight loss prescriptions, although evidence for successful weight loss with over-the-counter medications and supplements is weak. Commercial weight loss programs have helped many individuals achieve their goals, although few programs have been carefully evaluated and compared, limiting recommendations of one program over another. For the very obese, bariatric surgery is an option that leads to significant weight loss and improved health, although risks must be carefully weighed. Lifestyle changes, including regular physical activity, healthy food choices, and portion control, must be adopted, regardless of the weight loss approach, which requires ongoing support. Patients can best decide the appropriate approach working with a multidisciplinary team, including their health care provider and experts in nutrition, exercise, and behavioral intervention.


A phosphohistidine proteomics strategy based on elucidation of a unique gas-phase phosphopeptide fragmentation mechanism.
Protein histidine phosphorylation is increasingly recognized as a critical posttranslational modification (PTM) in central metabolism and cell signaling. Still, the detection of phosphohistidine (pHis) in the proteome has remained difficult due to the scarcity of tools to enrich and identify this labile PTM. To address this, we report the first global proteomic analysis of pHis proteins, combining selective immunoenrichment of pHis peptides and a bioinformatic strategy based on mechanistic insight into pHis peptide gas-phase fragmentation during LC-MS/MS. We show that collision-induced dissociation (CID) of pHis peptides produces prominent characteristic neutral losses of 98, 80, and 116 Da. Using isotopic labeling studies, we also demonstrate that the 98 Da neutral loss occurs via gas-phase phosphoryl transfer from pHis to the peptide C-terminal α-carboxylate or to Glu/Asp side chain residues if present. To exploit this property, we developed a software tool that screens LC-MS/MS spectra for potential matches to pHis-containing peptides based on their neutral loss pattern. This tool was integrated into a proteomics workflow for the identification of endogenous pHis-containing proteins in cellular lysates. As an illustration of this strategy, we analyzed pHis peptides from glycerol-fed and mannitol-fed Escherichia coli cells. We identified known and a number of previously speculative pHis sites inferred by homology, predominantly in the phosphoenolpyruvate:sugar transferase system (PTS). Furthermore, we identified two new sites of histidine phosphorylation on aldehyde-alcohol dehydrogenase (AdhE) and pyruvate kinase (PykF) enzymes, previously not known to bear this modification. This study lays the groundwork for future pHis proteomics studies in bacteria and other organisms.


Catalytic asymmetric dearomatization (CADA) reactions of phenol and aniline derivatives.
Phenols are widely used as starting materials in both industrial and academic society. Dearomatization reactions of phenols provide an efficient way to construct highly functionalized cyclohexadienones. The main challenge to make them asymmetric by catalytic methods is to control the selectivity while overcoming the loss of aromaticity. In this tutorial review, an up to date summary of recent progress in CADA reactions of phenol and aniline derivatives is presented.


Structural footprinting in protein structure comparison: the impact of structural fragments.
One approach for speeding-up protein structure comparison is the projection approach, where a protein structure is mapped to a high-dimensional vector and structural similarity is approximated by distance between the corresponding vectors. Structural footprinting methods are projection methods that employ the same general technique to produce the mapping: first select a representative set of structural fragments as models and then map a protein structure to a vector in which each dimension corresponds to a particular model and "counts" the number of times the model appears in the structure. The main difference between any two structural footprinting methods is in the set of models they use; in fact a large number of methods can be generated by varying the type of structural fragments used and the amount of detail in their representation. How do these choices affect the ability of the method to detect various types of structural similarity? To answer this question we benchmarked three structural footprinting methods that vary significantly in their selection of models against the CATH database. In the first set of experiments we compared the methods' ability to detect structural similarity characteristic of evolutionarily related structures, i.e., structures within the same CATH superfamily. In the second set of experiments we tested the methods' agreement with the boundaries imposed by classification groups at the Class, Architecture, and Fold levels of the CATH hierarchy. In both experiments we found that the method which uses secondary structure information has the best performance on average, but no one method performs consistently the best across all groups at a given classification level. We also found that combining the methods' outputs significantly improves the performance. Moreover, our new techniques to measure and visualize the methods' agreement with the CATH hierarchy, including the threshholded affinity graph, are useful beyond this work. In particular, they can be used to expose a similar composition of different classification groups in terms of structural fragments used by the method and thus provide an alternative demonstration of the continuous nature of the protein structure universe.


Pan-Canadian Estimates of Chronic Pain Prevalence From 2000 to 2014: A Repeated Cross-Sectional Survey Analysis.
Recent temporal trends in the population prevalence of chronic pain in Canada on a national and provincial level are unknown. Five cycles of the Canadian Community Health Survey (2000/2001, 2007/2008, 2009/2010, 2011/2012, and 2013/2014) were used to derive population-based estimates of the self-reported prevalence of chronic pain. Sensitivity analyses examined chronic pain prevalence among those reporting no other chronic health conditions. The prevalence of chronic pain among the general Canadian population increased by almost 4.0% (to 21.0%) in 2011/2012, after being in the range of 15.7 to 17.2% from 2000 to 2009/2010. The sudden increase in prevalence was observed 1) across all provinces in Canada, 2) in all age categories, and 3) among Canadians with no other chronic health conditions. Increasing chronic pain prevalence in Canada, most significantly occurring between 2010 and 2012, and including among healthy and young individuals, emphasizes the need for targeted research and resources to help alleviate chronic pain. PERSPECTIVE: This study uncovers a significant increase in chronic pain prevalence in Canada between 2009/2010 and 2011/2012, driven by younger Canadians that are free of the most common chronic health conditions. This discovery emphasizes the importance of further directed research and resources to help mitigate the trend of increasing chronic pain.


Microarray analysis and motif detection reveal new targets of the Salmonella enterica serovar Typhimurium HilA regulatory protein, including hilA itself.
DNA regulatory motifs reflect the direct transcriptional interactions between regulators and their target genes and contain important information regarding transcriptional networks. In silico motif detection strategies search for DNA patterns that are present more frequently in a set of related sequences than in a set of unrelated sequences. Related sequences could be genes that are coexpressed and are therefore expected to share similar conserved regulatory motifs. We identified coexpressed genes by carrying out microarray-based transcript profiling of Salmonella enterica serovar Typhimurium in response to the spent culture supernatant of the probiotic strain Lactobacillus rhamnosus GG. Probiotics are live microorganisms which, when administered in adequate amounts, confer a health benefit on the host. They are known to antagonize intestinal pathogens in vivo, including salmonellae. S. enterica serovar Typhimurium causes human gastroenteritis. Infection is initiated by entry of salmonellae into intestinal epithelial cells. The expression of invasion genes is tightly regulated by environmental conditions, as well as by many bacterial factors including the key regulator HilA. One mechanism by which probiotics may antagonize intestinal pathogens is by influencing invasion gene expression. Our microarray experiment yielded a cluster of coexpressed Salmonella genes that are predicted to be down-regulated by spent culture supernatant. This cluster was enriched for genes known to be HilA dependent. In silico motif detection revealed a motif that overlaps the previously described HilA box in the promoter region of three of these genes, spi4_H, sicA, and hilA. Site-directed mutagenesis, beta-galactosidase reporter assays, and gel mobility shift experiments indicated that sicA expression requires HilA and that hilA is negatively autoregulated.


Enhanced determination of Streptococcus pneumoniae serotypes associated with invasive disease in Laos by using a real-time polymerase chain reaction serotyping assay with cerebrospinal fluid.
A prospective hospital-based study was undertaken to define the incidence of invasive pneumococcal disease (IPD) and circulating serotypes in Laos. Of 10,799 patients with hemocultures and 353 patients with cerebrospinal fluid samples, 0.21% and 5.4%, respectively, were positive for Streptococcus pneumoniae, giving a total of 35 IPD patients. We developed a real-time polymerase chain reaction to detect serotypes represented in the 13-valent pneumococcal vaccine. A blinded evaluation comparing serotype as defined by the Quellung reaction versus the polymerase chain reaction demonstrated 100% concordance. The most frequent serotype (n = 33 patients) was 1 (n = 6), followed by serotypes 5, 6A/B/C, 14, and 23F. Serotypes represented in the 7-valent polysaccharide-protein conjugate vaccine (PCV-7) infected 39% of patients, with 73% coverage for the PCV-10 and PCV-13 vaccines. Although the sample size is small, these data suggest that the PCV-7 vaccine may have relatively low efficacy in Laos. Further studies are urgently needed to guide pneumococcal vaccine policy in Laos.


Development and Validation of a Classification System to Identify High-Grade Dysplasia and Esophageal Adenocarcinoma in Barrett's Esophagus Using Narrow-Band Imaging.
Although several classification systems have been proposed for characterization of Barrett's esophagus (BE) surface patterns based on narrow-band imaging (NBI), none have been widely accepted. The Barrett's International NBI Group (BING) aimed to develop and validate an NBI classification system for identification of dysplasia and cancer in patients with BE. The BING working group, composed of NBI experts from the United States, Europe, and Japan, met to develop a validated, consensus-driven NBI classification system for identifying dysplasia and cancer in BE. The group reviewed 60 NBI images of nondysplastic BE, high-grade dysplasia, and esophageal adenocarcinoma to characterize mucosal and vascular patterns visible by NBI; these features were used to develop the BING criteria. We then recruited adult patients undergoing surveillance or endoscopic treatment for BE at 4 institutions in the United States and Europe, obtaining high-quality NBI images and performing histologic analysis of biopsies. Experts individually reviewed 50 NBI images to validate the BING criteria, and then evaluated 120 additional NBI images (not previously viewed) to determine whether the criteria accurately predicted the histology results. The BING criteria identified patients with dysplasia with 85% overall accuracy, 80% sensitivity, 88% specificity, 81% positive predictive value, and 88% negative predictive value. When dysplasia was identified with a high level of confidence, these values were 92%, 91%, 93%, 89%, and 95%, respectively. The overall strength of inter-observer agreement was substantial (κ = 0.681). The BING working group developed a simple, internally validated system to identify dysplasia and EAC in patients with BE based on NBI results. When images are assessed with a high degree of confidence, the system can classify BE with >90% accuracy and a high level of inter-observer agreement.


Relationship education and marital satisfaction in newlywed couples: A propensity score analysis.
The purpose of this study was to investigate whether premarital relationship education and characteristics of relationship education in a community sample of newlywed couples predicted marital trajectories over 27 months. Newlywed couples (N = 191) completed measures of marital satisfaction 9 times over 27 months, and prior to marriage they provided information about relationship education and demographic, personal, and relationship risk factors for marital distress. Propensity scores (i.e., the probability of receiving relationship education) were estimated using the marital distress risk factors, and used to derive a matched sample of 72 couples who participated in relationship education and 86 couples who did not. Multilevel analyses of the propensity score matched sample (n = 158) indicated that wives who participated in relationship education had declines in marital satisfaction while wives who did not receive relationship education maintained satisfaction over time. Furthermore, the more hours of relationship education the couple participated in, the less steeply their marital satisfaction declined. Findings indicate that participation in community-based relationship education may not prevent declines in marital satisfaction for newlywed couples. A possible explanation is that the quality of relationship education available to couples is generally poor and could be greatly improved by inclusion of empirically based relationship information and skills training that are known to lead to stronger marriages.


Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line.
Resveratrol (Calbiochem, La Jolla, California) is a naturally occurring stilbene reported to cause apoptosis in various cultured cancer cells. In the current study the effect of resveratrol was determined in the androgen insensitive DU 145 prostate cancer cell line. Induction of apoptosis and activation of apoptosis related signal transduction pathways were measured. DU 145 cells were treated with resveratrol and apoptosis was measured by determining nucleosome content. Activation of mitogen activated protein kinase (MAPK) (extracellular signal-regulated kinase 1/2), p53 content and serine-15 phosphorylation of p53 were measured by immunoblot. Electrophoretic mobility shift assay of p53 binding to DNA, and measurement of p21 and glyceraldehyde-3-phosphate dehydrogenase messenger RNA were also done. Resveratrol induced apoptosis in DU 145 cells. The stilbene activated MAPK and caused increased abundance of p53 and serine-15 phosphorylated p53. Resveratrol induced serine-15 phosphorylation of p53 was blocked by PD 98059 (Calbiochem), a MAPK kinase inhibitor, implicating MAPK activation in the phosphorylation of p53. PD 98059 also inhibited resveratrol induced apoptosis. These results suggest that apoptosis induction by resveratrol in DU 145 cells requires serine-15 phosphorylation of p53 by MAPK. Inhibition of MAPK dependent serine-15 phosphorylation resulted in reduced p53 binding to a p53 specific oligonucleotide on electrophoretic mobility shift assay. Pifithrin-alpha (Calbiochem), a p53 inhibitor, blocked resveratrol induced serine-15 phosphorylation of p53 and p53 binding to DNA. Resveratrol caused a p53 stimulated increase in p21 messenger RNA. Transfection of additional wild-type p53 into DU 145 cells induced apoptosis, which was further enhanced by resveratrol treatment. Resveratrol causes apoptosis in DU 145 prostate cancer cells. This action depends on the activation of MAPK, increase in cellular p53 content, serine-15 phosphorylation of p53 and increased p53 binding to DNA.


Integrating docking scores and key interaction profiles to improve the accuracy of molecular docking: towards novel B-RafV600E inhibitors.
A set of ninety-eight B-RafV600E inhibitors was used for the development of a molecular docking based QSAR model using linear and non-linear regression models. The integration of docking scores and key interaction profiles significantly improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.935, Rtest2 = 0.728 and QCV2 = 0.905). The established MD-SVR (molecular docking based SMV regression) model as well as model screening of a natural product database was carried out and two natural products (quercetin and myricetin) with good prediction activities were biologically evaluated. Both compounds exhibited promising B-RafV600E inhibitory activities (ICQuercetin50 = 7.59 μM and ICMyricetin50 = 1.56 μM), suggesting a high reliability and good applicability of the established MD-SVR model in the future development of B-RafV600E inhibitors with high efficacy.


Basal plasma levels of insulin, leptin, ghrelin, and amylin do not signal adiposity in rats recovering from forced overweight.
This study examined how adiposity signals are related to adiposity during recovery from forced overweight (OW). Rats were rendered OW by chronic intragastric overfeeding (OW). Overfeeding was stopped when OW rats reached 126-129% of saline-infused normal-weight (NW) rats. Adipose tissue (AT) mass was estimated by computed tomography, and blood was drawn from chronic atrial cannulas throughout. Basal levels (i.e. after 2-3 h fasts late in the diurnal phase) of the hypothesized adiposity signals insulin, leptin, ghrelin, and amylin were assayed. OW rats gained approximately 130 g more body weight (BW) and approximately 100 g more AT mass during overfeeding. Plasma levels of insulin and leptin increased, whereas those of ghrelin decreased, linearly with AT mass; amylin did not change reliably. During recovery, OW rats' BW and AT mass decreased but were still elevated vs. NW rats after 39 d. OW rats' insulin returned to NW levels on d 1 of recovery and decreased below NW levels thereafter. Leptin was no longer elevated after d 8 of recovery. Ghrelin and amylin did not change reliably during recovery. Although AT mass decreased in OW rats during each intermeasurement interval between d 0 and d 23 of recovery, insulin and leptin did so during only the first interval (d 0-5). Insulin and leptin levels were exponentially related to AT mass during recovery. These data indicate that basal insulin, leptin, ghrelin, and amylin do not encode AT mass in rats dynamically regulating BW and adiposity during recovery from OW.


Identification of lectin-purified neural glycoproteins, GPs 180, 116, and 110, with NMDA and AMPA receptor subunits: conservation of glycosylation at the synapse.
The postsynaptic apparatus is associated with a number of glycoproteins with apparent molecular masses of 180, 116, and 110 kDa, which are highly concentrated in and may be uniquely associated with this structure. These glycoproteins, purified by concanavalin A lectin-affinity chromatography, showed immunoreactivity in the present study with subunit-specific antibodies to glutamate receptors as follows: GP 180, NMDA receptor subunits NR2A/NR2B; GP 116, NMDA receptor NR1 (1a); and GP 110, pan-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (pan-AMPA) receptors. Sensitivities to the glycosidases peptide N-glycosidase F and endo-beta-N-acetylglucosaminidase H on both western blots and silver-stained gels suggested that the glutamate receptors were at least major constituents of the glycoprotein bands. Similar detailed glycosylation was observed for all three glycoproteins, with neutral oligosaccharides being dominant. Oligomannosidic glycans (with from five to nine mannoses) accounted for approximately 50% of the neutral sugars, with Man 5 (at almost 20% of the neutral sugars) always the major glycan. Other abundant neutral oligosaccharides were of the complex type. Similar sensitivities to peptide N-glycosidase F and endo-beta-N-acetylglucosaminidase H were observed for cell line-expressed NMDA receptor subunits, suggesting that irrespective of the glycosylation processing available, the least highly processed oligosaccharides will be expressed. This may be indicative of glycosylation sites in these receptors that are inaccessible to the later processing enzymes and favours the oligomannosidic class of glycans in functional roles.


Primary renal lymphoma.
A 62-year-old male patient presented with right flank pain and right renal mass on CT scan. Patient left against medical advice and had nephrectomy done elsewhere. Histopathology revealed a diffuse large cell B-cell lymphoma. Patient presented again, with disseminated disease and was started on chemotherapy. Although a rare disorder, missing primary renal lymphoma as one of the causes of renal mass can lead to disseminated disease and unnecessary nephrectomy, in spite of chemotherapy being standard management.


Responses of wind erosion to climate-induced vegetation changes on the Colorado Plateau.
Projected increases in aridity throughout the southwestern United States due to anthropogenic climate change will likely cause reductions in perennial vegetation cover, which leaves soil surfaces exposed to erosion. Accelerated rates of dust emission from wind erosion have large implications for ecosystems and human well-being, yet there is poor understanding of the sources and magnitude of dust emission in a hotter and drier climate. Here we use a two-stage approach to compare the susceptibility of grasslands and three different shrublands to wind erosion on the Colorado Plateau and demonstrate how climate can indirectly moderate the magnitude of aeolian sediment flux through different responses of dominant plants in these communities. First, using results from 20 y of vegetation monitoring, we found perennial grass cover in grasslands declined with increasing mean annual temperature in the previous year, whereas shrub cover in shrublands either showed no change or declined as temperature increased, depending on the species. Second, we used these vegetation monitoring results and measurements of soil stability as inputs into a field-validated wind erosion model and found that declines in perennial vegetation cover coupled with disturbance to biological soil crust resulted in an exponential increase in modeled aeolian sediment flux. Thus the effects of increased temperature on perennial plant cover and the correlation of declining plant cover with increased aeolian flux strongly suggest that sustained drought conditions across the southwest will accelerate the likelihood of dust production in the future on disturbed soil surfaces.