Simultaneous assessment of gastric emptying and secretion in rats by a novel computed tomography-based method.
Gastric emptying and gastric secretion are two major physiological functions of the stomach. The assessment of these functions in particular in small animals is challenging; no method currently available allows the simultaneous measurement of both functions, and methods used are lethal or invasive and often limited by spatial, temporal, or quantitative resolution. Here, we report the establishment and validation of a quantitative noninvasive high-throughput computed tomography-based method to measure simultaneously gastric emptying and secretion in rats in vivo. The imaging strategy enables one to visualize stomach anatomy and to quantify stomach volume and stomach contrast agent content. The method was validated by comparing the results to classical lethal methods (stomach phenol red content and stomach wet weight). Additionally, we showed that the use of a mild anesthetic does not interfere with normal gastric function, thereby enabling high-resolution temporal studies within single animals. These combined advantages were applied to reevaluate the impact of cholecystokinin (CCK), histamine, and oral glucose solutions on gastric function with high temporal resolution. CCK inhibited gastric emptying completely for 20 min, leading to the accumulation of gastric juice in the stomach. The CCK antagonist devazepide blocked this effect. Histamine stimulated both gastric secretion and delayed emptying. Oral glucose solution emptied at a fixed rate of 24-31 cal/min and stimulated gastric secretion. These results confirm previous observations and add volumetric changes as a new dimension. As computed tomography scanners become broadly available, this method is an excellent approach to measure the combined gastric functional readout and to reduce the number of animals used.


Performance of e-ASPECTS software in comparison to that of stroke physicians on assessing CT scans of acute ischemic stroke patients.
The Alberta Stroke Program Early CT score (ASPECTS) is an established 10-point quantitative topographic computed tomography scan score to assess early ischemic changes. We compared the performance of the e-ASPECTS software with those of stroke physicians at different professional levels. The baseline computed tomography scans of acute stroke patients, in whom computed tomography and diffusion-weighted imaging scans were obtained less than two hours apart, were retrospectively scored by e-ASPECTS as well as by three stroke experts and three neurology trainees blinded to any clinical information. The ground truth was defined as the ASPECTS on diffusion-weighted imaging scored by another two non-blinded independent experts on consensus basis. Sensitivity and specificity in an ASPECTS region-based and an ASPECTS score-based analysis as well as receiver-operating characteristic curves, Bland-Altman plots with mean score error, and Matthews correlation coefficients were calculated. Comparisons were made between the human scorers and e-ASPECTS with diffusion-weighted imaging being the ground truth. Two methods for clustered data were used to estimate sensitivity and specificity in the region-based analysis. In total, 34 patients were included and 680 (34 × 20) ASPECTS regions were scored. Mean time from onset to computed tomography was 172 ± 135 min and mean time difference between computed tomographyand magnetic resonance imaging was 41 ± 31 min. The region-based sensitivity (46.46% [CI: 30.8;62.1]) of e-ASPECTS was better than three trainees and one expert (p ≤ 0.01) and not statistically different from another two experts. Specificity (94.15% [CI: 91.7;96.6]) was lower than one expert and one trainee (p < 0.01) and not statistically different to the other four physicians. e-ASPECTS had the best Matthews correlation coefficient of 0.44 (experts: 0.38 ± 0.08 and trainees: 0.19 ± 0.05) and the lowest mean score error of 0.56 (experts: 1.44 ± 1.79 and trainees: 1.97 ± 2.12). e-ASPECTS showed a similar performance to that of stroke experts in the assessment of brain computed tomographys of acute ischemic stroke patients with the Alberta Stroke Program Early CT score method.


A systematic review of urban green space research over the last 30 years: A bibliometric analysis.
Worldwide, due to rapid urbanization, the provision of urban green spaces (UGSs) has become a primary goal of urban planning. As such, research on the benefits, effects, and challenges of UGSs has gained widespread attention among scholars. This paper comprehensively analyzes three decades of UGS research and its evolution; it conducts a bibliometric analysis of approximately 4000 articles and reviews from the Web of Science platform to discover the patterns and trends characterizing UGS research over time. We found that the pioneers of initial UGS research were the United States and Canada, whereas recently the European Union and China have become the global engines of research in the field. UGS research initially focused on studying urban forests, gradually shifting toward green spaces located in inner urban areas. Early on, researchers investigated UGSs (i.e., urban forests) from an ecological perspective. However, the most current research phase focuses on the social aspects of UGSs, characterized by such keywords as environmental justice and accessibility. Furthermore, the introduction of geographic information systems (GIS) has given new impetus to the evolution of UGS research and has remained the most used technological advancement besides remote sensing techniques. As the social aspects of UGS research have gained importance, new research methods have been employed, such as machine learning, big data and social media data analysis, and artificial intelligence, most recently.


A Multidisciplinary Toxicity Team for Cancer Immunotherapy-Related Adverse Events.
Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought. Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team's recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed. The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought. A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.


Binding of porphyrin to human serum albumin. Structure-activity relationships.
The equilibrium binding of hydroxyethyl vinyl deuteroporphyrin (HVD) and of irreversible porphyrin aggregates to human serum albumin was studied at the molecular level. This protein may function as an endogenous drug carrier for porphyrins in photodynamic therapy of tumours. HVD-protein binding studies revealed two types of binding sites, which are attributed to the two HVD isomers. The binding constant for the high-affinity isomer, 2.1 (+/- 0.3) x 10(8) M-1, is similar to that previously determined for protoporphyrin. At the same time the binding constant for the lower-affinity HVD isomer, 1.8(+/- 0.3) x 10(6) M-1, is similar to that previously determined for haematoporphyrin. Irreversible porphyrin aggregates were purified from the haematoporphyrin derivative and from Photofrin and are defined by spectral and chromatographic data. Gel-exclusion studies indicate that the dominant size of these aggregates is ten porphyrin monomeric units. The protein-binding constant of these aggregates is 1.7(+/- 0.2) x 10(5) M-1, with four binding sites per protein molecule. The distinction between the HVD isomers along the porphyrin-protein affinity sequence gives insight into the relationship of porphyrin structure to porphyrin-albumin binding. On the basis of this study an evaluation of human serum albumin as an endogenous carrier for porphyrins (at various aggregation states) in photodynamic therapy of tumours is presented.


Betacellulin regulates hair follicle development and hair cycle induction and enhances angiogenesis in wounded skin.
Betacellulin (BTC) belongs to the EGF family, whose members play important roles in skin morphogenesis, homeostasis, and repair. However, the role of BTC in skin biology is still unknown. We employed transgenic mice overexpressing BTC ubiquitously to study its role in skin physiology. Immunohistochemistry revealed increased levels of BTC especially in the hair follicles and in the epidermis of transgenic animals. Expression of key markers of epithelial differentiation was unaltered, but keratinocyte proliferation was significantly increased. At post-natal day 1 (P1), transgenic mice displayed a significant retardation of hair follicle morphogenesis. At P17, when most follicles in control mice had initiated hair follicle cycling and had already entered into their first late catagen or telogen phase, all follicles of transgenic mice were still at the mid- to late catagen phases, indicating retarded initiation of hair follicle cycling. Healing of full-thickness excisional wounds and bursting strength of incisional wounds were similar in control and transgenic mice. However, an increase in the area covered by blood vessels at the wound site was detected in transgenic animals. These results provide evidence for a role of BTC in the regulation of epidermal homeostasis, hair follicle morphogenesis and cycling, and wound angiogenesis.


Pyrintegrin Induces Soft Tissue Formation by Transplanted or Endogenous Cells.
Focal adipose deficiency, such as lipoatrophy, lumpectomy or facial trauma, is a formidable challenge in reconstructive medicine, and yet scarcely investigated in experimental studies. Here, we report that Pyrintegrin (Ptn), a 2,4-disubstituted pyrimidine known to promote embryonic stem cells survival, is robustly adipogenic and induces postnatal adipose tissue formation in vivo of transplanted adipose stem/progenitor cells (ASCs) and recruited endogenous cells. In vitro, Ptn stimulated human adipose tissue derived ASCs to differentiate into lipid-laden adipocytes by upregulating peroxisome proliferator-activated receptor (PPARγ) and CCAAT/enhancer-binding protein-α (C/EBPα), with differentiated cells increasingly secreting adiponectin, leptin, glycerol and total triglycerides. Ptn-primed human ASCs seeded in 3D-bioprinted biomaterial scaffolds yielded newly formed adipose tissue that expressed human PPARγ, when transplanted into the dorsum of athymic mice. Remarkably, Ptn-adsorbed 3D scaffolds implanted in the inguinal fat pad had enhanced adipose tissue formation, suggesting Ptn's ability to induce in situ adipogenesis of endogenous cells. Ptn promoted adipogenesis by upregulating PPARγ and C/EBPα not only in adipogenesis induction medium, but also in chemically defined medium specifically for osteogenesis, and concurrently attenuated Runx2 and Osx via BMP-mediated SMAD1/5 phosphorylation. These findings suggest Ptn's novel role as an adipogenesis inducer with a therapeutic potential in soft tissue reconstruction and augmentation.


Social-psychological profiles of identity styles: attitudinal and social-cognitive correlates in late adolescence.
This study examined the relationships between three identity styles (i.e. the information style, the normative style, and the diffuse/avoidant style) and a number of social-cognitive and attitudinal variables (including empathy, prejudice, and conservatism). Discriminant analysis on a sample of late adolescents (N=393) led to the conclusion that two classes of variables differentiate between the three identity styles. Maladaptive coping strategies and, to a lesser extent, low empathy distinguished mainly between the information style and the normative style on the one hand and the diffuse/avoidant style on the other hand. Need for closure and measures of prejudice and conservatism differentiated primarily between the normative style and the two other styles. These two classes of variables can be related to two basic dimensions in current theory on adolescents' identity styles, that is, active vs. superficial processing of information and adherence to traditional opinions vs. openmindedness.


The therapeutic role of Cannabidiol in mental health: a systematic review.
The therapeutic application of cannabidiol (CBD) is gaining interest due to expanding evidence for its use. To summarize the clinical outcomes, study designs and limitations for the use of CBD and nabiximols (whole plant extract from Cannabis sativa L. that has been purified into 1:1 ratio of CBD and delta-9-tetrahydrocannabinol) in the treatment of psychiatric disorders. A systematic review was conducted including case reports, case series, open-label trials, non-randomized and randomized controlled trials (RCTs). The search resulted in 23 relevant studies on CBD and nabiximols in the treatment of a wide range of psychiatric disorders. The quality of evidence was judged by using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence that ranges from Level 1 to Level 5 based on the quality and study design. These levels of evidence help in grading the recommendations, including Grade A (strong), Grade B (moderate), Grade C (weak), and Grade D (weakest). CBD and CBD-containing compounds such as nabiximols were helpful in alleviating psychotic symptoms and cognitive impairment in patients with a variety of conditions, and several studies provided evidence of effectiveness in the treatment of cannabis withdrawal and moderate to severe cannabis use disorder with Grade B recommendation. There is Grade B recommendation supporting the use of CBD for the treatment of schizophrenia, social anxiety disorder and autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). Grade C recommendation exists for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. These recommendations should be considered in the context of limited number of available studies. CBD and CBD-containing compounds such as nabiximols were helpful in alleviating symptoms of cannabis-related disorders, schizophrenia, social anxiety disorder, and comorbidities of ASD, and ADHD with moderate recommendation. However, there is weaker evidence for insomnia, anxiety, bipolar disorder, posttraumatic stress disorder, and Tourette syndrome. The evidence for the use of CBD and CBD-containing compounds for psychiatric disorders needs to be explored in future studies, especially large-scale and well-designed RCTs.


The prevalence of hepatitis B co-infection in a South African urban government HIV clinic.
There are an estimated 350 million hepatitis B carriers worldwide. In South Africa the prevalence of mono-infection with hepatitis B has been estimated to range from 1% in urban areas to approximately 10% in rural areas. The exact prevalence of hepatitis B in the HIV-infected population has not been well established. Hepatitis B screening is not standard practice in government HIV clinics. Co-infection with hepatitis B and HIV can influence antiretroviral treatment and prognosis of both diseases. The purpose of this study was to evaluate the prevalence of hepatitis B/HIV coinfection. This is believed to be the first prospective observational report on the prevalence of hepatitis B/HIV co-infection in South Africa. Patients on whom hepatitis B serological tests could not have been done previously were recruited from an HIV clinic in a regional hospital in Johannesburg. Standard hepatitis B serological tests were performed. Five hundred and two participants were screened. The cohort's average age was 37 +/- 9 years and the average CD4 count was 128 cells/pi. Twenty-four (4.80%) were hepatitis B surface antigen positive. Nearly half (47%) of the participants showed some evidence of hepatitis B exposure. The risk of hepatitis B co-infection was not significantly different when analysed in terms of sex, race, CD4 count or age. Liver function tests were not a good predictor of hepatitis B infection. The rate of hepatitis B infection, as defined by hepatitis B surface antigen positivity in HIV-infected individuals in urban South Africa was 5 times the rate in people who were not HIV-infected. A 5% rate of hepatitis B/HIV co-infection is a reason to increase the accessibility of tenofovir/emtricitabine (Truvada) for first-line treatment for this population.


Assembly of nonnative floras along elevational gradients explained by directional ecological filtering.
Nonnative species richness typically declines along environmental gradients such as elevation. It is usually assumed that this is because few invaders possess the necessary adaptations to succeed under extreme environmental conditions. Here, we show that nonnative plants reaching high elevations around the world are not highly specialized stress tolerators but species with broad climatic tolerances capable of growing across a wide elevational range. These results contrast with patterns for native species, and they can be explained by the unidirectional expansion of nonnative species from anthropogenic sources at low elevations and the progressive dropping out of species with narrow elevational amplitudes--a process that we call directional ecological filtering. Independent data confirm that climatic generalists have succeeded in colonizing the more extreme environments at higher elevations. These results suggest that invasion resistance is not conferred by extreme conditions at a particular site but determined by pathways of introduction of nonnative species. In the future, increased direct introduction of nonnative species with specialized ecophysiological adaptations to mountain environments could increase the risk of invasion. As well as providing a general explanation for gradients of nonnative species richness and the importance of traits such as phenotypic plasticity for many invasive species, the concept of directional ecological filtering is useful for understanding the initial assembly of some native floras at high elevations and latitudes.


Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies.
Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM.


Cyanobacteriochrome-based photoswitchable adenylyl cyclases (cPACs) for broad spectrum light regulation of cAMP levels in cells.
Class III adenylyl cyclases generate the ubiquitous second messenger cAMP from ATP often in response to environmental or cellular cues. During evolution, soluble adenylyl cyclase catalytic domains have been repeatedly juxtaposed with signal-input domains to place cAMP synthesis under the control of a wide variety of these environmental and endogenous signals. Adenylyl cyclases with light-sensing domains have proliferated in photosynthetic species depending on light as an energy source, yet are also widespread in nonphotosynthetic species. Among such naturally occurring light sensors, several flavin-based photoactivated adenylyl cyclases (PACs) have been adopted as optogenetic tools to manipulate cellular processes with blue light. In this report, we report the discovery of a cyanobacteriochrome-based photoswitchable adenylyl cyclase (cPAC) from the cyanobacterium Microcoleus sp. PCC 7113. Unlike flavin-dependent PACs, which must thermally decay to be deactivated, cPAC exhibits a bistable photocycle whose adenylyl cyclase could be reversibly activated and inactivated by blue and green light, respectively. Through domain exchange experiments, we also document the ability to extend the wavelength-sensing specificity of cPAC into the near IR. In summary, our work has uncovered a cyanobacteriochrome-based adenylyl cyclase that holds great potential for the design of bistable photoswitchable adenylyl cyclases to fine-tune cAMP-regulated processes in cells, tissues, and whole organisms with light across the visible spectrum and into the near IR.


Inhibition of prostaglandin synthesis and actions by genistein in human prostate cancer cells and by soy isoflavones in prostate cancer patients.
Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer (PCa). Our study in both cultured cells and PCa patients reveals a novel pathway for the actions of genistein, namely the inhibition of the synthesis and biological actions of prostaglandins (PGs), known stimulators of PCa growth. In the cell culture experiments, genistein decreased cyclooxygenase-2 (COX-2) mRNA and protein expression in both human PCa cell lines (LNCaP and PC-3) and primary prostate epithelial cells and increased 15-hydroxyprostaglandin dehydrogenase (15-PGDH) mRNA levels in primary prostate cells. As a result genistein significantly reduced the secretion of PGE(2) by these cells. EP4 and FP PG receptor mRNA were also reduced by genistein, providing an additional mechanism for the suppression of PG biological effects. Further, the growth stimulatory effects of both exogenous PGs and endogenous PGs derived from precursor arachidonic acid were attenuated by genistein. We also performed a pilot randomised double blind clinical study in which placebo or soy isoflavone supplements were given to PCa patients in the neo-adjuvant setting for 2 weeks before prostatectomy. Gene expression changes were measured in the prostatectomy specimens. In PCa patients ingesting isoflavones, we observed significant decreases in prostate COX-2 mRNA and increases in p21 mRNA. There were significant correlations between COX-2 mRNA suppression, p21 mRNA stimulation and serum isoflavone levels. We propose that the inhibition of the PG pathway contributes to the beneficial effect of soy isoflavones in PCa chemoprevention and/or treatment.


Pharmacological and immunocytochemical characterization of metabotropic glutamate receptors in cultured Purkinje cells.
Metabotropic glutamate receptor (mGluR) is highly expressed in cerebellar Purkinje cells. The purpose of this study was pharmacological and immunocytochemical characterization of the mGluR in single cerebellar neurons, especially Purkinje cells. Ca2+ imaging with fura-2 in cultured cerebellar neurons, identified immunocytochemically, was used to record the direct effects of drugs in stable conditions. In addition, the expression of mGluR was examined, and expression of the intracellular receptor for inositol trisphosphate (IP3) produced by mGluR activation was studied immunocytochemically with specific antibodies. Purkinje neurons and some other neurons showed Ca(2+)-mobilizing responses to mGluR agonists. These responses were mediated by mGluR because they were not blocked by ionotropic GluR antagonists, were independent of the caffeine-sensitive Ca2+ pool, and were blocked by inhibitors of IP3-induced Ca2+ release. This is the first pharmacological characterization of mGluR at single Purkinje cells. The results differed as follows from those in earlier studies in which phosphoinositide turnover of the entire population of cerebellar cells was monitored: (1) the mGluR responses were not blocked by pertussis toxin or D,L-2-amino-3-phosphonopropionic acid; (2) glutamate was a potent agonist, whereas L-aspartate was ineffective; and (3) the dose-response relationship showed an all-or-none tendency. The metaboltropic response of Purkinje cells changed markedly during development, with a sharp peak after day 4 of culture, whereas mGluR and IP3 receptor proteins increased steadily during maturation. This apparent desensitization of mGluR was not blocked by inhibitors of protein kinase C (PKC) or ADP-ribosyltransferase. The metabotropic responses were mainly localized to the center of the somata of Purkinje cells even on day 4, whereas both receptor proteins were expressed throughout the cell. These results suggest that the function of mGluR is spatially and developmentally controlled by a posttranslational mechanism involving a mechanism other than phosphorylation by PKC or ADP-ribosylation.


Quality of life, dietary intake and nutritional status assessment in hospital admitted cancer patients.
The objectives of this study were to assess the quality of life (QoL), nutritional status, and quantitative food intakes of non-terminal admitted cancer patients receiving oral feeding. As well as to evaluate what kind of relation exists between the quality of life, and the nutritional status and current intake. Medical Oncology and Radiotherapy Service ward at the Hospital Clinic de Barcelona. Fifty admitted patients in the Service ward. There was a follow-up of the dietary intake during 3 working days through direct observation, as well as an assessment of anthropometrical and biochemical parameters, a record of symptomatology related data, and a QoL assessment through the EORTC QLQ-C30 questionnaire. Our data show that 32.6% of the patients did not reach 25 kcal/kg/day, and 23.3% did not even fulfill 1 g protein/kg/day. Concerning QoL, mean score for global health status and overall QoL for all patients was 46.2. Compared to the general population, there were important deficits among cancer patients regarding physical, role and social functioning. The most pronounced differences in the symptom scales were for fatigue, and in single items for appetite loss and constipation. A low protein intake was associated to a poorer perception on physical functioning (p = 0.01), and fatigue was close to significance (p = 0.058). No significant differences were found regarding caloric intake and QoL. A significant percentage of patients who received exclusive oral feeding did not cover a minimum acceptable quantity of their protein-energy requirements. Our results point-out that poor food intakes can affect QoL by themselves.


ACRIN CT colonography trial: does reader's preference for primary two-dimensional versus primary three-dimensional interpretation affect performance?
To determine whether the reader's preference for a primary two-dimensional (2D) or three-dimensional (3D) computed tomographic (CT) colonographic interpretation method affects performance when using each technique. In this institutional review board-approved, HIPAA-compliant study, images from 2531 CT colonographic examinations were interpreted by 15 trained radiologists by using colonoscopy as a reference standard. Through a survey at study start, study end, and 6-month intervals, readers were asked whether their interpretive preference in clinical practice was to perform a primary 2D, primary 3D, or both 2D and 3D interpretation. Readers were randomly assigned a primary interpretation method (2D or 3D) for each CT colonographic examination. Sensitivity and specificity of each method (primary 2D or 3D), for detecting polyps of 10 mm or larger and 6 mm or larger, based on interpretive preference were estimated by using resampling methods. Little change was observed in readers' preferences when comparing them at study start and study end, respectively, as follows: primary 2D (eight and seven readers), primary 3D (one and two readers), and both 2D and 3D (six and six readers). Sensitivity and specificity, respectively, for identifying examinations with polyps of 10 mm or larger for readers with a primary 2D preference (n = 1128 examinations) were 0.84 and 0.86, which was not significantly different from 0.84 and 0.83 for readers who preferred 2D and 3D (n = 1025 examinations) or from 0.76 and 0.82 for readers with a primary 3D preference (n = 378 examinations). When performance by using the assigned 2D or 3D method was evaluated on the basis of 2D or 3D preference, there was no difference among those readers by using their preferred versus not preferred method of interpretation. Similarly, no significant difference among readers or preferences was seen when performance was evaluated for detection of polyps of 6 mm or larger. The reader's preference for interpretive method had no effect on CT colonographic performance.


Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. GUSTO-I Investigators.
Despite remarkable advances in the treatment of acute myocardial infarction, substantial early patient mortality remains. Appropriate choices among alternative therapies and the use of clinical resources depend on an estimate of the patient's risk. Individual patients reflect a combination of clinical features that influence prognosis, and these factors must be appropriately weighted to produce an accurate assessment of risk. Prior studies to define prognosis either were performed before widespread use of thrombolysis or were limited in sample size or spectrum of data. Using the large population of the GUSTO-I trial, we performed a comprehensive analysis of relations between baseline clinical data and 30-day mortality and developed a multivariable statistical model for risk assessment in candidates for thrombolytic therapy. For the 41,021 patients enrolled in GUSTO-I, a randomized trial of four thrombolytic strategies, relations between clinical descriptors routinely collected at initial presentation, and death within 30 days (which occurred in 7% of the population) were examined with both univariable and multivariable analyses. Variables studied included demographics, history and risk factors, presenting characteristics, and treatment assignment. Risk modeling was performed with logistic multiple regression and validated with bootstrapping techniques. Multivariable analysis identified age as the most significant factor influencing 30-day mortality, with rates of 1.1% in the youngest decile (< 45 years) and 20.5% in patients > 75 (adjusted chi 2 = 717, P < .0001). Other factors most significantly associated with increased mortality were lower systolic blood pressure (chi 2 = 550, P < .0001), higher Killip class (chi 2 = 350, P < .0001), elevated heart rate (chi 2 = 275, P < .0001), and anterior infarction (chi 2 = 143, P < .0001). Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data. Other significant though less important factors included previous myocardial infarction, height, time to treatment, diabetes, weight, smoking status, type of thrombolytic, previous bypass surgery, hypertension, and prior cerebrovascular disease. Combining prognostic variables through logistic regression, we produced a validated model that stratified patient risk and accurately estimated the likelihood of death. The clinical determinants of mortality in patients treated with thrombolytic therapy within 6 hours of symptom onset are multifactorial and the relations complex. Although a few variables contain most of the prognostic information, many others contribute additional independent prognostic information. Through consideration of multiple characteristics, including age, medical history, physiological significance of the infarction, and medical treatment, the prognosis of an individual patient can be accurately estimated.


Allergic disease is associated with epilepsy in childhood: a US population-based study.
Previous studies using animal models suggest an association between allergic disease and epilepsy. We sought to determine whether allergic disease is associated with epilepsy in children. We used the 2007-2008 National Survey of Children's Health, a US population-based study of 91 642 children aged 0-17 years to determine the association between the prevalence of epilepsy and allergic disease, including asthma, atopic dermatitis (AD)/eczema, hay fever, and food allergies. Multivariate logistic regression models were constructed that controlled for confounding variables. The US lifetime prevalence of childhood epilepsy was 1.03% and was significantly associated with older age, male sex, lower household income, family structure and history of brain injury or concussion. Children with ≥1 allergic disease had more epilepsy in their lifetime than nonallergic children (logistic regression, adjusted odds ratio [95% confidence interval] = 1.79 [1.37-2.33]). Lifetime prevalence (2.30 [1.50-3.52]) and one-year prevalence of asthma (2.00 [1.41-2.84]), AD/eczema (1.73 [1.17-2.56]), hay fever (1.93 [1.41-2.65]) and food allergies (2.69 [1.38-4.01]) were associated with increased odds of ever being diagnosed with epilepsy. Similar results were found for current history of epilepsy. Severe AD/eczema (3.89 [1.34-11.32]) [corrected] and hay fever (2.46 [1.11-5.41]) were associated with even higher odds of epilepsy compared with mild/moderate disease. As the number of allergic diseases increased, so did the odds of lifetime history and current history of epilepsy. The US prevalence of epilepsy is associated with allergic diseases in children. Further studies are needed to determine whether allergic inflammation contributes toward epileptogenesis.


Chelating agents exert distinct effects on biofilm formation in Staphylococcus aureus depending on strain background: role for clumping factor B.
Staphylococcus aureus is a leading cause of catheter infections, and biofilm formation plays a key role in the pathogenesis. Metal ion chelators inhibit bacterial biofilm formation and viability, making them attractive candidates as components in catheter lock solutions. The goal of this study was to characterize further the effect of chelators on biofilm formation. The effect of the calcium chelators ethylene glycol tetraacetic acid (EGTA) and trisodium citrate (TSC) on biofilm formation by 30 S. aureus strains was tested. The response to subinhibitory doses of EGTA and TSC varied dramatically depending on strain variation. In some strains, the chelators prevented biofilm formation, in others they had no effect, and they actually enhanced biofilm formation in others. The molecular basis for this phenotypic variability was investigated using two related strains: Newman, in which biofilm formation was inhibited by chelators, and 10833, which formed strong biofilms in the presence of chelators. It was found that deletion of the gene encoding the surface adhesin clumping factor B (clfB) completely eliminated chelator-induced biofilm formation in strain 10833. The role of ClfB in biofilm formation activity in chelators was confirmed in additional strains. It was concluded that biofilm-forming ability varies strikingly depending on strain background, and that ClfB is involved in biofilm formation in the presence EGTA and citrate. These results suggest that subinhibitory doses of chelating agents in catheter lock solutions may actually augment biofilm formation in certain strains of S. aureus, and emphasize the importance of using these agents appropriately so that inhibitory doses are achieved consistently.


Distribution of lymphoid depletion and viral antigen in alpacas experimentally infected with Bovine viral diarrhea virus 1.
It was hypothesized that acute postnatal Bovine viral diarrhea virus 1 (BVDV-1) infection leads to leukopenia and lymphoid depletion of gut-associated lymphoid tissues similar to acute disease in calves. The objectives of the current study were to characterize the pathologic effects, viremia, viral shedding, and viral antigen deposition in 6-24-month-old, acutely infected alpacas following experimental infection with noncytopathic BVDV-1 subgenotype 1b (BVDV C0-6). The BVDV-1 isolate was obtained from a cria with naturally occurring persistent infection. Lymphocytopenia occurred 3-7 days postinfection, with a 50% reduction in peripheral lymphocytes in infected alpacas. Depletion of B-cell populations in gut-associated lymphoid tissues was evident microscopically. Populations of T cells in parafollicular zones and in nodular aggregates along the superficial submucosa remained intact. The BVDV antigen was deposited most consistently in submucosal gastrointestinal aggregated lymphoid tissues of ileum, proximal colon, and stomach compartment three. Viral antigen was more variably evident in other lymphoid tissues. Antigen distribution correlated well with histologic lesions in gastrointestinal aggregated lymphoid tissues, confirming the role of virus in lymphoid depletion. Nasal shedding was detected in all challenged alpacas on day 6 and in 4 out of 12 challenged alpacas on day 9. Viremia was present as early as day 3, and present in all challenged alpacas on days 5, 6, 7, and 9 postchallenge. Lymphocytopenia and depletion of gastrointestinal aggregated lymphoid tissues associated with acute BVDV-1 infection likely results in immune compromise and is expected to exacerbate concurrent infections even though uncomplicated BVDV-1 infection was clinically unapparent.


Pharmacological characterization of inward current evoked by N-methyl-D-aspartate in dopamine neurons in the rat brain slice.
In midbrain dopamine neurons in vitro, N-methyl-D-aspartate (NMDA) evokes oscillation of membrane potential and burst firing which are dependent on a ouabain-sensitive sodium pump. In the present study, we investigated the ionic dependence and pharmacological modulation of NMDA-mediated currents which might be important in burst firing. By use of patch pipettes to record membrane currents in whole-cell voltage clamps, we found that NMDA (10 microM) evoked inward currents that were significantly reduced in a low extracellular concentration of Na+ (25 mM), but not when extracellular Ca+2 was decreased from 2.5 to 0.5 mM. The current-voltage relationship for subtracted NMDA currents showed a prominent region of negative slope conductance which was absent when the slice was perfused with solution containing zero Mg++. 7-Chlorokynurenic acid, an antagonist at the nonstrychnine-sensitive glycine binding site, produced a concentration-dependent reduction in amplitude of excitatory postsynaptic currents mediated by NMDA receptors (IC50 = 15 +/- 3 microM). NMDA-activated currents were blocked by phencyclidine (IC50 = 130 +/- 65 nM), dizocilpine maleate (MK-801) (1 microM) and ketamine (100 microM), but not by amantadine (1 mM). Spermine (100 microM), a polyamine which reportedly modulates NMDA currents in other neurons, presynaptically inhibited excitatory postsynaptic currents mediated by NMDA receptors but had no effect on the currents mediated by NMDA. We conclude that the most important factors for NMDA-induced burst firing are the relatively large Na+ influx through NMDA-gated channels and the strong voltage-dependent block of conductance by Mg++.


Successful treatment strategy in corporating mogamulizumab and cord blood transplantation in aggressive adult T-cell leukemia-lymphoma: a case report.
Adult T-cell leukemia-lymphoma (ATL) is a rare type of mature T cell lymphoma caused by human T-lymphotropic virus type 1 (HTLV-1) with dismal outcome with conventional chemotherapy. A humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab (MOG), has been shown to be effective for CCR4-positive ATL. However, MOG administration before allogeneic hematopoietic stem cell transplantation (allo-HSCT) was reported to be associated with an increased risk of severe acute graft-versus-host disease (aGVHD) after allo-HSCT due to reduction of donor-derived regulatory T cells (Tregs). We herein present a patient with ATL who underwent allo-HSCT after MOG administration without developing severe GVHD while referring to serum MOG concentration. The clinical course of our case suggests that it might be possible to determine the appropriate timing of allo-HSCT with monitoring of residual MOG level while avoiding the detrimental effect of MOG on post-transplant clinical outcome without increasing the risk of relapse/progression.


Mutations in normal breast tissue and breast tumours.
The accumulation of mutations is a feature of all normal cells. The probability of any individual gene in any cell acquiring a mutation is, however, low. Cancer is therefore a rare disease in comparison with the number of susceptible cells. Mutations in normal tissue are stochastic, vary widely among cells and are therefore difficult to detect using standard methods because each change is so rare. If, however, a tissue such as the breast undergoes considerable clonal expansion, particularly if relatively late in life, normal tissue may have accumulated many thousands of detectable mutations. Since breast cancers are clonal and have almost certainly undergone many more cell divisions than normal cells, each tumour may have many millions of mutations, most of which are entirely innocent and some of which have accumulated in the cell of origin prior to tumorigenesis. Despite some claims to the contrary, even at normal mutation rates, clonal expansion within a tumour is quite sufficient to account for the mutations of five or six genes that are generally supposed necessary for carcinogenesis to occur. Hypermutability does, however, contribute to the pathogenesis of many cancers and, although evidence is indirect in breast cancer, may take forms such as karyotypic instability via centrosome amplification.


A family of antimicrobial and immunomodulatory peptides related to the frenatins from skin secretions of the Orinoco lime frog Sphaenorhynchus lacteus (Hylidae).
Peptidomic analysis of norepinephrine-stimulated skin secretions of the Orinoco lime tree frog Sphaenorhynchus lacteus (Hylidae, Hylinae) revealed the presence of three structurally related host-defense peptides with limited sequence similarity to frenatin 2 from Litoria infrafrenata (Hylidae, Pelodryadinae) and frenatin 2D from Discoglossus sardus (Alytidae). Frenatin 2.1S (GLVGTLLGHIGKAILG.NH2) and frenatin 2.2S (GLVGTLLGHIGKAILS.NH2) are C-terminally α-amidated but frenatin 2.3S (GLVGTLLGHIGKAILG) is not. Frenatin 2.1S and 2.2S show potent bactericidal activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MIC ≤16μM) but are less active against a range of Gram-negative bacteria. Frenatin 2.1S (LC50=80±6 μM) and 2.2S (LC50=75±5 μM) are cytotoxic against non-small cell lung adenocarcinoma A549 cells but are less hemolytic against human erythrocytes (LC50=167±8 μM for frenatin 2.1S and 169±7 μM for 2.2S). Weak antimicrobial and cytotoxic potencies of frenatin 2.3S demonstrate the importance of C-terminal α-amidation for activity. Frenatin 2.1S and 2.2S significantly (P<0.05) increased production of proinflammatory cytokines IL-1β and IL-23 by lipopolysaccharide (LPS)-stimulated mouse peritoneal macrophages and frenatin 2.1S also enhanced production of TNF-α. Effects on IL-6 production were not significant. Frenatin 2.2S significantly downregulated production of the anti-inflammatory cytokine IL-10 by LPS-stimulated cells. The data support speculation that frenatins act on skin macrophages to produce a cytokine-mediated stimulation of the adaptive immune system in response to invasion by microorganisms. They may represent a template for the design of peptides with therapeutic applications as immunostimulatory agents.


The instrumental variable method to study self-selection mechanism: a case of influenza vaccination.
To assess whether estimates of the effectiveness of influenza vaccination in reducing rates of hospitalizations and all-cause mortality derived from cross-sectional data could be improved by applying the instrumental variable (IV) method to data representing the community-dwelling elderly population in the United States in order to adjust for self-selection bias. Secondary data analysis, using the 1996-97 Medicare Current Beneficiary Survey data. First, using single-equation probit regressions this study analyzed influenza-related hospitalization and death due to all causes predicted by vaccination status, which was measured by claims or survey data. Second, to adjust for potential self-selection of the vaccine receipt, for example, higher vaccination rates among high-risk individuals, bivariate probit (BVP) models and two-stage least squares (2SLS) models were employed. The IV was having either arthritis or gout. In single-equation probit models, vaccination appeared to be ineffective or even to increase the probability of adverse outcomes. Based on BVP and 2SLS models, vaccination was demonstrated to be effective in reducing influenza-related hospitalization by at least 31%. The BVP model results implied significant self-selection in the single-equation probit models. Adjusting for self-selection, BVP analyses yielded vaccine effectiveness estimates for a nationally representative cross-sectional sample of the community-dwelling elderly population that are consistent with previous estimates based on randomized controlled trials, prospective cohort studies, and meta-analyses. This result suggests that analyses with 2SLS and BVP in particular may be useful for the analysis of observational data regarding prevention in which self-selection is an important potential source of bias.


Radiotherapy for recurrent choroidal neovascularisation complicating age related macular degeneration.
To report the safety and visual outcome data of external beam irradiation for recurrent choroidal neovascularisation complicating age related macular degeneration. Eighteen consecutive eyes received external beam irradiation with seven fractions of 2 Gy (total dose 14 Gy). The next 16 consecutive eyes received external beam irradiation with five fractions of 3 Gy (total dose 15 Gy). Main outcome measure was change in visual acuity. Secondary outcome variables were contrast sensitivity and fundus photographic/fluorescein angiographic progression. The 3 Gy fraction group lost fewer lines of distance visual acuity at the three and six month follow up. At one year follow up, this difference was not maintained with 2 Gy fraction and 3 Gy fraction eyes. At one year follow up a decrease in visual acuity of three or more lines (moderate visual loss) occurred in 58% of 2 Gy and 42% of 3 Gy fraction eyes (p<0.36). At one year follow up a decrease in visual acuity of six or more lines (severe visual loss) occurred in 41% of 2 Gy eyes and 17% of 3 Gy eyes (p<0.23). At three months follow up, 3 Gy eyes were less likely (0%) than 2 Gy eyes (47%) to show moderate visual loss (p<0.003). However, Kaplan Meier curves estimate a significantly lower rate of severe visual loss in the 3 Gy group (p = 0.02). There were no significant differences in contrast sensitivity loss or fluorescein angiographic stabilisation rates. No evidence of radiation toxicity was observed. Our results are consistent with trends for a palliative benefit with higher fraction sizes and doses. The radiobiologic differences between low and high fraction size groups in this study are modest and correlate with the modest and short term difference in visual outcomes. These trends support further investigation of radiotherapy using fraction sizes of 4 Gy or higher.


Gut-microbiota-on-a-chip: an enabling field for physiological research.
Overwhelming scientific evidence today confirms that the gut microbiota is a central player in human health. Knowledge about interactions between human gut microbiota and human health has evolved rapidly in the last decade, based on experimental work involving analysis of human fecal samples or animal models (mainly rodents). A more detailed and cost-effective description of this interplay is now being enabled by the use of in vitro systems (i.e., gut-microbiota-on-chip systems) that recapitulate key aspects of the interaction between microbiota and human cells. Here, we review recent examples of the design and use of pioneering on-chip platforms for the study of the cross-talk between representative members of human microbiota and human microtissues. In these systems, the combined use of state-of-the-art microfluidics, biomaterials, cell culture techniques, classical microbiology, and a touch of genetic expression profiling have converged for the development of gut-on-chip platforms capable of recreating key features of the interplay between human microbiota and host human tissues. We foresee that the integration of novel microfabrication techniques and stem cell technologies will further accelerate the development of more complex and physiologically relevant microbiota-on-chip platforms. In turn, this will foster the faster acquisition of knowledge regarding human microbiota and will enable important advances in the understanding of how to control or prevent disease.


Systems pharmacology of adverse event mitigation by drug combinations.
Drugs are designed for therapy, but medication-related adverse events are common, and risk/benefit analysis is critical for determining clinical use. Rosiglitazone, an efficacious antidiabetic drug, is associated with increased myocardial infarctions (MIs), thus limiting its usage. Because diabetic patients are often prescribed multiple drugs, we searched for usage of a second drug ("drug B") in the Food and Drug Administration's Adverse Event Reporting System (FAERS) that could mitigate the risk of rosiglitazone ("drug A")-associated MI. In FAERS, rosiglitazone usage is associated with increased occurrence of MI, but its combination with exenatide significantly reduces rosiglitazone-associated MI. Clinical data from the Mount Sinai Data Warehouse support the observations from FAERS. Analysis for confounding factors using logistic regression showed that they were not responsible for the observed effect. Using cell biological networks, we predicted that the mitigating effect of exenatide on rosiglitazone-associated MI could occur through clotting regulation. Data we obtained from the db/db mouse model agreed with the network prediction. To determine whether polypharmacology could generally be a basis for adverse event mitigation, we analyzed the FAERS database for other drug combinations wherein drug B reduced serious adverse events reported with drug A usage such as anaphylactic shock and suicidality. This analysis revealed 19,133 combinations that could be further studied. We conclude that this type of crowdsourced approach of using databases like FAERS can help to identify drugs that could potentially be repurposed for mitigation of serious adverse events.


Lower extremity muscle activation and knee flexion during a jump-landing task.
Decreased sagittal-plane motion at the knee during dynamic tasks has been reported to increase impact forces during landing, potentially leading to knee injuries such as anterior cruciate ligament rupture. To describe the relationship between lower extremity muscle activity and knee-flexion angle during a jump-landing task. Cross-sectional study. Research laboratory. Thirty recreationally active volunteers (15 men, 15 women: age = 21.63 ± 2.01 years, height = 173.95 ± 11.88 cm, mass = 72.57 ± 14.25 kg). Knee-flexion angle and lower extremity muscle activity were collected during 10 trials of a jump-landing task. Simple correlation analyses were performed to determine the relationship between each knee-flexion variable (initial contact, peak, and displacement) and electromyographic amplitude of the gluteus maximus (GMAX), quadriceps (VMO and VL), hamstrings, gastrocnemius, and quadriceps : hamstring (Q : H) ratio. Separate forward stepwise multiple regressions were conducted to determine which combination of muscle activity variables predicted each knee-flexion variable. During preactivation, VMO and GMAX activity and the Q : H ratio were negatively correlated with knee-flexion angle at initial contact (VMO: r = 0.382, P = .045; GMAX: r = 0.385, P = .043; Q : H ratio: r = 0.442, P = .018). The VMO, VL, and GMAX deceleration values were negatively correlated with peak knee-flexion angle (VMO: r = 0.687, P = .001; VL: r = 0.467, P = .011; GMAX: r = 0.386, P = .043). The VMO and VL deceleration values were negatively correlated with knee-flexion displacement (VMO: r = 0.631, P = .001; VL: r = 0.453, P = .014). The Q : H ratio and GM activity predicted 34.7% of the variance in knee-flexion angle at initial contact (P = .006). The VMO activity predicted 47.1% of the variance in peak knee-flexion angle (P = .001). The VMO and VL activity predicted 49.5% of the variance in knee-flexion displacement (P = .001). Greater quadriceps and GMAX activation and less hamstrings and gastrocnemius activation were correlated with smaller knee-flexion angles. This landing strategy may predispose an individual to increased impact forces due to the negative influence on knee-flexion position.


On-chip monitoring of chemical syntheses in microdroplets via surface-enhanced Raman spectroscopy.
Conducting organic syntheses in microfluidic chips allows studying and optimising chemical reactions at minimal time-scales and resource consumption. Herein, we describe a multi-channel microdroplet chip, which allows fast and directed dispensing of reactants into individual droplets in a segmented flow. This gives access to study the reaction progress in situ via surface-enhanced Raman spectroscopic monitoring of fast moving individual droplets. This opens up new avenues for high-throughput screening of organic reactions at the micro- and nano-scale.


Seismic constraints on rotation of Sun-like star and mass of exoplanet.
Rotation is thought to drive cyclic magnetic activity in the Sun and Sun-like stars. Stellar dynamos, however, are poorly understood owing to the scarcity of observations of rotation and magnetic fields in stars. Here, inferences are drawn on the internal rotation of a distant Sun-like star by studying its global modes of oscillation. We report asteroseismic constraints imposed on the rotation rate and the inclination of the spin axis of the Sun-like star HD 52265, a principal target observed by the CoRoT satellite that is known to host a planetary companion. These seismic inferences are remarkably consistent with an independent spectroscopic observation (rotational line broadening) and with the observed rotation period of star spots. Furthermore, asteroseismology constrains the mass of exoplanet HD 52265b. Under the standard assumption that the stellar spin axis and the axis of the planetary orbit coincide, the minimum spectroscopic mass of the planet can be converted into a true mass of 1.85(-0.42)(+0.52)M(Jupiter), which implies that it is a planet, not a brown dwarf.


Listening to the patients: using participatory design in the development of a cardiac telerehabilitation web portal.
Cardiovascular disease is the leading cause of all deaths worldwide. Cardiac rehabilitation is an effective approach for preventing secondary complications, but it remains a complex intervention because of the need for lifestyle changes. One solution is to employ interactive telerehabilitation or eHealth web portals. However, these have not been implemented as intended by developers. The aim of this study was to evaluate the design and usability of a cardiac telerehabilitation web portal, called the 'HeartPortal', for use among heart failure (HF) patients. The HeartPortal was designed using participatory design (PD). The design process involved HF patients, their relatives, healthcare professionals (HCP), healthcare company specialists and researchers. Self-determination theory (SDT) was used to enable the design to elicit intrinsic motivation within the patients. With eHealth literacy skills in mind, the goal of the HeartPortal was to successfully target the end-users. The PD process and data collection techniques included cultural probes, workshops, participant-observation, questionnaires, and problem-solving tasks. The PD process helped us design an interactive web portal, the HeartPortal. Based on participants' feedback, the design incorporated features such as being able to make notes and to communicate with HCP, view data from self-tracking devices in a graphic form, and to obtain information on rehabilitation in the form of text, audio, and video. More than half of those testing the HeartPortal found that it was easy to navigate, and most of the users stated that it had an excellent structure and that using it could possibly improve their condition. Overall, the HeartPortal was found to be logical and easy to navigate and will now be tested in a clinical trial within the Future Patient Telerehabilitation Program.


The role of GLP-1 in neuronal activity and neurodegeneration.
Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). The underlying mechanism behind this unexpected link is most likely linked to the observed desensitization of insulin receptors in the brain. Insulin acts as a growth factor in the brain and supports neuronal repair, dendritic sprouting, and differentiation. Several drugs have been developed to treat type 2 diabetes which re-synthesize insulin receptors and may be of use to prevent neurodegenerative developments in AD. The incretin glucagon-like peptide-1 (GLP-1) is a hormone that facilitates insulin release under high blood sugar conditions. Interestingly, GLP-1 also has very similar growth factor like properties as insulin, and has been shown to protect neurons from toxic effects. In preclinical studies, GLP-1 and longer lasting analogues reduce apoptosis, protect neurons from oxidative stress, induce neurite outgrowth, protect synaptic plasticity and memory formation from the detrimental effects of β-amyloid, and reduce plaque formation and the inflammation response in the brains of mouse models of AD. An advantage of GLP-1 is that it does not affect blood sugar levels in nondiabetic people. Furthermore, recent research has shown that some GLP-1 analogues can cross the blood-brain barrier, including two that are on the market as a treatment for type 2 diabetes. Therefore, GLP-1 analogues show great promise as a novel treatment for AD or other neurodegenerative conditions.


Heterotrimeric G proteins as fluoride targets in bone (review).
Fluoride is an acknowledged bone anabolic agent. Nevertheless, a narrow therapeutic window and the adverse effects at higher therapeutic doses prevent broad clinical application of fluoride for treatment of diseases of bone loss, such as osteoporosis. The cellular and molecular mechanisms of fluoride action are poorly understood. recent advances in the elucidation of signal transduction pathways induced by fluoride in osteoblastic cells are reviewed. Fluoride and traces of aluminum form a complex, fluoroaluminate, which stimulates cellular heterotrimeric G proteins. Such complex can form in food, drinking water and in the organism after administration of sodium fluoride. Fluoroaluminate crosses the cell membrane and directly binds to the membrane-associated inactive G alpha protein subunits. Within the G alpha subunit, fluoroaluminate occupies the position next to GDP. The resulting G alpha-GDP-AlF4- complex assumes an active state conformation, which resembles that of G alpha-GTP complex. Under physiological conditions, G alpha-GTP complex is formed upon activation of seven transmembrane receptors that couple to heterotrimeric G proteins. Both fluoroaluminate-activated and receptor-activated G alpha subunits are capable of transmitting intracellular signals that lead to cellular responses. In bone-forming cells osteoblasts, fluoroaluminate stimulates pertussis toxin-sensitive G alpha i proteins. G alpha i activation leads to the reduction in cAMP (cyclic adenosine monophosphate) levels and to the activation of mitogen activated protein kinases, Erks (extracellular signal-regulated kinases) and p70 S6 kinase. These kinases are involved in the regulation of gene transcription and protein syntheses. Fluoroaluminate also stimulates pertussis toxin-insensitive proteins. Pertussis toxin-insensitive G proteins, most likely from G alpha 12 class, cause the activation of several cytoplasmic protein tyrosine kinases [Src, Pyk2 (proline-rich tyrosine kinase 2), and Fak (focal adhesion kinase)]. Activation of Erks can lead to osteoblast proliferation and differentiation, while activation of Src, Pyk2 and Fak can modulate the adhesion properties of osteoblasts. Osteoblast adhesion may, in turn, influence differentiation, migration, and apoptosis of these cells. The susceptibility of osteoblasts to fluoroaluminate can be achieved by their specific cellular context and by the rigidity of the surrounding bone tissue. In particular, higher levels of G alpha i proteins and of certain focal adhesion proteins are expressed by osteoblastic rather than by fibroblastic cells. The rigidity of adhesion substratum of osteoblasts may signal on its own and potentiate the signaling by fluoroaluminate. The information on mechanisms of intracellular signaling by fluoroaluminate can be utilized to identify a fluoroaluminate mimic, a drug that exhibits anabolic action on bone with a broader therapeutic range and less adverse effects than fluoride.


Beyond imitation: Zero-shot task transfer on robots by learning concepts as cognitive programs.
Humans can infer concepts from image pairs and apply those in the physical world in a completely different setting, enabling tasks like IKEA assembly from diagrams. If robots could represent and infer high-level concepts, then it would notably improve their ability to understand our intent and to transfer tasks between different environments. To that end, we introduce a computational framework that replicates aspects of human concept learning. Concepts are represented as programs on a computer architecture consisting of a visual perception system, working memory, and action controller. The instruction set of this cognitive computer has commands for parsing a visual scene, directing gaze and attention, imagining new objects, manipulating the contents of a visual working memory, and controlling arm movement. Inferring a concept corresponds to inducing a program that can transform the input to the output. Some concepts require the use of imagination and recursion. Previously learned concepts simplify the learning of subsequent, more elaborate concepts and create a hierarchy of abstractions. We demonstrate how a robot can use these abstractions to interpret novel concepts presented to it as schematic images and then apply those concepts in very different situations. By bringing cognitive science ideas on mental imagery, perceptual symbols, embodied cognition, and deictic mechanisms into the realm of machine learning, our work brings us closer to the goal of building robots that have interpretable representations and common sense.


The Trade Secret Taboo: Open Science Methods are Required to Improve Prediction Models in Sports Medicine and Performance.
Clinical prediction models in sports medicine that utilize regression or machine learning techniques have become more widely published, used, and disseminated. However, these models are typically characterized by poor methodology and incomplete reporting, and an inadequate evaluation of performance, leading to unreliable predictions and weak clinical utility within their intended sport population. Before implementation in practice, models require a thorough evaluation. Strong replicable methods and transparency reporting allow practitioners and researchers to make independent judgments as to the model's validity, performance, clinical usefulness, and confidence it will do no harm. However, this is not reflected in the sports medicine literature. As shown in a recent systematic review of models for predicting sports injury models, most were typically characterized by poor methodology, incomplete reporting, and inadequate performance evaluation. Because of constraints imposed by data from individual teams, the development of accurate, reliable, and useful models is highly reliant on external validation. However, a barrier to collaboration is a desire to maintain a competitive advantage; a team's proprietary information is often perceived as high value, and so these 'trade secrets' are frequently guarded. These 'trade secrets' also apply to commercially available models, as developers are unwilling to share proprietary (and potentially profitable) development and validation information. In this Current Opinion, we: (1) argue that open science is essential for improving sport prediction models and (2) critically examine sport prediction models for open science practices.


Reversing oncogenic transformation with iron chelation.
Cancer cells accumulate iron to supplement their aberrant growth and metabolism. Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. Iron chelators are effective at combating a range of cancers including those which are difficult to treat such as androgen insensitive prostate cancer and cancer stem cells. This review will evaluate the impact of iron chelation on cancer cell survival and the underlying mechanisms of action. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. In addition to this, iron chelators stimulate apoptotic and ER stress signalling pathways inducing cell death even in cells lacking a functional p53 gene. Iron chelators can sensitise cancer cells to PARP inhibitors through mimicking BRCAness; a feature of cancers trademark genomic instability. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis. Moreover, iron chelators may reverse the major characteristics of oncogenic transformation. Iron chelation therefore represent a promising selective mode of cancer therapy.


Updated and validated solar irradiance reference spectra for estimating environmental photodegradation rates.
Irradiance reference spectra are used to calculate environmentally relevant photodegradation half-lives, but the currently used spectra were originally published in the 1980s with limited validation. The goal of this work is to provide updated irradiance reference spectra using the Simple Model of the Atmospheric Radiative Transfer of Sunshine (SMARTS). The SMARTS irradiance spectra were validated against measurements from several high-resolution spectroradiometers, and the updated irradiance reference spectra use current measurements for atmospheric species that can affect the irradiance that reaches the Earth's surface. These updated irradiance spectra are provided in 1 nm increments from 280 to 800 nm for 0° to 70° latitude at 10° increments in both the northern and southern hemisphere. Lastly, the influence of the input parameters on the modeled irradiance spectra was investigated. This work will allow users to calculate more accurate photodegradation half-lives using the updated irradiance reference spectra, and it also provides insight for users to calculate their own location- and time-specific irradiance spectra using SMARTS.


Impact of Computer-Interpreted ECGs on the Accuracy of Healthcare Professionals.
The interpretation of electrocardiograms (ECGs) involves a dynamic interplay between computerized ECG interpretation (CEI) software and human overread. However, the impact of computer ECG interpretation on the performance of healthcare professionals remains largely unexplored. The aim of this study was to evaluate the interpretation proficiency of various medical professional groups, with and without access to the CEI report. Healthcare professionals from diverse disciplines, training levels, and countries sequentially interpreted 60 standard 12-lead ECGs, demonstrating both urgent and nonurgent findings. The interpretation process consisted of 2 phases. In the first phase, participants interpreted 30 ECGs with clinical statements. In the second phase, the same 30 ECGs and clinical statements were randomized and accompanied by a CEI report. Diagnostic performance was evaluated based on interpretation accuracy, time per ECG (in seconds [s]), and self-reported confidence (rated 0 [not confident], 1 [somewhat confident], or 2 [confident]). A total of 892 participants from various medical professional groups participated in the study. This cohort included 44 (4.9%) primary care physicians, 123 (13.8%) cardiology fellows-in-training, 259 (29.0%) resident physicians, 137 (15.4%) medical students, 56 (6.3%) advanced practice providers, 82 (9.2%) nurses, and 191 (21.4%) allied health professionals. The inclusion of the CEI was associated with a significant improvement in interpretation accuracy by 15.1% (95% confidence interval, 14.3-16.0; P < 0.001), decrease in interpretation time by 52 s (-56 to -48; P < 0.001), and increase in confidence by 0.06 (0.03-0.09; P = 0.003). Improvement in interpretation accuracy was seen across all professional subgroups, including primary care physicians by 12.9% (9.4-16.3; P = 0.003), cardiology fellows-in-training by 10.9% (9.1-12.7; P < 0.001), resident physicians by 14.4% (13.0-15.8; P < 0.001), medical students by 19.9% (16.8-23.0; P < 0.001), advanced practice providers by 17.1% (13.3-21.0; P < 0.001), nurses by 16.2% (13.4-18.9; P < 0.001), allied health professionals by 15% (13.4-16.6; P < 0.001), physicians by 13.2% (12.2-14.3; P < 0.001), and nonphysicians by 15.6% (14.3-17.0; P < 0.001).CEI integration improves ECG interpretation accuracy, efficiency, and confidence among healthcare professionals.


The impact of extrusion on the nutritional composition, dietary fiber and in vitro digestibility of gluten-free snacks based on rice, pea and carob flour blends.
Consumers and the food industry are demanding healthier products. Expanded snacks with a high nutritional value were developed from different rice, pea and carob flour blends. The proximate composition, starch (total and resistant), amylose and amylopectin, dietary fiber (soluble and insoluble) contents, and the in vitro protein digestibility of different rice-legume formulations, were evaluated before and after the extrusion process. Compared with the corresponding non-extruded blends (control), the extrusion treatment did not change the total protein content, however, it reduced the soluble protein (61-86%), the fat (69-92%) and the resistant starch contents (100%). The total starch content of all studied blends increased (2-19%) after extrusion. The processing increased the in vitro protein digestibility, reaching values around 88-95% after extrusion. Total dietary fiber was reduced around 30%, and the insoluble fraction was affected to a larger extent than the soluble fraction by the extrusion process. Because of its balanced nutritional composition, high dietary fiber content, as well as low energy density, these novel gluten-free snack-like foods could be considered as functional foods and a healthier alternative to commercially available gluten-containing or gluten-free and low nutritional value snacks.


Predictors of response to physical therapy intervention for plantar heel pain.
Age, weight, and duration of symptoms have been associated with a poor response to treatment for plantar heel pain (PHP), but no studies were identified that examined predictors of response to physical therapy intervention. The purpose of this investigation was to examine the influence of age, body mass index (BMI), and symptom duration on treatment response to physical therapy intervention. Sixty participants received 6 visits over 4 weeks of physical therapy intervention that included manual therapy and exercise or electrophysiological agents and exercise. Outcomes were assessed using the Foot and Ankle Ability Measure (FAAM), Numeric Pain Rating Scale (NPRS), and Global Rating of Change Scale (GRC). Logistic regression (P < .05) was used to analyze age, BMI, and symptom duration as potential predictors of a successful response based on the minimal clinically important difference of the outcome measures. Sensitivity analysis was used to assess the influence of success based on minimal clinically important changes in the FAAM, NPRS, and GRC or only the FAAM and NPRS. Receiver operating curves were used to determine the cut point for the significant predictor. At the 6-month follow-up to physical therapy intervention, NPRS was improved by 3 points (95% CI, 2.4-3.6) and FAAM improved by 22.5 points (95% CI, 16.8-28.2). Individuals with symptoms less than 7.2 months were 4.2 (95% CI, 1.3-13.8; P = .016) and 8.5 (95% CI, 2.5-28.9; P = .001) times more likely to respond to treatment based on the NPRS/FAAM/GRC and NPRS/FAAM success criteria, respectively. Age and BMI were not significant predictors (P ≥ .455 and P ≥ .450, respectively). Age and BMI were not associated with outcomes and obese individuals did achieve a successful outcome with the physical therapy intervention used in the clinical trial. Individuals with PHP symptoms longer than 7 months require additional consideration and further investigation of effective strategies to improve treatment response. Prognosis, level 2b comparative study.


Individual use of antiasthmatic drugs in the European Community Respiratory Health Survey.
A previous analysis of drug utilization in the European Community Respiratory Health Survey found that only between 8 and 29% of subjects with asthma-related symptoms were using antiasthmatic medication in the different areas studied. The aim of this analysis was to investigate which variables were related to individual use of antiasthmatic medication in different geographical areas. Thirty-three centres in 14 countries were analysed, in which a total of 16,854 people (52.1% females, mean age 33.8 yrs, range 20-48) underwent a structured interview, measurement of specific immunoglobin E, spirometry and methacholine challenge test. The use of antiasthmatic drugs in individuals was, in most countries, independently related to asthma-related respiratory symptoms, bronchial hyperresponsiveness (BHR) and atopy. In all countries smokers with respiratory symptoms were less likely to be using antiasthmatic drugs than nonsmokers and exsmokers. In four of 14 countries females were significantly more likely to use antiasthmatic medication than males, while age and socioeconomic status were unrelated to medication. The use of inhaled anti-inflammatory drugs was positively related to symptoms, BHR and atopy and negatively related to current smoking. In conclusion, in many countries smokers were less likely to be using antiasthmatic drugs than were nonsmokers with comparable levels of symptoms and bronchial hyperresponsiveness. Age and socioeconomic status were unrelated to medication, while in some countries females were more likely than males to use antiasthmatic medication.


A Pharmacogenetic Prediction Model of Progression-Free Survival in Breast Cancer using Genome-Wide Genotyping Data from CALGB 40502 (Alliance).
Genome-wide genotyping data are increasingly available for pharmacogenetic association studies, but application of these data for development of prediction models is limited. Prediction methods, such as elastic net regularization, have recently been applied to genetic studies but only limitedly to pharmacogenetic outcomes. An elastic net was applied to a pharmacogenetic study of progression-free survival (PFS) of 468 patients with advanced breast cancer in a clinical trial of paclitaxel, nab-paclitaxel, and ixabepilone. A final model included 13 single nucleotide polymorphisms (SNPs) in addition to clinical covariates (prior taxane status, hormone receptor status, disease-free interval, and presence of visceral metastases) with an area under the curve (AUC) integrated over time of 0.81, an increase compared to an AUC of 0.64 for a model with clinical covariates alone. This model may be of value in predicting PFS with microtubule targeting agents and may inform reverse translational studies to understand differential response to these drugs.


Conformational changes during the gating of a potassium channel revealed by structural mass spectrometry.
Potassium channels are dynamic proteins that undergo large conformational changes to regulate the flow of K(+) ions across the cell membrane. Understanding the gating mechanism of these channels therefore requires methods for probing channel structure in both their open and closed conformations. Radiolytic footprinting is used to study the gating mechanism of the inwardly-rectifying potassium channel KirBac3.1. The purified protein stabilized in either open or closed conformations was exposed to focused synchrotron X-ray beams on millisecond timescales to modify solvent accessible amino acid side chains. These modifications were identified and quantified using high-resolution mass spectrometry. The differences observed between the closed and open states were then used to reveal local conformational changes that occur during channel gating. The results provide support for a proposed gating mechanism of the Kir channel and demonstrate a method of probing the dynamic gating mechanism of other integral membrane proteins and ion channels.


Wavelength-scanning interferometry of a transparent parallel plate with refractive-index dispersion.
Testing for flatness of an optical parallel plate in a Fizeau interferometer suffers from problems caused by multiple-beam interference noise. Each internal-reflection component can be separated from the signal by its modulation frequency in a wavelength-scanned interferometer; however, the frequency depends on the thickness and the refractive-index dispersion of the test plate and on the nonlinearity of the scanning source. With a new 19-sample wavelength-scanning algorithm we demonstrate the elimination of the reflection noise, the effect of the dispersion up to the second order of the reflectance of the test plate, and as the nonlinearity of the source. The algorithm permits large tolerance in the air-gap distance, thus making it somewhat independent of the thickness of the test plate. The minimum residual reflection noise with this algorithm for testing a glass plate is approximately lambda/600. Experimental results show that the front surface of the test plate was measured within 1 nm rms of its true shape over a 230-mm-diameter aperture.


A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis.
Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m(2), and a urine protein to creatinine ratio over 1.8 mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4 mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73 m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2 mg/mg with all three Black patients having a mean decline of 3.6 mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary.


Diabetes and Diet: A Patient and Dietitian's Perspective.
This article has been co-authored by a patient with type 2 diabetes and a specialist dietitian. Here they discuss the patient's experience and difficulties with controlling weight and strategies that can help a patient in this situation. The patient discusses how stress and her corresponding comfort eating dampened weight loss progress, and how adopting a lifestyle change aided through group support helped to deal with this. The physician discusses the importance of recognizing the mental and physical challenges faced by patients in this situation.


Temporal lobe resection for intractable epilepsy: review of 11 cases.
OBJECTIVE: To review the management of medically intractable epilepsy by performing temporal lobe resection. DESIGN: Retrospective study. SETTING: University teaching hospital, Hong Kong. PATIENTS: Eleven patients: seven women and four men (mean age, 28 years; range, 19-49 years) who underwent temporal lobe resection for intractable epilepsy from 1994 through 1998. MAIN OUTCOME MEASURES: Preoperative and operative aspects of treatment, postoperative complications, mortality, and seizure control before and after surgery. RESULTS: All but one patient had long-standing medically intractable temporal lobe epilepsy; the duration between the onset of seizure and surgery ranged from 12 to 27 years (mean, 17.2 years). A total of 12 resections were performed without any mortalities or major postoperative complications. After surgery, two patients became seizure-free without the need for antiepileptic medication; six patients were seizure-free but required medication; and two patients showed >90% of improvement in seizure control, whereas one patient showed between 50% and 90% of improvement. Nine (81%) of the 11 patients reported significant improvement in their social life and performance of daily activities. Two (18%) patients, including one with improved seizure control, reported no improvement in their performance of daily functions. CONCLUSIONS: Temporal lobe resection can produce significant improvements in patients who have medically intractable epilepsy. The risks of surgery are relatively small and justifiable.


Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus.
CXCR4 is a chemokine with multiple effects on the immune system. In murine lupus models, we demonstrated that monocytes, neutrophils, and B cells overexpressed CXCR4 and that its ligand, CXCL12, was up-regulated in diseased kidneys. We undertook this study to determine whether CXCR4 expression was increased in peripheral blood leukocytes from patients with systemic lupus erythematosus (SLE) and whether CXCL12 expression was increased in kidneys from patients with SLE. Peripheral blood leukocytes from 31 SLE patients, 8 normal controls, and 9 patients with rheumatoid arthritis were prospectively analyzed by flow cytometry for CXCR4 expression. Biopsy samples (n = 14) from patients with lupus nephritis (LN) were immunostained with anti-CXCL12 antibody. CD19+ B cells and CD4+ T cells from SLE patients displayed a >2-fold increase (P = 0.0001) and >3-fold increase (P < 0.0001), respectively, in median CXCR4 expression compared with that in controls (n = 7-8). Moreover, CXCR4 expression on B cells was 1.61-fold higher in patients with SLE Disease Activity Index (SLEDAI) scores >10 (n = 8) than in patients with SLEDAI scores ≤10 (n = 16) (P = 0.0008), 1.71-fold higher in patients with class IV LN (n = 5) than in patients with other classes of LN (n = 7) (P = 0.02), and 1.40-fold higher in patients with active neuropsychiatric SLE (NPSLE) (n = 6) than in patients with inactive NPSLE (n = 18) (P = 0.01). CXCL12 was significantly up-regulated in the tubules and glomeruli of kidneys in patients with LN (n = 14), with the percentage of positive cells correlating positively with the severity of LN. CXCR4 appears to be up-regulated in multiple leukocyte subsets in SLE patients. The heightened expression of CXCR4 on B cells in active NPSLE and of CXCL12 in nephritic kidneys suggests that the CXCR4/CXCL12 axis might be a potential therapeutic target for SLE patients with kidney and/or central nervous system involvement.


Bidirectional cross-regulation between ErbB2 and β-adrenergic signalling pathways.
Despite the observation that ErbB2 regulates sensitivity of the heart to doxorubicin or ErbB2-targeted cancer therapies, mechanisms that regulate ErbB2 expression and activity have not been studied. Since isoproterenol up-regulates ErbB2 in kidney and salivary glands and β2AR and ErbB2 complex in brain and heart, we hypothesized that β-adrenergic receptors (AR) modulate ErbB2 signalling status. ErbB2 transfection of HEK293 cells up-regulates β2AR, and β2AR transfection of HEK293 up-regulates ErbB2. Interestingly, cardiomyocytes isolated from myocyte-specific ErbB2-overexpressing (ErbB2(tg)) mice have amplified response to selective β2-agonist zinterol, and right ventricular trabeculae baseline force generation is markedly reduced with β2-antagonist ICI-118 551. Consistently, receptor binding assays and western blotting demonstrate that β2ARs levels are markedly increased in ErbB2(tg) myocardium and reduced by EGFR/ErbB2 inhibitor, lapatinib. Intriguingly, acute treatment of mice with β1- and β2-AR agonist isoproterenol resulted in myocardial ErbB2 increase, while inhibition with either β1- or β2-AR antagonist did not completely prevent isoproterenol-induced ErbB2 expression. Furthermore, inhibition of ErbB2 kinase predisposed mice hearts to injury from chronic isoproterenol treatment while significantly reducing isoproterenol-induced pAKT and pERK levels, suggesting ErbB2's role in transactivation in the heart. Our studies show that myocardial ErbB2 and βAR signalling are linked in a feedback loop with βAR activation leading to increased ErbB2 expression and activity, and increased ErbB2 activity regulating β2AR expression. Most importantly, ErbB2 kinase activity is crucial for cardioprotection in the setting of β-adrenergic stress, suggesting that this mechanism is important in the pathophysiology and treatment of cardiomyopathy induced by ErbB2-targeting antineoplastic drugs.


Improving the Metrics and Data Reporting for Maternal Mortality: A Challenge to Public Health Surveillance and Effective Prevention.
The current measuring metric and reporting methods for assessing maternal mortality are seriously flawed. Evidence-based prevention strategies require consistently reported surveillance data and validated measurement metrics. Main Body: The denominator of live births used in the maternal mortality ratio reinforces the mistaken notion that all maternal deaths are consequent to a live birth and, at the same time, inappropriately inflates the value of the ratio for subpopulations of women with the highest percentage of pregnancies ending in outcomes other than a live birth. Inadequate methods for identifying induced or spontaneous abortion complications assure that most maternal deaths associated with those pregnancy outcomes are unlikely to be attributed. Absent the ability to identify all maternal deaths, and without the ability to differentiate those deaths by specific pregnancy outcomes, existing variations in pregnancy outcome-specific maternal deaths are masked by the use of an aggregated (all outcome) numerator. Under these circumstances, clear and accurate data is not available to inform evidence-based preventive strategies. As the result, algorithms applied for analyzing maternal mortality data may return distorted results Conclusion: Improvement in the effectiveness of maternal mortality surveillance will require: mandatory certification of all fetal losses; linkage of death, birth and all fetal loss (induced and natural) certificates; modification of the structure of the overall maternal mortality ratio to enable pregnancy outcome-specific ratio calculations; development of the appropriate ICD codes which are specific to induced and spontaneous abortions; education for providers on identifying and reporting early pregnancy losses; and, flexible information systems and methods which integrate these capabilities and inform users.


Effects of Weight Loss with and without Exercise on Regional Body Fat Distribution in Postmenopausal Women.
The purpose was to determine whether lifestyle interventions have different effects on regional fat in women with normal glucose tolerance vs. impaired glucose tolerance (NGT vs. IGT). Changes in glucose metabolism (2-h oral glucose-tolerance tests), android to gynoid fat mass ratio (dual energy X-ray absorptiometry [DXA]), visceral to subcutaneous abdominal fat area ratio (CT), and abdominal to gluteal subcutaneous fat cell weight (FCW; adipose tissue biopsies) were determined in 60 overweight postmenopausal women (45-80 years) following 6 months of weight loss alone (WL; n = 28) or with aerobic exercise (AEX + WL; n = 32). The interventions led to ∼8% decrease in weight, but only the AEX + WL group improved fitness (↑11% in VO2max) and reduced the android-to-gynoid fat mass ratio (↓5%; p < 0.05). Both NGT and IGT groups reduced visceral and subcutaneous abdominal fat areas and abdominal and gluteal FCWs, which related to improvements in homeostatic model assessment (r = 0.34-0.42) and 2-h glucose (r = 0.34-0.35), respectively (p < 0.05). The decline in FCW was 2× greater in women with IGT following WL (p < 0.05). The ratios of abdominal-to-gluteal FCW did not change following either intervention. The mechanisms by which WL with and without exercise impact regional fat loss should be explored as reductions in abdominal fat area and subcutaneous FCW appear to influence glucose metabolism. This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply. Published by S. Karger AG, Basel.


Isolation and no-entry marine reserves mitigate anthropogenic impacts on grey reef shark behavior.
Reef sharks are vulnerable predators experiencing severe population declines mainly due to overexploitation. However, beyond direct exploitation, human activities can produce indirect or sub-lethal effects such as behavioral alterations. Such alterations are well known for terrestrial fauna but poorly documented for marine species. Using an extensive sampling of 367 stereo baited underwater videos systems, we show modifications in grey reef shark (Carcharhinus amblyrhynchos) occurrence and feeding behavior along a marked gradient of isolation from humans across the New Caledonian archipelago (South-Western Pacific). The probability of occurrence decreased by 68.9% between wilderness areas (more than 25 hours travel time from the capital city) and impacted areas while the few individuals occurring in impacted areas exhibited cautious behavior. We also show that only large no-entry reserves (above 150 km²) can protect the behavior of grey reef sharks found in the wilderness. Influencing the fitness, human linked behavioral alterations should be taken into account for management strategies to ensure the persistence of populations.


Synthesis of a molecularly imprinted polymer and its application for microextraction by packed sorbent for the determination of fluoroquinolone related compounds in water.
Molecularly imprinted polymer (MIP) has been synthesized by precipitation polymerization using ciprofloxacin (CIP) as template for the analysis of fluoroquinolone antibiotics (FQs). This MIP material was packed as sorbent in a device for microextraction by packed sorbent (MEPS) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the analysis of selected FQs drugs including CIP, norfloxacin (NOR) and ofloxacin (OFLO) in municipal wastewater samples. In comparison to the new MIP-MEPS procedure, the target compounds were also determined by solid-phase extraction (MISPE) using the new molecular imprinted polymer material to validate the new MIP-MEPS method. The ability of the MIP for molecular recognition of CIP, NOR and OFLO was proved in presence of structurally different environmental relevant substances such as quinolones (Qs), flumequine (FLU), di(methyl)phthalate (DMP), technical 4-nonylphenol (NP), caffeine, Galaxolide(®), Tonalid(®), di(butyl)phthalate (DBP), Triclosan, bisphenol-A (BPA), carbamazepine, di(ethylhexyl)phthalate (DEHP), estradiol and octocrylene. The analysis of wastewater samples revealed the high selectivity of the synthesized polymer which was able to recognize and retain the target analytes by both extraction methods, the offline SPE with MIP material and the semi-automated MEPS packed with MIP material.


Development and application of the adverse outcome pathway framework for understanding and predicting chronic toxicity: II. A focus on growth impairment in fish.
Adverse outcome pathways (AOPs) organize knowledge on the progression of toxicity through levels of biological organization. By determining the linkages between toxicity events at different levels, AOPs lay the foundation for mechanism-based alternative testing approaches to hazard assessment. Here, we focus on growth impairment in fish to illustrate the initial stages in the process of AOP development for chronic toxicity outcomes. Growth is an apical endpoint commonly assessed in chronic toxicity tests for which a replacement is desirable. Based on several criteria, we identified reduction in food intake to be a suitable key event for initiation of middle-out AOP development. To start exploring the upstream and downstream links of this key event, we developed three AOP case studies, for pyrethroids, selective serotonin reuptake inhibitors (SSRIs) and cadmium. Our analysis showed that the effect of pyrethroids and SSRIs on food intake is strongly linked to growth impairment, while cadmium causes a reduction in growth due to increased metabolic demands rather than changes in food intake. Locomotion impairment by pyrethroids is strongly linked to their effects on food intake and growth, while for SSRIs their direct influence on appetite may play a more important role. We further discuss which alternative tests could be used to inform on the predictive key events identified in the case studies. In conclusion, our work demonstrates how the AOP concept can be used in practice to assess critically the knowledge available for specific chronic toxicity cases and to identify existing knowledge gaps and potential alternative tests.


Characterization of the blood-oxygen level-dependent (BOLD) response in cat auditory cortex using high-field fMRI.
Much of what is known about the cortical organization for audition in humans draws from studies of auditory cortex in the cat. However, these data build largely on electrophysiological recordings that are both highly invasive and provide less evidence concerning macroscopic patterns of brain activation. Optical imaging, using intrinsic signals or dyes, allows visualization of surface-based activity but is also quite invasive. Functional magnetic resonance imaging (fMRI) overcomes these limitations by providing a large-scale perspective of distributed activity across the brain in a non-invasive manner. The present study used fMRI to characterize stimulus-evoked activity in auditory cortex of an anesthetized (ketamine/isoflurane) cat, focusing specifically on the blood-oxygen-level-dependent (BOLD) signal time course. Functional images were acquired for adult cats in a 7 T MRI scanner. To determine the BOLD signal time course, we presented 1s broadband noise bursts between widely spaced scan acquisitions at randomized delays (1-12 s in 1s increments) prior to each scan. Baseline trials in which no stimulus was presented were also acquired. Our results indicate that the BOLD response peaks at about 3.5s in primary auditory cortex (AI) and at about 4.5 s in non-primary areas (AII, PAF) of cat auditory cortex. The observed peak latency is within the range reported for humans and non-human primates (3-4 s). The time course of hemodynamic activity in cat auditory cortex also occurs on a comparatively shorter scale than in cat visual cortex. The results of this study will provide a foundation for future auditory fMRI studies in the cat to incorporate these hemodynamic response properties into appropriate analyses of cat auditory cortex.