MRI findings in soccer players with long-standing adductor-related groin pain and asymptomatic controls.
Soccer players are commonly affected by long-standing adductor-related groin pain (ARGP), but the clinical significance of MRI findings in these athletes is largely unknown. Our aims were (1) to evaluate whether MRI findings are associated with long-standing ARGP in soccer players, (2) to assess MRI findings in asymptomatic soccer players and non-soccer playing controls. This cross-sectional study included 28 male soccer players with long-standing ARGP, 17 male asymptomatic soccer players and 20 male asymptomatic non-soccer playing athletes of matching age and athletic exposure. Participants underwent identical standardised and reliable clinical examination, and MRI scans (3 T) of the pelvis performed by a blinded observer. Images were consensus rated by three blinded radiologists according to a standardised MRI evaluation protocol. The associations between clinical adductor-related findings and pathological MRI findings were investigated with χ(2) statistics and OR. Central disc protrusion (p=0.027) and higher grades of pubic bone marrow oedema (BMO; p=0.027) were significantly more present in symptomatic players than asymptomatic players. However, up to 71% of asymptomatic soccer players displayed different positive MRI findings, and asymptomatic soccer players had significantly higher odds (OR ranging from 6.3 to 13.3) for BMO, adductor tendinopathy and degenerative changes than non-soccer players. ARGP in soccer players was associated with central disc protrusion and higher grades of pubic BMO. Moreover, positive MRI findings were significantly more frequent in soccer players compared with non-soccer players irrespective of symptoms, suggesting that these MRI changes may be associated with soccer play itself rather than clinical symptoms.


Antiepileptic drugs prescribed in pregnancy and prevalence of major congenital malformations: comparative prevalence studies.
The aim of this study was to examine the prevalence of major congenital malformations associated with antiepileptic drug (AED) treatment in pregnancy. Using data from The Health Improvement Network, we identified women who have given live birth and their offspring. Four subgroups were selected based on the AED treatment in early pregnancy, valproate, carbamazepine, lamotrigine and women not receiving AED treatment. We compared the prevalence of major congenital malformations within children of these four groups and estimated prevalence ratios (PRs) using Poisson regression adjusted for maternal age, sex of child, quintiles of Townsend deprivation score and indication for treatment. In total, 240,071 women were included in the study. A total of 229 women were prescribed valproate in pregnancy, 357 were prescribed lamotrigine and 334 were prescribed carbamazepine and 239,151 women were not prescribed AEDs. Fifteen out of 229 (6.6%) women prescribed valproate gave birth to a child with a major congenital malformation. The figures for lamotrigine, carbamazepine and women not prescribed AEDs were 2.7%, 3.3% and 2.2%, respectively. The prevalence of major congenital malformation was similar for women prescribed lamotrigine or carbamazepine compared to women with no AED treatment in pregnancy. For women prescribed valproate in polytherapy, the prevalence was fourfold higher. After adjustments, the effect of estimates attenuated, but the prevalence remained two- to threefold higher in women prescribed valproate. The results of our study suggest that lamotrigine and carbamazepine are safer treatment options than valproate in pregnancy and should be considered as alternative treatment options for women of childbearing potential and in pregnancy.


Effectiveness of a multiple intervention to reduce antibiotic prescribing for respiratory tract symptoms in primary care: randomised controlled trial.
To assess the effectiveness of a multiple intervention aimed at reducing antibiotic prescription rates for symptoms of the respiratory tract in primary care. Randomised controlled trial. Twelve peer review groups including 100 general practitioners with their collaborating pharmacists in the region of Utrecht, Netherlands. The intervention consisted of group education meetings, with a consensus procedure on indication for and type of antibiotics and with training in communication skills; monitoring and feedback on prescribing behaviour; group education for assistants of general practitioners and pharmacists; and education material for patients. The control group did not receive any of these elements. Antibiotic prescription rates for acute symptoms of the respiratory tract and patients' satisfaction. 89 general practitioners completed the study (89%). At baseline, prescription rates for antibiotics for respiratory tract symptoms did not differ between intervention and control group (27% v 29%, respectively). After nine months, the prescription rates in the intervention group fell to 23%, whereas the control group's rose to 37% (mean difference in change -12%, 95% confidence interval -18.9% to -4.0%). Multilevel analysis confirmed the results of the unadjusted analysis (intervention effect -10.7%, -20.3% to -1.0%). Patients' satisfaction was high and did not differ in the two groups at baseline or after the intervention. A multiple intervention reduced prescribing rates of antibiotics for respiratory tract symptoms while maintaining a high degree of satisfaction among patients. Further research should focus on the sustainability and cost effectiveness of this intervention.


Effects of detectability on estimates of geographic range size in Bignonieae.
Extinction risk has not been evaluated for 96% of all described plant species. Given that the Global Strategy for Plant Conservation proposes preliminary conservation assessments of all described plant species by 2010, herbarium specimens (i.e., primary occurrence data) are increasingly being used to infer threat components from estimates of geographic range size. Nevertheless, estimates of range size based on herbarium data may be inaccurate due to collection bias associated with interspecific variation in detectability. We used data on 377 species of Bignonieae to test the hypothesis that there is a positive relationship between detectability and estimates of geographic range size derived from herbarium specimens. This relationship is expected if the proportion of the true geographic range size of a species that is documented by herbarium specimens is given by the product of the true geographic range size and the detectability of the species, assuming no relationship between true geographic range size and detectability. We developed 4 measures of detectability that can be estimated from herbarium data and examined the relationship between detectability and 2 types of estimates of geographic range size: area of occupancy and extent of occurrence. Our results from regressing estimates of extent of occurrence and area of occupancy on detectability across genera provided no support for this hypothesis. The same was true for regressions of estimated extent of occurrence on detectability across species within genera. Nevertheless, regressions of estimated area of occupancy on detectability across species within genera provided partial support for our hypothesis. We considered 3 possible explanations for this mixed outcome: violation of the assumption of no relationship between true geographic range size and detectability; the relationships between estimated geographic range size and detectability may be an artifact of a negative relationship between estimated area of occupancy and the sampling variance of detectability; detectability may have had 2 opposite effects on estimated species range sizes: one determines the proportion of the true range of a species documented by herbarium specimens and the other determines the distribution of true range size for the species actually observed with herbarium data. Our findings should help improve understanding of the potential biases incurred with the use of herbarium data.


Clinical review: Cardiovascular consequences of ovarian disruption: a focus on functional hypothalamic amenorrhea in physically active women.
Evidence indicates that hypoestrogenemia is linked with accelerated progression of atherosclerosis. Premenopausal women presenting with ovulatory disruption due to functional hypothalamic amenorrhea (FHA) are characterized by hypoestrogenemia. One common and reversible form of FHA in association with energy deficiency is exercise-associated amenorrhea (EAA). Articles were found via PubMed search for both original and review articles based on peer review publications between 1974 and 2011 reporting on cardiovascular changes in women with FHA, with emphasis placed on women with EAA. Despite participation in regular exercise training, hypoestrogenic women with EAA demonstrate paradoxical changes in cardiovascular function, including endothelial dysfunction, a known permissive factor for the progression and development of atherosclerosis. Such alterations suggest that the beneficial effects of regular exercise training on vascular function are obviated in the face of hypoestrogenemia. The long-term cardiovascular consequences of altered vascular function in response to ovulatory disruption in women with EAA remain to be determined. Retrospective data, however, suggest premature development and progression of coronary artery disease in older premenopausal women reporting a history of hypothalamic ovulatory disruption. Importantly, in women with EAA, estrogen therapy, folic acid supplementation without change in menstrual status, and resumption of menses restores endothelial function. In this review, we focus on the influence of hypoestrogenemia in association with energy deficiency in mediating changes in cardiovascular function in women with EAA, including endothelial function, regional blood flow, lipid profile, and autonomic control of blood pressure, heart rate, and baroreflex sensitivity. The influence of exercise training is also considered. With the premenopausal years typically considered to be cardioprotective in association with normal ovarian function, ovarian disruption in women with EAA is of importance. Further investigation of the short-term, and potentially long-term, cardiovascular consequences of hypoestrogenemia in women with EAA is recommended.


Assessment of North American arthropod collections: prospects and challenges for addressing biodiversity research.
Over 300 million arthropod specimens are housed in North American natural history collections. These collections represent a "vast hidden treasure trove" of biodiversity -95% of the specimen label data have yet to be transcribed for research, and less than 2% of the specimens have been imaged. Specimen labels contain crucial information to determine species distributions over time and are essential for understanding patterns of ecology and evolution, which will help assess the growing biodiversity crisis driven by global change impacts. Specimen images offer indispensable insight and data for analyses of traits, and ecological and phylogenetic patterns of biodiversity. Here, we review North American arthropod collections using two key metrics, specimen holdings and digitization efforts, to assess the potential for collections to provide needed biodiversity data. We include data from 223 arthropod collections in North America, with an emphasis on the United States. Our specific findings are as follows: (1) The majority of North American natural history collections (88%) and specimens (89%) are located in the United States. Canada has comparable holdings to the United States relative to its estimated biodiversity. Mexico has made the furthest progress in terms of digitization, but its specimen holdings should be increased to reflect the estimated higher Mexican arthropod diversity. The proportion of North American collections that has been digitized, and the number of digital records available per species, are both much lower for arthropods when compared to chordates and plants. (2) The National Science Foundation's decade-long ADBC program (Advancing Digitization of Biological Collections) has been transformational in promoting arthropod digitization. However, even if this program became permanent, at current rates, by the year 2050 only 38% of the existing arthropod specimens would be digitized, and less than 1% would have associated digital images. (3) The number of specimens in collections has increased by approximately 1% per year over the past 30 years. We propose that this rate of increase is insufficient to provide enough data to address biodiversity research needs, and that arthropod collections should aim to triple their rate of new specimen acquisition. (4) The collections we surveyed in the United States vary broadly in a number of indicators. Collectively, there is depth and breadth, with smaller collections providing regional depth and larger collections providing greater global coverage. (5) Increased coordination across museums is needed for digitization efforts to target taxa for research and conservation goals and address long-term data needs. Two key recommendations emerge: collections should significantly increase both their specimen holdings and their digitization efforts to empower continental and global biodiversity data pipelines, and stimulate downstream research.


Effects of Glycyrrhizic Acid on Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), Lipoprotein Lipase (LPL), Serum Lipid and HOMA-IR in Rats.
Studies on ligand binding potential of glycyrrhizic acid, a potential agonist to PPARgamma, displayed encouraging results in amelioration of metabolic syndrome. The regulation of gene cassettes by PPARgamma affects glucose homeostasis, lipid, lipoprotein metabolism and adipogenesis. This study was performed to determine the effects of GA on total PPARgamma and LPL expression levels, lipid parameters and HOMA-IR. Oral administration of 100 mg/kg GA for 24 hours resulted in an increase in insulin sensitivity with decreases in blood glucose, serum insulin and HOMA-IR. Improvement in serum lipid parameters was also observed with a decrease in triacylglycerol, total cholesterol and LDL-cholesterol and an elevation in HDL-cholesterol. GA administration also resulted in up-regulation of total PPARgamma and LPL expression levels in the visceral and subcutaneous adipose tissues, abdominal and quadriceps femoris muscles, as well as liver and kidney, with a significant up-regulation only in the visceral adipose tissue, abdominal and quadriceps femoris muscles. Thus, oral administration of 100 mg/kg GA for 24 hours improved insulin sensitivity and lipid profiles and induced upregulation of total PPARgamma and LPL expression levels in all studied tissues.


Spatial Scale Gap Filling Using an Unmanned Aerial System: A Statistical Downscaling Method for Applications in Precision Agriculture.
Applications of satellite-borne observations in precision agriculture (PA) are often limited due to the coarse spatial resolution of satellite imagery. This paper uses high-resolution airborne observations to increase the spatial resolution of satellite data for related applications in PA. A new variational downscaling scheme is presented that uses coincident aerial imagery products from "AggieAir", an unmanned aerial system, to increase the spatial resolution of Landsat satellite data. This approach is primarily tested for downscaling individual band Landsat images that can be used to derive normalized difference vegetation index (NDVI) and surface soil moisture (SSM). Quantitative and qualitative results demonstrate promising capabilities of the downscaling approach enabling effective increase of the spatial resolution of Landsat imageries by orders of 2 to 4. Specifically, the downscaling scheme retrieved the missing high-resolution feature of the imageries and reduced the root mean squared error by 15, 11, and 10 percent in visual, near infrared, and thermal infrared bands, respectively. This metric is reduced by 9% in the derived NDVI and remains negligibly for the soil moisture products.


A crucial role for beta 2 integrin in the activation of eosinophils stimulated by IgG.
An IgG-coated surface, such as found on parasites, is one of the most effective physiologic stimuli for eosinophil activation. Recent evidence suggests that cellular adhesion, especially that through the beta 2 integrin, is an important step in cellular activation and accumulation. Therefore, we investigated the role of adhesion molecules in IgG-stimulated eosinophil functions. Cross-linking of eosinophil cytophilic IgG by anti-IgG immobilized to tissue culture plates induced degranulation, whereas soluble anti-IgG did not. Similarly, eosinophils exposed to human IgG immobilized to plates adhered and degranulated; in addition, adherence and subsequent degranulation were inhibited by mAbs to CD18 and CD11b, but not by mAb to CD29, suggesting an important role of beta 2 integrin for these responses. Eosinophil degranulation induced by IgG covalently coupled to Sepharose 4B beads was also inhibited by mAb to CD18. Furthermore, fibrinogen, a ligand for CD11b/18, showed synergistic enhancement of IgG-induced degranulation when it was co-immobilized with IgG to plates. A morphologic study showed that eosinophils, stimulated by immobilized IgG, protrude numerous pseudopods; this morphologic change was inhibited by mAb to CD18. This cellular adhesion seems to affect the early signaling events in eosinophils because the production of inositol phosphates was abolished by mAb to CD18. Interestingly, although superoxide production by eosinophils triggered by immobilized IgG was inhibited by mAb to CD18, superoxide production and morphologic change of neutrophils were not. These results suggest that cell adhesion through CD11b/18 is a crucial step for the activation, signaling, and effector function of eosinophils stimulated by IgG.


Biochemical and structural changes in cultured heart cells induced by metabolic inhibition.
We examined the relationship between ionic homeostasis, ATP, and irreversible cell injury in cultured embryonic chick heart cells treated with rotenone (10(-4) M) alone or in combination with iodoacetate (IAA) (10(-3) M), in the presence of extracellular calcium (Ca0) (2.7 mM) and its nominal absence. Changes in Na, K, and total cell Ca content did not correlate with parameters indicative of irreversible injury, i.e., ultrastructural damage or lactate dehydrogenase (LDH) release. Because structural defects in the plasma membrane occurred without a significant release of LDH after exposure to rotenone plus IAA for 1 h, LDH release appears to be a relatively late event in cell injury. In addition, cells exposed to rotenone in the presence of Ca0 for 2.5 h showed a significant fall in ATP and a rise in LDH release. This response was attenuated in the nominal absence of Ca0, and the addition of rotenone caused an eightfold increase in intracellular sodium (Nai), whereas in the presence of Ca0, Nai increased only threefold in 2.5 h. Thus Ca0 appears to promote Nai-Ca0 exchange and lead to an increase in cell Ca that can then stimulate ATP breakdown by Ca-activated ATPases. Of the measured variables associated with myocardial cell injury, a decline in ATP correlates best with changes in either LDH or morphology. The apparent lack of correlation between changes in intracellular ion content, LDH release, and morphology supports the conclusion that myocardial cell injury is a multifactorial process.


Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. Resting-state functional magnetic resonance imaging. Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. Our findings provide novel biological evidence that DM1 is a clinical condition that also involves an alteration of functional connectivity of the brain. We speculate that these functional brain abnormalities, similarly to frank psychiatric disorders, may account for the atypical personality traits observed in patients with DM1.


Proton-evolved local-field solid-state NMR studies of cytochrome b5 embedded in bicelles, revealing both structural and dynamical information.
Structural biology of membrane proteins has rapidly evolved into a new frontier of science. Although solving the structure of a membrane protein with atomic-level resolution is still a major challenge, separated local field (SLF) NMR spectroscopy has become an invaluable tool in obtaining structural images of membrane proteins under physiological conditions. Recent studies have demonstrated the use of rotating-frame SLF techniques to accurately measure strong heteronuclear dipolar couplings between directly bonded nuclei. However, in these experiments, all weak dipolar couplings are suppressed. On the other hand, weak heteronuclear dipolar couplings can be measured using laboratory-frame SLF experiments, but only at the expense of spectral resolution for strongly dipolar coupled spins. In the present study, we implemented two-dimensional proton-evolved local-field (2D PELF) pulse sequences using either composite zero cross-polarization (COMPOZER-CP) or windowless isotropic mixing (WIM) for magnetization transfer. These PELF sequences can be used for the measurement of a broad range of heteronuclear dipolar couplings, allowing for a complete mapping of protein dynamics in a lipid bilayer environment. Experimental results from magnetically aligned bicelles containing uniformly (15)N-labeled cytochrome b(5) are presented and theoretical analyses of the new PELF sequences are reported. Our results suggest that the PELF-based experimental approaches will have a profound impact on solid-state NMR spectroscopy of membrane proteins and other membrane-associated molecules in magnetically aligned bicelles.


Body art: attitudes and practices regarding body piercing among urban undergraduates.
To describe the knowledge, attitudes, and practices of young adults toward body piercing. An anonymous 30-item survey was given to 103 undergraduate students at the campus health service of a large urban university. The questionnaire collected data on students' perceptions regarding the social acceptability of body piercing, their experiences with and attitudes toward this form of body art, and their knowledge of associated health risks. One hundred (97%) out of the 103 surveys distributed had sufficient data for analysis. Fifty-six percent of participants (age range, 17 to 25 years) reported having a body piercing at one time. Participants with a piercing were more likely to have a tattoo (OR, 4.13; 95% CI, 1.10-15.56; P=.04). The majority of participants (65 [78%]) reported "liking" body piercing on others, though a smaller percentage (45 [52%]) reported "liking" it on themselves (z=3.58, P<.001). Participants estimated the chance of potential health risks as a result of body piercing as follows: bleeding (60%), infection (56%), keloid scarring (43%), bruising (41%), allergic reaction (38%), cyst or tetanus (each 24%), hepatitis B (20%), and human immunodeficiency virus (16%). Nonpierced participants assessed the probability of adverse events as a result of body piercing at 43%, whereas their pierced counterparts estimated the risk at 30% (F(1,83)14.06, P<.001). Forty-three percent of all participants reported knowing someone (ie, other than themselves) who experienced a health problem as a result of body piercing, though few (10 of 52 [19%]) pierced participants reported similar personal experiences. Young adults believe that body piercing is highly acceptable among the general public. Furthermore, though they believe such body art is acceptable on others, they feel it is less acceptable on themselves. Study participants displayed a high level of awareness regarding the potential health risks of body art, and, in fact, overestimate those risks. Implications for patient education are addressed.


Hydrogen peroxide mediates the killing of U937 tumor cells elicited by pharmacologically attainable concentrations of ascorbic acid: cell death prevention by extracellular catalase or catalase from cocultured erythrocytes or fibroblasts.
Pharmacologically attainable concentrations of ascorbic acid are highly toxic for U937 cells (a human promyelocytic cell line), and this response appears to be mediated by H2O2. This inference finds experimental support in the following observations: 1) toxic levels of H2O2 are readily generated upon dissolution of survival-range concentrations of ascorbic acid in the culture medium; 2) the lethal effects elicited by ascorbic acid or reagent H2O2 are prevented by the addition of either catalase or the intracellular iron chelator o-phenanthroline and are characterized by similar temporal dependence; 3) U937 cells resistant to hydrogen peroxide are cross-resistant to ascorbic acid; 4) under the conditions utilized in this study, H2O2 and ascorbate promote similar modes of cell death (i.e., necrosis); and 5) cell killing provoked by H2O2 or ascorbate is an inverse function of cell density and is suppressed by coculturing U937 target cells with human erythrocytes (at a density far below that present in the blood) and human fibroblasts. Cytoprotection was not observed using catalase-depleted erythrocytes. Taken together, these results strongly suggest that H2O2 is entirely responsible for the ascorbate-induced U937 cell killing. We therefore propose that it is unlikely that the vitamin damages or kills tumor cells of normal tissues in vivo via the H2O2 based mechanism, because the oxidant would be removed promptly by the neighboring cells.


Hemispheric lateralization of a molecular signal for pain modulation in the amygdala.
The extracellular signal-regulated kinase (ERK) cascade has been shown to be a key modulator of pain processing in the central nucleus of the amygdala (CeA) in mice. ERK is activated in the CeA during persistent inflammatory pain and this activation is both necessary and sufficient to induce peripheral tactile hypersensitivity. Interestingly, biochemical studies show that inflammation-induced ERK activation in the CeA only occurs in the right, but not the left hemisphere. This inflammation-induced ERK activation in the right CeA is independent of the side of peripheral inflammation, suggesting that there is a dominant role of the right hemisphere in the modulation of pain by ERK activation in the CeA. However, the functional significance of this biochemical lateralization has yet to be determined. In the present study, we tested the hypothesis that modulation of pain by ERK signaling in the CeA is functionally lateralized. We acutely blocked ERK activation in the CeA by infusing the MEK inhibitor U0126 into the right or the left hemisphere and then measured the behavioral effects on inflammation-induced mechanical hypersensitivity in mice. Our results show that blockade of ERK activation in the right, but not the left CeA, decreases inflammation-induced peripheral hypersensitivity independent of the side of peripheral injury. These findings demonstrate that modulation of pain by ERK signaling in the CeA is functionally lateralized to the right hemisphere, suggesting a dominant role of the right amygdala in pain processing.


Masked hypertension: a systematic review.
The purpose of this research was to review the literature on masked hypertension. Studies, reviews and editorials on masked hypertension were identified by PubMed, Pascal BioMed and Cochrane literature systematic searches. Then, we carried out a meta-analysis of the six cohort studies reporting quantitative data for masked hypertension prognosis. There is still no clear consensus definition of masked hypertension and the reproducibility of the phenomenon is unknown. Nevertheless, the prevalence of masked hypertension seems to lie between 8 and 20%, and can be up to 50% in treated hypertensive patients. Subjects with masked hypertension have a higher risk of cardiovascular accidents [hazard ratios: 1.92 (1.51-2.44)] than normotensive subjects. This is due to a possible failure to recognize and appropriately manage this particular form of hypertension, the frequent association with other risk factors and coexisting target organ damage. The remaining unresolved questions are as follows: is masked hypertension a clinical entity that requires identification and characterization or a statistical phenomenon linked to the variability of blood pressure measurements?; because screening of the entire population is not feasible, how to identify individuals with masked hypertension?; and, in the absence of randomized trial, how to treat masked hypertension?


New insights into the functional roles of CrRLKs in the control of plant cell growth and development.
Receptor-like kinases (RLKs) are a family of transmembrane proteins with a variable ligand-binding extracellular domain and a cytoplasmic kinase domain. In Arabidopsis, there are ~600 RLKs believed to have diverse functions during plant growth, development and interactions with the environment. Based on the variable extracellular domain, RLKs can be classified into different subfamilies. The CrRLK subfamily contains 17 members in Arabidopsis and characterization of some of its members suggests a role for these proteins in the regulation of growth and reproduction. The present review focuses on the roles of CrRLKs in the regulation of polarized growth with emphasis on the newly identified signal transduction pathways activated downstream of CrRLKs. A picture is emerging where CrRLKs are part of a conserved signal transduction cascade important for growth maintenance in different cell types.


CRISPR-Cas9 mediated CD133 knockout inhibits colon cancer invasion through reduced epithelial-mesenchymal transition.
We previously reported that CD133, as a putative cancer stem cell marker, plays an important role in cell proliferation and invasion in colon cancer. To understand the role of CD133 expression in colon cancer, we evaluated the inhibitory effect of CD133 in colon cancer cells. In this study, we generated CD133knockout colon cancer cells (LoVo) using the CRISPR-Cas9 gene editing system. CD133+ colon cancer cells (LoVo) were infected with the lentiviral vector carrying CD133 gRNA and purified cell by culturing single cell colonies. CD133knockout cells was validated by western blot and flow cytometry analysis. In functional study, we observed a significant reduction in cell proliferation and colony formation in CRISPR-Cas9 mediated CD133 knockout cells in compare with control (P < 0.001). We also found the anticancer effect of stattic was dependent on CD133 expression in colon cancer cells. Although CD133knockout cells could not completely block the tumorigenic property, they showed remarkable inhibitory effects on the ability of cell migration and invasion (P < 0.001). In addition, we examined the epithelial mesenchymal transition (EMT)-related protein expression by western blot. The result clearly showed a loss of vimentin expression in CD133knockout cells. Therefore, CRISPR-Cas9 mediated CD133knockout can be an effective treatment modality for CD133+ colon cancer through reducing the characteristics of cancer stem cells.


The elasmobranch spiracular organ. I. Morphological studies.
The spiracular organ is a lateral line derived receptor associated with the first gill cleft (spiracle). Its functional morphology was studied in the little skate, Raja erinacea, and a shark, the smooth dogfish, Mustelus canis, with light and electron microscopy. The spiracular organ is a tube (skate) or pouch (shark) with a single pore opening into the spiracle. The lumen is lined with patches of sensory hair cells, and filled with a gelatinous cupula. In the little skate, hair cells form synapses with afferents but apparently not with efferent fibers. In both species, the spiracular organs are deformed by flexion of the hyomandibular cartilage at its articulation with the cranium. The hyomandibula is a suspensory element of the jaws; hyomandibular flexion results in jaw protrusion. The little skate spiracular organ is anchored at one end to the cranium and at the other to the hyomandibula so that it is stretched or relaxed during hyomandibular extension and flexion, respectively. In Mustelus, the effects of hyomandibular flexion on the spiracular organ are mediated indirectly by the superior post-spiracular ligament which inserts on the distal end of the hyomandibula. Deformation of the dogfish shark cupula during hyomandibular movement was observed. In the little skate, as revealed by transmission electron microscopy, there is a measurable deflection of the hair cell ciliary bundles from spiracular organs fixed with the hyomandibula in the flexed relative to the extended positions. In both species, hyomandibula flexion should result in hair cell depolarization, and sensory afferent excitation, based on the direction of the observed (skate) or expected (shark) deflection of hair cell cilia.


High-Resolution Manometry Evaluation of the Pharynx and Upper Esophageal Sphincter Motility in Patients with Achalasia.
The motility of the pharynx and upper esophageal sphincter (UES) is still poorly understood. It is also unclear if the motility of this area may be compromised in patients with achalasia. This study aims to evaluate the motility of the pharynx, UES, and proximal esophagus in patients with esophageal achalasia. Sixty patients with achalasia underwent high-resolution manometry (HRM) (52 % females, mean age 54 years). Esophageal dilatation was classified according to the radiologic diameter in Type I (<4 cm): 6 %; Type II (4-7 cm): 36 %; Type III (7-10 cm): 34 %; and Type IV (>10 cm): 24 %. HRM classified 43 % of the patients as Chicago Type I and 57 % as Type II. Manometric parameters were compared to normal values obtained from a previous study in volunteers. The motility of the velopharynx showed short, premature, and hypertonic contraction. The epiglottis also showed hypertonic contraction. The UES had increased residual pressure. Chicago classification Type II patients had higher UES residual pressure (p = 0.03). The degree of esophageal dilatation did not correlate with manometric parameters. Achalasia may affect the motility of the pharyngo-upper esophageal area. The changes observed may represent functional alterations to prevent aspiration, especially in patients with Chicago classification Type II achalasia.


Slow sleep spindle and procedural memory consolidation in patients with major depressive disorder.
Evidence has accumulated, which indicates that, in healthy individuals, sleep enhances procedural memory consolidation, and that sleep spindle activity modulates this process. However, whether sleep-dependent procedural memory consolidation occurs in patients medicated for major depressive disorder remains unclear, as are the pharmacological and physiological mechanisms that underlie this process. Healthy control participants (n=17) and patients medicated for major depressive disorder (n=11) were recruited and subjected to a finger-tapping motor sequence test (MST; nondominant hand) paradigm to compare the averaged scores of different learning phases (presleep, postsleep, and overnight improvement). Participants' brain activity was recorded during sleep with 16 electroencephalography channels (between MSTs). Sleep scoring and frequency analyses were performed on the electroencephalography data. Additionally, we evaluated sleep spindle activity, which divided the spindles into fast-frequency spindle activity (12.5-16 Hz) and slow-frequency spindle activity (10.5-12.5 Hz). Sleep-dependent motor memory consolidation in patients with depression was impaired in comparison with that in control participants. In patients with depression, age correlated negatively with overnight improvement. The duration of slow-wave sleep correlated with the magnitude of motor memory consolidation in patients with depression, but not in healthy controls. Slow-frequency spindle activity was associated with reduction in the magnitude of motor memory consolidation in both groups. Because the changes in slow-frequency spindle activity affected the thalamocortical network dysfunction in patients medicated for depression, dysregulated spindle generation may impair sleep-dependent memory consolidation. Our findings may help to elucidate the cognitive deficits that occur in patients with major depression both in the waking state and during sleep.


Distinct developmental pathways from blood monocytes generate human lung macrophage diversity.
The study of human macrophages and their ontogeny is an important unresolved issue. Here, we use a humanized mouse model expressing human cytokines to dissect the development of lung macrophages from human hematopoiesis in vivo. Human CD34+ hematopoietic stem and progenitor cells (HSPCs) generated three macrophage populations, occupying separate anatomical niches in the lung. Intravascular cell labeling, cell transplantation, and fate-mapping studies established that classical CD14+ blood monocytes derived from HSPCs migrated into lung tissue and gave rise to human interstitial and alveolar macrophages. In contrast, non-classical CD16+ blood monocytes preferentially generated macrophages resident in the lung vasculature (pulmonary intravascular macrophages). Finally, single-cell RNA sequencing defined intermediate differentiation stages in human lung macrophage development from blood monocytes. This study identifies distinct developmental pathways from circulating monocytes to lung macrophages and reveals how cellular origin contributes to human macrophage identity, diversity, and localization in vivo.


The interrelationship between balance, Tai Chi and depression in Latino older adults.
Falls and associated injuries are the most serious medical problem affecting the functional independence among both White non-Hispanics and Latino older adults. Studies have shown the effectiveness of Tai Chi exercise in reducing falls but have primarily focused on White non-Hispanic older adults. There is limited research that examines the effectiveness of this exercise on balance among different racial/ethnic minority older adults. This study focused on the interrelationship between functional status (balance performance) and psychosocial status (depression) before and after a 12-week Tai Chi program among Latinos in a Midwestern metropolitan city. Results indicated that at baseline, prior to the start of the Tai Chi program, participants who were more depressed had poorer functional status. Participants who had higher depression at baseline, experienced greater improvement in functional status, following the 12-week Tai Chi exercise program, compared with those who had lower levels of depression.


Combining shape and connectivity analysis: an MRI study of thalamic degeneration in Alzheimer's disease.
Alzheimer's disease (AD) is associated with neuronal loss not only in the hippocampus and amygdala but also in the thalamus. Anterodorsal, centromedial, and pulvinar nuclei are the main sites of degeneration in AD. Here we combined shape analysis and diffusion tensor imaging (DTI) tractography to study degeneration in AD in the thalamus and its connections. Structural and diffusion tensor MRI scans were obtained from 16 AD patients and 22 demographically similar healthy volunteers. The thalamus, hippocampus, and amygdala were automatically segmented using our locally developed algorithm, and group comparisons were carried out for each surface vertex. We also employed probabilistic diffusion tractography to obtain connectivity measures between individual thalamic voxels and hippocampus/amygdala voxels and to segment the internal medullary lamina (IML). Shape analysis showed significant bilateral regional atrophy in the dorsal-medial part of the thalamus in AD patients compared to controls. Probabilistic tractography demonstrated that these regions are mainly connected with the hippocampus, temporal, and prefrontal cortex. Intrathalamic FA comparisons showed reductions in the anterodorsal region of thalamus. Intrathalamic tractography from this region revealed that the IML was significantly smaller in AD patients than in controls. We suggest that these changes can be attributed to the degeneration of the anterodorsal and intralaminar nuclei, respectively. In addition, based on previous neuropathological reports, ventral and dorsal-medial shape change in the thalamus in AD patients is likely to be driven by IML atrophy. This combined shape and connectivity analysis provides MRI evidence of regional thalamic degeneration in AD.


Study of the Therapeutic Effects of Intercessory Prayer (STEP): study design and research methods.
The effect of intercessory prayer (IP) on outcome in cardiac cases has been evaluated previously, but results are controversial. The goals of the Study of the Therapeutic Effects of Intercessory Prayer (STEP) are to evaluate the effects of receipt of additional study IP and awareness of receipt of additional study IP on outcomes in patients undergoing coronary artery bypass graft surgery. STEP is not designed to determine whether God exists or whether God does or does not respond to IP. STEP is a multicenter, controlled trial of 1802 patients in 6 US hospitals, randomized to 1 of 3 groups. Two groups were informed that they may or may not receive 14 consecutive days of additional IP starting the night before coronary artery bypass graft surgery; Group 1 received IP, Group 2 did not. A third group (Group 3) was informed that they would receive additional IP and did so. Three mainstream religious sites provided daily IP for patients assigned to receive IP. At each hospital, research nurses blinded to patient group assignment reviewed medical records to determine whether complications occurred, on the basis of the Society for Thoracic Surgeons definitions. A blinded nurse auditor from the Coordinating Center reviewed every study patient's data against the medical record before release of study forms. The STEP Data and Safety Monitoring Board reviewed patient safety and outcomes in the first 900 study patients. Patients were enrolled in STEP from January 1998 to November 2000.


Prevalence and causes of vision loss in high-income countries and in Eastern and Central Europe: 1990-2010.
To assess prevalence and causes of blindness and vision impairment in high-income regions and in Central/Eastern Europe in 1990 and 2010. Based on a systematic review of medical literature, prevalence of moderate and severe vision impairment (MSVI; presenting visual acuity <6/18 but ≥3/60 in the better eye) and blindness (presenting visual acuity <3/60) was estimated for 1990 and 2010. Age-standardised prevalence of blindness and MSVI decreased from 0.2% to 0.1% (3.314 million to 2.736 million people) and from 1.6% to 1.0% (25.362 million to 22.176 million), respectively. Women were generally more affected than men. Cataract was the most frequent cause of blindness in all subregions in 1990, but macular degeneration and uncorrected refractive error became the most frequent causes of blindness in 2010 in all high-income countries, except for Eastern/Central Europe, where cataract remained the leading cause. Glaucoma and diabetic retinopathy were fourth and fifth most common causes for blindness for all regions at both times. Uncorrected refractive error, followed by cataract, macular degeneration, glaucoma and diabetic retinopathy, was the most common cause for MSVI in 1990 and 2010. In highly developed countries, prevalence of blindness and MSVI has been reduced by 50% and 38%, respectively, and the number of blind people and people with MSVI decreased by 17.4% and 12.6%, respectively, even with the increasing number of older people in the population. In high-income countries, macular degeneration has become the most important cause of blindness, but uncorrected refractive errors continue to be the leading cause of MSVI.


Induction of cyclooxygenase-2 in rat vascular smooth muscle cells in vitro and in vivo.
Prostaglandins are synthesized from arachidonic acid by the rate-limiting enzyme cyclooxygenase (prostaglandin G/H synthase). Active cyclooxygenase is encoded by two distinct and independently regulated genes, termed cyclooxygenase-1 (cox1) and cyclooxygenase-2 (cox2). In this investigation, we examined the expression of cox1 and cox2 mRNA in rat aorta following balloon deendothelialization (BDE) in vivo and in rat aortic smooth muscle cells (SMC) after serum stimulation in vitro. Two h after BDE, rat aortic cox2 mRNA levels increased greater than 50-fold relative to the lowest detectable levels on days 2 and 14. No message was detectable in non-BDE control rat aortas. Similar to the results found in vivo, cultured SMC exhibited a greater than 45-fold increase in cox2 mRNA levels after a 2-h exposure to serum. This increase was transient because cox2 levels declined at 4 and 8 h. In contrast, minimal changes in cox1 mRNA levels were observed after BDE or serum treatments. Increased levels of cox2 mRNA and corresponding protein synthesis led to an accumulation of total cyclooxygenase protein, which remained elevated 24 h after serum stimulation. Serum-treated SMC also generated greater amounts of cyclooxygenase-dependent metabolites than quiescent SMC as evidenced by marked increases in prostaglandin E2 content in conditioned media. This increase is associated with a 2.5-3.0-fold increased rate of arachidonic acid conversion to prostaglandin E2. Our data indicate that injury and serum stimulation differentially regulate mRNA and protein expression of two distinct cox genes in vascular SMC in vivo and in vitro. The findings suggest that the prostanoid responses after vascular injury are, in part, mediated by acute increases in cox2 mRNA and cyclooxygenase-2 protein.


Isolation and characterization of a subset of erythropoietin glycoforms with cytoprotective but minimal erythropoietic activity.
Although historically used for the treatment of anemia, erythropoietin (EPO) has emerged as a neurotrophic and neuroprotective agent in different conditions of neuronal damage (traumatic brain injury, ischemia, spinal cord compression, peripheral neuropathy, retinal damage, epilepsy, Parkinson's Disease, among others). Nonetheless, EPO's therapeutic application is limited due to its hematological side-effects. With the aim of obtaining EPO derivatives resembling the hormone isolated from cells and tissues of neural origin, a novel combination of less acidic EPO glycoforms -designated as neuroepoetin (rhNEPO)- was purified to homogeneity from the supernatant of a CHO-producing cell line by a four-step chromatographic procedure. This simple and single process allowed us to prepare two EPO derivatives with distinct therapeutic expectations: the hematopoietic version and a minimally hematopoietic, but mainly in vitro cytoprotective, alternative. Further biological characterization showed that the in vivo erythropoietic activity of rhNEPO was 25-times lower than that of rhEPO. Interestingly, using different in vitro cytoprotective assays we found that this molecule exerts cytoprotection equivalent to, or better than, that of rhEPO in cells of neural phenotype. Furthermore, despite its shorter plasma half-life, rhNEPO was rapidly absorbed and promptly detected in the cerebrospinal fluid after intravenous administration in rats (5 min postinjection, in comparison with 30 min for rhEPO). Therefore, our results support the study of neuroepoetin as a potential drug for the treatment of neurological diseases, combining high cytoprotective activity with reduced hematological side-effects.


Floral Markers in Honey of Various Botanical and Geographic Origins: A Review.
In view of the expanding global market, authentication and characterization of botanical and geographic origins of honey has become a more important task than ever. Many studies have been performed with the aim of evaluating the possibilities to characterize honey samples of various origins by using specific chemical marker compounds. These have been identified and quantified for numerous honey samples. This article is aimed at summarizing the studies carried out during the last 2 decades. An attempt is made to find useful chemical markers for unifloral honey, based on the analysis of the compositional data of honey volatile compounds, phenolic acids, flavonoids, carbohydrates, amino acids, and some other constituents. This review demonstrates that currently it is rather difficult to find reliable chemical markers for the discrimination of honey collected from different floral sources because the chemical composition of honey also depends on several other factors, such as geographic origin, collection season, mode of storage, bee species, and even interactions between chemical compounds and enzymes in the honey. Therefore, some publications from the reviewed period have reported different floral markers for honey of the same floral origin. In addition, the results of chemical analyses of honey constituents may also depend on sample preparation and analysis techniques. Consequently, a more reliable characterization of honey requires the determination of more than a single class of compounds, preferably in combination with modern data management of the results, for example, principal component analysis or cluster analysis.


Metabolic and molecular action of Trigonella foenum-graecum (fenugreek) and trace metals in experimental diabetic tissues.
Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycaemia resulting in defective insulin secretion, resistance to insulin action or both. The use of biguanides, sulphonylurea and other drugs are valuable in the treatment of diabetes mellitus; their use, however, is restricted by their limited action, pharmacokinetic properties, secondary failure rates and side effects. Trigonella foenum-graecum, commonly known as fenugreek, is a plant that has been extensively used as a source of antidiabetic compounds from its seeds and leaf extracts. Preliminary human trials and animal experiments suggest possible hypoglycaemic and antihyperlipedemic properties of fenugreek seed powder taken orally. Our results show that the action of fenugreek in lowering blood glucose levels is almost comparable to the effect of insulin. Combination with trace metal showed that vanadium had additive effects and manganese had additive effects with insulin on in vitro system in control and diabetic animals of young and old ages using adipose tissue. The Trigonella and vanadium effects were studied in a number of tissues including liver, kidney, brain peripheral nerve, heart, red blood cells and skeletal muscle. Addition of Trigonella to vanadium significantly removed the toxicity of vanadium when used to reduce blood glucose levels. Administration of the various combinations of the antidiabetic compounds to diabetic animals was found to reverse most of the diabetic effects studied at physiological, biochemical, histochemical and molecular levels. Results of the key enzymes of metabolic pathways have been summarized together with glucose transporter, Glut-4 and insulin levels. Our findings illustrate and elucidate the antidiabetic/insulin mimetic effects of Trigonella, manganese and vanadium.


Penetration and development of Meloidogyne arenaria on two new grape rootstocks.
Penetration, development, and reproduction of a virulent 'Harmony' population of Meloidogyne arenaria was studied on two nematode-resistant grape rootstocks 10-17A and 6-19B. 'Cabernet Sauvignon' was used as a susceptible control for comparison. Plants were inoculated with 100 freshly hatched second-stage juveniles (J2) of M. arenaria. Greater numbers of J2 penetrated roots of 'Cabernet' than 10-17A, and none penetrated roots of 6-19B 4 days after inoculation (DAI). At 7 DAI, vermiform J2 advanced to sausage-shaped J2 in roots of 'Cabernet,' penetrated roots of 6-19B, and had egressed from roots of 10-17A. Resistant rootstocks expressed hypersensitive responses to penetrating J2 along the root epidermis, among the cortical cells, and along the differentiating vascular bundles. At 13 DAI, 68% of the J2 had attained globose stage in roots of 'Cabernet,' whereas there was no development of vermiform J2 in roots of the other two rootstocks. The nematodes reproduced only in roots of 'Cabernet.' Lack of development of J2 in roots of the two resistant grape rootstocks might be the result of a hypersensitive response to J2 feeding.


AGA Institute Clinical Practice Update: Endoscopic Submucosal Dissection in the United States.
Endoscopic submucosal dissection (ESD) is an established endoscopic resection method in Asian countries, which is increasingly practiced in Europe and by early adopters in the United States for removal of early cancers and large lesions from the luminal gastrointestinal tract. The intent of this expert review is to provide an update regarding the clinical practice of ESD with a particular focus on its use in the United States. This review is framed around the 16 best practice advice points agreed upon by the authors, which reflect landmark and recent published articles in this field. This expert review also reflects our experience as advanced endoscopists with extensive experience in performing and teaching others to perform ESD in the United States. Best Practice Advice 1: Endoscopic submucosal dissection should be recognized as a mature endoscopic technique that enables complete removal of lesions that are too large for en bloc endoscopic mucosal resection or are at increased risk of containing cancer. Best Practice Advice 2: The safety and feasibility of endoscopic submucosal dissection for early gastric cancer is well established. The absolute indications for curative endoscopic resection include moderately and well-differentiated, nonulcerated, mucosal lesions that are ≤2 cm in size. Best Practice Advice 3: Other relative (expanded) indications for gastric endoscopic submucosal dissection include moderately and well-differentiated superficial cancers that are >2 cm, lesions ≤3 cm with ulceration or that contain early submucosal invasion, and poorly differentiated superficial cancers ≤2 cm in size. The risk of lymph node metastasis when endoscopic submucosal dissection is performed for these indications is higher than when it is performed for absolute indications but remains acceptably low. Best Practice Advice 4: Endoscopic submucosal dissection may be considered in selected patients with Barrett's esophagus with the following features: large or bulky area of nodularity, lesions with a high likelihood of superficial submucosal invasion, recurrent dysplasia, endoscopic mucosal resection specimen showing invasive carcinoma with positive margins, equivocal preprocedural histology, and intramucosal carcinoma. Best Practice Advice 5: Endoscopic submucosal dissection is the primary modality for treatment of squamous cell dysplasia and cancer confined to the superficial esophageal mucosa. Any degree of submucosal invasion caries an increased risk of lymph node metastasis and alternative/additional therapy should be considered. Best Practice Advice 6: Duodenal endoscopic submucosal dissection is associated with an increased risk of intraprocedural perforation and delayed adverse events. Duodenal endoscopic submucosal dissection should be limited to endoscopists with extensive experience in performing endoscopic submucosal dissection in other locations. It is strongly suggested that endoscopists in the United States refrain from performing duodenal endoscopic submucosal dissection during the early phase of their endoscopic submucosal dissection practice. Best Practice Advice 7: All colorectal lesions should be evaluated for suitability for endoscopic resection. Accumulating evidence has shown that the majority of colorectal neoplasms without signs of deep submucosal invasion or advanced cancer can be treated by advanced endoscopic resection techniques. Best Practice Advice 8: Colorectal neoplasms containing dysplasia confined to the mucosa have no risk for lymph node metastasis and endoscopic resection should be considered as the criterion standard. Best Practice Advice 9: Large (>2 cm) colorectal lesions frequently (>43%) require piecemeal removal when endoscopic mucosal resection is used, which is associated with increased (up to 20%) rates of recurrent neoplasia. Endoscopic submucosal dissection enables higher rates of en bloc resection and lower recurrence rates for these lesions. Patients with large complex colorectal polyps should be referred to a high-volume, specialized center for endoscopic removal by endoscopic mucosal resection or endoscopic submucosal dissection. Best Practice Advice 10: Endoscopic resection for colorectal lesions offers significant cost benefit compared with surgery, and case-based endoscopic submucosal dissection selection for high-risk lesions could offer cost savings. Best Practice Advice 11: Endoscopists in the United States embarking on performing endoscopic submucosal dissection should be familiar with currently available endoscopic tissue closure devices. Both clip closure and endoscopic suturing techniques have been shown to be effective in managing intraprocedural perforation. Complete closure of a post-endoscopic submucosal dissection site may be considered in certain circumstances based on patient factors, procedural factors, and the location of the lesion. Best Practice Advice 12: Careful coagulation of exposed blood vessels in the resection site may reduce the risk of delayed bleeding after endoscopic submucosal dissection. The use of low-voltage coagulation current is recommended for this technique. Best Practice Advice 13: Endoscopists should affix the endoscopic submucosal dissection specimen to a flat surface (eg, pin the specimen to cork board) and immerse it in formalin. An expert gastrointestinal pathologist should evaluate the specimen for margin involvement, degree of differentiation, presence or absence of lymphovascular invasion, depth of submucosal invasion (if present), and tumor budding. Best Practice Advice 14: Acquiring high-level competency in endoscopic submucosal dissection is achievable in the United States. Alternative educational models should be used in the United States because of the limited number of experts and the differing prevalence of gastrointestinal luminal diseases as compared with Asia. Best Practice Advice 15: The endoscopic submucosal dissection educational model most suited for the current environment in the United States is a stepwise approach consisting of didactic self-study, attending training courses with increasing levels of complexity, self-practice on animal models, and observation of live cases performed by experts. Endoscopists should perform their initial endoscopic submucosal dissections on patients with lesions that have well-established indications for endoscopic submucosal dissection and are of the lowest technical complexity. Best Practice Advice 16: Endoscopists in the United States who perform endoluminal resection should educate referring physicians to avoid practices that may induce submucosal fibrosis hampering future endoscopic mucosal resection or endoscopic submucosal dissection. These practices include tattooing in close proximity to or beneath a lesion for marking and partial snare resection of a portion of a lesion for histopathology.


National hospital ratings systems share few common scores and may generate confusion instead of clarity.
Attempts to assess the quality and safety of hospitals have proliferated, including a growing number of consumer-directed hospital rating systems. However, relatively little is known about what these rating systems reveal. To better understand differences in hospital ratings, we compared four national rating systems. We designated "high" and "low" performers for each rating system and examined the overlap among rating systems and how hospital characteristics corresponded with performance on each. No hospital was rated as a high performer by all four national rating systems. Only 10 percent of the 844 hospitals rated as a high performer by one rating system were rated as a high performer by any of the other rating systems. The lack of agreement among the national hospital rating systems is likely explained by the fact that each system uses its own rating methods, has a different focus to its ratings, and stresses different measures of performance.


Cytokinesis failure due to derailed integrin traffic induces aneuploidy and oncogenic transformation in vitro and in vivo.
Aneuploidy is frequently detected in solid tumors but the mechanisms regulating the generation of aneuploidy and their relevance in cancer initiation remain under debate and are incompletely characterized. Spatial and temporal regulation of integrin traffic is critical for cell migration and cytokinesis. Impaired integrin endocytosis, because of the loss of Rab21 small GTPase or mutations in the integrin β-subunit cytoplasmic tail, induces failure of cytokinesis in vitro. Here, we describe that repeatedly failed cytokinesis, because of impaired traffic, is sufficient to trigger the generation of aneuploid cells, which display characteristics of oncogenic transformation in vitro and are tumorigenic in vivo. Furthermore, in an in vivo mouse xenograft model, non-transformed cells with impaired integrin traffic formed tumors with a long latency. More detailed investigation of these tumors revealed that the tumor cells were aneuploid. Therefore, abnormal integrin traffic was linked with generation of aneuploidy and cell transformation also in vivo. In human prostate and ovarian cancer samples, downregulation of Rab21 correlates with increased malignancy. Loss-of-function experiments demonstrate that long-term depletion of Rab21 is sufficient to induce chromosome number aberrations in normal human epithelial cells. These data are the first to demonstrate that impaired integrin traffic is sufficient to induce conversion of non-transformed cells to tumorigenic cells in vitro and in vivo.


Esomeprazole-based Helicobacter pylori eradication therapy and the effect of antibiotic resistance: results of three US multicenter, double-blind trials.
To determine the efficacy of once-daily esomeprazole plus antibiotics for eradication of Helicobacter pylori, to assess the effect of antibiotic resistance on eradication rate, and to define the rate of emergent resistance. Three separate randomized trials were performed in H. pylori-positive patients with a duodenal ulcer or history of documented duodenal ulcer within 5 yrs: 1) esomeprazole (40 mg once daily), amoxicillin (1 g b.i.d.), and clarithromycin (500 mg b.i.d.; this combination will be referred to as EAC) versus esomeprazole (40 mg once daily) plus clarithromycin (500 mg twice daily; this combination will be referred to as EC); 2) EAC versus esomeprazole (40 mg once daily; E); and 3) EC versus E. Therapy was given for 10 days. Endoscopy and biopsies for CLOtest, histology, and culture with susceptibility testing were done at baseline and 4 wk after completion of therapy. Per-protocol and intent-to-treat eradication rates, respectively, were as follows. For EAC versus EC in study 1 (N = 448), 84 versus 55% and 77 versus 52% (p < 0.001); for EAC versus E in study 2 (N = 98), 85 versus 5% and 78 versus 4% (p < 0.001); for EC versus E in study 3 (N = 66), 50% versus 0 and 46% versus 0 (p < 0.05). The 15% of patients in the combined studies with baseline clarithromycin resistance had significantly lower rates of eradication than those with susceptible strains (EAC: 45 vs. 89%; EC: 13 vs. 61%). Emergent resistance was less common after treatment with EAC [2/6 (33%)] than with EC (23/27 [85%]). Ten-day triple therapy with once-daily esomeprazole plus twice-daily amoxicillin and clarithromycin achieves an eradication rate virtually identical to that of the twice-daily proton pump inhibitor-based triple therapies. Baseline clarithromycin resistance, present in 15% of patients, predicts a markedly decreased rate. Use of an amoxicillin-containing regimen may decrease emergence of clarithromycin resistance.


Predictors of problematic adult alcohol, cannabis, and other substance use: A longitudinal study of two samples.
This study examined whether a key set of adolescent and early adulthood risk factors predicts problematic alcohol, cannabis, and other substance use in established adulthood. Two independent samples from the Child Development Project (CDP; n = 585; 48% girls; 81% White, 17% Black, 2% other race/ethnicity) and Fast Track (FT; n = 463; 45% girls; 52% White, 43% Black, 5% other race/ethnicity) were recruited in childhood and followed through age 34 (CDP) or 32 (FT). Predictors of substance use were assessed in adolescence based on adolescent and parent reports and in early adulthood based on adult self-reports. Adults reported their own problematic substance use in established adulthood. In both samples, more risk factors from adolescence and early adulthood predicted problematic alcohol use in established adulthood (compared to problematic cannabis use and other substance use). Externalizing behaviors and prior substance use in early adulthood were consistent predictors of problematic alcohol and cannabis misuse in established adulthood across samples; other predictors were specific to the sample and type of substance misuse. Prevention efforts might benefit from tailoring to address risk factors for specific substances, but prioritizing prevention of externalizing behaviors holds promise for preventing both alcohol and cannabis misuse in established adulthood.


Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India.
Regardless of the availability of newer and more sophisticated modalities of investigation, urinary tract cytology still remains the most commonly used non-invasive test for the diagnosis of bladder cancer. As hematuria is the commonest presenting symptom in patients with malignancy of urinary tract, we undertook this study to know the usefulness of urine cytology in evaluation of the hematuric patients for malignancy. A total of 21,557 fresh voided urine samples received at our tertiary care referral centre over a period of three years were included in the study. Of these, 1428 cases had hematuria, criteria of either gross or microscopic. Among these hematuric cases included in the study, 32.5% (464 cases) were found to have positive finding of atypical cells. In these cases with atypia, 9.5% (136 cases) were proved to have malignancy both with the histopathological biopsy and cystoscopic findings. Other cases of atypia were found to be of reactive origin, either due to instrumentation or foreign body. A large number of hematuric cases, that is, 964 cases (67.5%) were negative for atypical cells. The limited ability of urine cytology to detect low grade bladder tumors, its subjectivity and lack of uniformity in reporting, all render urine cytology a less than perfect tool. With added collaboration between clinician and cytopathologist, urine cytology can be used an adjunct tool in evaluation of patients with hematuria.


Temporal change in functional richness and evenness in the eastern African plio-pleistocene carnivoran guild.
We analyze functional richness and functional evenness of the carnivoran guild in eastern Africa from 3.5 Ma to 1.5 Ma, and compare them to the present day. The data consist of characters of the craniodental apparatus of 76 species of fossil and extant carnivorans, divided into four 0.5 Ma time slices from 3.5 to 1.5 Ma, together with the modern fauna. Focus is on large (>21.5 kg) carnivores. Results show that the large carnivore guild has lost nearly 99% of its functional richness since 3.5 Ma, in a process starting prior to 2 Ma. Measurement of functional evenness shows the modern large carnivore guild to be unique in being randomly distributed in morphospace while in all past time slices there is significant clustering of species. The results are analyzed in the light of known changes to climate and environment in eastern Africa. We conclude that climate change is unlikely to explain all of the changes found and suggest that the evolution of early hominins into carnivore niche space, especially the evolution of derived dietary strategies after 2 Ma, played a significant part in the reduction of carnivore functional richness.


Alternative splicing in plants: directing traffic at the crossroads of adaptation and environmental stress.
In recent years, high-throughput sequencing-based analysis of plant transcriptomes has suggested that up to ∼60% of plant gene loci encode alternatively spliced mature transcripts. These studies have also revealed that alternative splicing in plants can be regulated by cell type, developmental stage, the environment, and the circadian clock. Alternative splicing is coupled to RNA surveillance and processing mechanisms, including nonsense mediated decay. Recently, non-protein-coding transcripts have also been shown to undergo alternative splicing. These discoveries collectively describe a robust system of post-transcriptional regulatory feedback loops which influence RNA abundance. In this review, we summarize recent studies describing the specific roles alternative splicing and RNA surveillance play in plant adaptation to environmental stresses and the regulation of the circadian clock.


Surface structure of a "non-amphiphilic" protic ionic liquid.
The nanostructure of the ethanolammonium nitrate (EtAN)-air surface has been investigated using X-ray reflectometry (XRR), vibrational sum frequency spectroscopy (VSFS) and neutral impact collision ion scattering spectroscopy (NICISS). The XRR data decays more rapidly than expected for a perfectly sharp interface, indicating a diffuse electron (scattering length) density profile. Modelling of the XRR data using three different fitting routines produced consistent interfacial profiles that suggest the formation of interfacial EtAN clusters. Consistent with this, VSFS reveals that the EtAN surface is predominantly covered by -CH(2)- moieties, with the -NH(3)(+) and -OH groups of the cation buried slightly deeper in the interface. The elemental profiles determined using NICISS also show enrichment of carbon relative to nitrogen and oxygen in the outermost surface layer, which is consistent with the surface cation orientation deduced from VSFS, and with the presence of EtAN aggregates at the liquid surface.


Betacellulin regulates schwann cell proliferation and myelin formation in the injured mouse peripheral nerve.
When a nerve fiber is cut or crushed, the axon segment that is separated from the soma degenerates distal from the injury in a process termed Wallerian degeneration (WD). C57BL/6OlaHsd-WldS (WldS ) mutant mice exhibit significant delays in WD. This results in considerably delayed Schwann cell and macrophage responses and thus in impaired nerve regenerations. In our previous work, thousands of genes were screened by DNA microarrays and over 700 transcripts were found to be differentially expressed in the injured sciatic nerve of WldS compared with wild-type (WT) mice. One of these transcripts, betacellulin (Btc), was selected for further analysis since it has yet to be characterized in the nervous system, despite being known as a ligand of the ErbB receptor family. We show that Btc mRNA is strongly upregulated in immature and dedifferentiated Sox2+ Schwann cells located in the sciatic nerve distal stump of WT mice, but not WldS mutants. Transgenic mice ubiquitously overexpressing Btc (Tg-Btc) have increased numbers of Schmidt-Lantermann incisures compared with WT mice, as revealed by Coherent anti-Stokes Raman scattering (CARS). Tg-Btc mice also have faster nerve conduction velocity. Finally, we found that deficiency in Btc reduces the proliferation of myelinating Schwann cells after sciatic nerve injury, while Btc overexpression induces Schwann cell proliferation and improves recovery of locomotor function. Taken together, these results suggest a novel regulatory role of Btc in axon-Schwann cell interactions involved in myelin formation and nerve repair. GLIA 2017 GLIA 2017;65:657-669.


International organisations and their role in helping to protect the worldwide community against natural and intentional biological disasters.
Preventing the spread of disease through international movements is one of the key objectives of the World Organisation for Animal Health (OIE). One of the ways it seeks to achieve this is by publishing international standards and guidelines aimed at, inter alia, preventing the importation of pathogens that are dangerous for animals and humans and strengthening Veterinary Services so that they can improve their surveillance and response systems. The OIE works in close partnership with the Food and Agriculture Organization of the United Nations (FAO), and together the two organisations have developed a joint initiative - the Global Framework for the Progressive Control of Transboundary Animal Diseases (GF-TADs). Member Countries of these organisations could increase their capacity to manage the risks of disease occurrences, whether natural or deliberately introduced, if they would all strictly implement existing OIE international standards. Compliance with these standards greatly depends on the political willingness of national policy-makers and on a successful transfer of resources to developing countries in support of good governance and appropriate policy implementation. A United Nations Resolution obliging its Member Countries to implement OIE standards could prove invaluable in this respect.


Chronic impedance spectroscopy of an endovascular stent-electrode array.
Recently, we reported a minimally invasive stent-electrode array capable of recording neural signals from within a blood vessel. We now investigate the use of electrochemical impedance spectroscopy (EIS) measurements to infer changes occurring to the electrode-tissue interface from devices implanted in a cohort of sheep for up to 190 days. In a cohort of 15 sheep, endovascular stent-electrode arrays were implanted in the superior sagittal sinus overlying the motor cortex for up to 190 days. EIS was performed routinely to quantify viable electrodes for up to 91 days. An equivalent circuit model (ECM) was developed from the in vivo measurements to characterize the electrode-tissue interface changes occurring to the electrodes chronically implanted within a blood vessel. Post-mortem histological assessment of stent and electrode incorporation into the wall of the cortical vessels was compared to the electrical impedance measurements. EIS could be used to infer electrode viability and was consistent with x-ray analysis performed in vivo, and post-mortem evaluation. Viable electrodes exhibited consistent 1 kHz impedances across the 91 day measurement period, with the peak resistance frequency for the acquired data also stable over time. There was a significant change in 100 Hz phase angles, increasing from -67.8° ± 8.8° at day 0 to -43.8° ± 0.8° at day 91, which was observed to stabilize after eight days. ECM's modeled to the data suggested this change was due to an increase in the capacitance of the electrode-tissue interface. This was supported by histological assessment with >85% of the implanted stent struts covered with neointima and incorporated into the blood vessel within two weeks. This work demonstrated that EIS could be used to determine the viability of electrode implanted chronically within a blood vessel. Impedance measurements alone were not observed to be a useful predictor of alterations occurring at the electrode tissue interface. However, measurement of 100 Hz phase angles was in good agreement with the capacitive changes predicted by the ECM and consistent with suggestions that this represents protein absorption on the electrode surface. 100 Hz phase angles stabilized after 8 days, consistent with histologically assessed samples. These findings demonstrate the potential application of this technology for use as a chronic neural recording system and indicate the importance of conducting EIS as a measure to identify viable electrodes and changes occurring at the electrode-tissue interface.


Crystal structure of the human ubiquitin-activating enzyme 5 (UBA5) bound to ATP: mechanistic insights into a minimalistic E1 enzyme.
E1 ubiquitin-activating enzymes (UBAs) are large multidomain proteins that catalyze formation of a thioester bond between the terminal carboxylate of a ubiquitin or ubiquitin-like modifier (UBL) and a conserved cysteine in an E2 protein, producing reactive ubiquityl units for subsequent ligation to substrate lysines. Two important E1 reaction intermediates have been identified: a ubiquityl-adenylate phosphoester and a ubiquityl-enzyme thioester. However, the mechanism of thioester bond formation and its subsequent transfer to an E2 enzyme remains poorly understood. We have determined the crystal structure of the human UFM1 (ubiquitin-fold modifier 1) E1-activating enzyme UBA5, bound to ATP, revealing a structure that shares similarities with both large canonical E1 enzymes and smaller ancestral E1-like enzymes. In contrast to other E1 active site cysteines, which are in a variably sized domain that is separate and flexible relative to the adenylation domain, the catalytic cysteine of UBA5 (Cys(250)) is part of the adenylation domain in an alpha-helical motif. The novel position of the UBA5 catalytic cysteine and conformational changes associated with ATP binding provides insight into the possible mechanisms through which the ubiquityl-enzyme thioester is formed. These studies reveal structural features that further our understanding of the UBA5 enzyme reaction mechanism and provide insight into the evolution of ubiquitin activation.


Random laser spectroscopy for nanoscale perturbation sensing.
We report a spectroscopic method using coherent random lasers for a simple, yet nanoscale, sensing approach. Unique spectral properties of coherent random laser emission can be detectably altered when introducing nanoscale perturbations to a simple nanocomposite film that consists of dielectric nanospheres and laser-dye-doped polymer to serve as a transducer. Random lasing action provides a means to amplify subtle perturbations to readily detectable spectral shifts in multiple discrete emission peaks. Owing to several advantages, such as large-area detection, narrow and multiple emission peaks, straightforward detection, and simple fabrication, random laser spectroscopy has the potential for ultrasensitive, yet simple, biosensors in various applications.


Bioaccumulation of metals and metalloids in medicinal plant Ipomoea pes-caprae from areas impacted by tsunami.
Tsunami events may have an enormous impact on the functioning of aquatic and terrestrial ecosystems by altering various relationships with biotic components. Concentrations of acid-leachable fractions of heavy metals and metalloids in soils and plant samples from areas affected by the December 2004 tsunami in Thailand were determined. Ipomoea pes-caprae, a common plant species growing along the seashore of this region, and frequently used in folk medicine, was selected to assess the presence of selected elements. Elevated amounts of Cd, Pb, Zn, and As in soil samples, and Pb, Zn, As, Se, Cr, and Ni in plant samples were determined from the tsunami-impacted regions for comparison with reference locations. The flowers of Ipomoea pes-caprae contained the highest amounts of these metals, followed by its leaves, and stems. In addition, its bioaccumulation factor (BAF) supports this capability of high metal uptake by Ipomoea pes-caprae from the areas affected by the tsunami in comparison with a reference site. This uptake was followed by the translocation of these elements to the various plant components. The presence of these toxic metals in Ipomoea pes-caprae growing in contaminated soils should be a concern of those who use this plant for medicinal purposes. Further studies on the content of heavy metals and metalloids in this plant in relation to human health concerns are recommended.


Active children through individual vouchers - evaluation (ACTIVE): protocol for a mixed method randomised control trial to increase physical activity levels in teenagers.
Many teenagers are insufficiently active despite the health benefits of physical activity (PA). There is strong evidence to show that inactivity and low fitness levels increase the risk of non-communicable diseases such as coronary heart disease (CHD), type 2 diabetes and breast and colon cancers (Lee et al. Lancet 380:219-29, 2012). A major barrier facing adolescents is accessibility (e.g. cost and lack of local facilities). The ACTIVE project aims to tackle this barrier through a multi-faceted intervention, giving teenagers vouchers to spend on activities of their choice and empowering young people to improve their fitness and PA levels. ACTIVE is a mixed methods randomised control trial in 7 secondary schools in Swansea, South Wales. Quantitative and qualitative measures including PA (cooper run test (CRT), accelerometery over 7 days), cardiovascular (CV) measures (blood pressure, pulse wave analysis) and focus groups will be undertaken at 4 separate time points (baseline, 6 months,12 months and follow-up at 18 months). Intervention schools will receive a multi-component intervention involving 12 months of £20 vouchers to spend on physical activities of their choice, a peer mentor scheme and opportunities to attend advocacy meetings. Control schools are encouraged to continue usual practice. The primary aim is to examine the effect of the intervention in improving cardiovascular fitness. This paper describes the protocol for the ACTIVE randomised control trial, which aims to increase fitness, physical activity and socialisation of teenagers in Swansea, UK via a voucher scheme combined with peer mentoring. Results can contribute to the evidence base on teenage physical activity and, if effective, the intervention has the potential to inform future physical activity interventions and policy. ISRCTN75594310 (Assigned 06/03/2017).


R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4.
R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E₂ (PGE₂) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE₂ inside of the cells by inhibiting multidrug resistance-associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner.


The Unified Medical Language System (UMLS): integrating biomedical terminology.
The Unified Medical Language System (http://umlsks.nlm.nih.gov) is a repository of biomedical vocabularies developed by the US National Library of Medicine. The UMLS integrates over 2 million names for some 900,000 concepts from more than 60 families of biomedical vocabularies, as well as 12 million relations among these concepts. Vocabularies integrated in the UMLS Metathesaurus include the NCBI taxonomy, Gene Ontology, the Medical Subject Headings (MeSH), OMIM and the Digital Anatomist Symbolic Knowledge Base. UMLS concepts are not only inter-related, but may also be linked to external resources such as GenBank. In addition to data, the UMLS includes tools for customizing the Metathesaurus (MetamorphoSys), for generating lexical variants of concept names (lvg) and for extracting UMLS concepts from text (MetaMap). The UMLS knowledge sources are updated quarterly. All vocabularies are available at no fee for research purposes within an institution, but UMLS users are required to sign a license agreement. The UMLS knowledge sources are distributed on CD-ROM and by FTP.


Refractoriness to inhaled sodium metabisulphite in subjects with mild asthma.
Refractoriness occurs after challenges causing mediator release in asthma, by a mechanism which may involve inhibitory prostaglandins. Bronchoconstriction due to inhaled sodium metabisulphite is thought to involve neural pathways and to be independent of mediator release; whether it shows refractoriness is uncertain. We have sought evidence of refractoriness to the bronchoconstrictor response to inhaled sodium metabisulphite in subjects with mild asthma, and have tested the hypothesis that the development of refractoriness involves inhibitory prostaglandins. Twelve subjects were challenged twice with a dose of sodium metabisulphite, previously shown to cause a 20% fall in forced expiratory volume in one second (FEV1); the second challenge proceeded after recovery from the first. The response to sodium metabisulphite was expressed as the maximum % fall in FEV1 and area under the change in FEV1 curve over 20 min (AUC). Nine subjects were studied after double-blind treatment with oral indomethacin, 50 mg t.d.s., or placebo, for 3 days. The second sodium metabisulphite challenge caused significantly less bronchoconstriction than the first (mean maximum fall in FEV1 13.1 and 24.3%, respectively). Nine subjects showed a greater than 50% reduction in the response to the second challenge (mean reduction in AUC 73.7%). In these subjects, indomethacin did not alter the response to the first sodium metabisulphite challenge, or the mean maximum fall in FEV1 in response to the second challenge (placebo 9.7%, indomethacin 11.2%), but significantly increased the AUC of the second challenge (placebo 55, indomethacin 114). The mean reduction in AUC from first to second challenge was 78% with placebo and 48% with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)


Processing arctic eddy-flux data using a simple carbon-exchange model embedded in the ensemble Kalman filter.
Continuous time-series estimates of net ecosystem carbon exchange (NEE) are routinely made using eddy covariance techniques. Identifying and compensating for errors in the NEE time series can be automated using a signal processing filter like the ensemble Kalman filter (EnKF). The EnKF compares each measurement in the time series to a model prediction and updates the NEE estimate by weighting the measurement and model prediction relative to a specified measurement error estimate and an estimate of the model-prediction error that is continuously updated based on model predictions of earlier measurements in the time series. Because of the covariance among model variables, the EnKF can also update estimates of variables for which there is no direct measurement. The resulting estimates evolve through time, enabling the EnKF to be used to estimate dynamic variables like changes in leaf phenology. The evolving estimates can also serve as a means to test the embedded model and reconcile persistent deviations between observations and model predictions. We embedded a simple arctic NEE model into the EnKF and filtered data from an eddy covariance tower located in tussock tundra on the northern foothills of the Brooks Range in northern Alaska, USA. The model predicts NEE based only on leaf area, irradiance, and temperature and has been well corroborated for all the major vegetation types in the Low Arctic using chamber-based data. This is the first application of the model to eddy covariance data. We modified the EnKF by adding an adaptive noise estimator that provides a feedback between persistent model data deviations and the noise added to the ensemble of Monte Carlo simulations in the EnKF. We also ran the EnKF with both a specified leaf-area trajectory and with the EnKF sequentially recalibrating leaf-area estimates to compensate for persistent model-data deviations. When used together, adaptive noise estimation and sequential recalibration substantially improved filter performance, but it did not improve performance when used individually. The EnKF estimates of leaf area followed the expected springtime canopy phenology. However, there were also diel fluctuations in the leaf-area estimates; these are a clear indication of a model deficiency possibly related to vapor pressure effects on canopy conductance.


Initial characterization of the Pf-Int recombinase from the malaria parasite Plasmodium falciparum.
Genetic variation is an essential means of evolution and adaptation in many organisms in response to environmental change. Certain DNA alterations can be carried out by site-specific recombinases (SSRs) that fall into two families: the serine and the tyrosine recombinases. SSRs are seldom found in eukaryotes. A gene homologous to a tyrosine site-specific recombinase has been identified in the genome of Plasmodium falciparum. The sequence is highly conserved among five other members of Plasmodia. The predicted open reading frame encodes for a ∼57 kDa protein containing a C-terminal domain including the putative tyrosine recombinase conserved active site residues R-H-R-(H/W)-Y. The N-terminus has the typical alpha-helical bundle and potentially a mixed alpha-beta domain resembling that of λ-Int. Pf-Int mRNA is expressed differentially during the P. falciparum erythrocytic life stages, peaking in the schizont stage. Recombinant Pf-Int and affinity chromatography of DNA from genomic or synthetic origin were used to identify potential DNA targets after sequencing or micro-array hybridization. Interestingly, the sequences captured also included highly variable subtelomeric genes such as var, rif, and stevor sequences. Electrophoretic mobility shift assays with DNA were carried out to verify Pf-Int/DNA binding. Finally, Pf-Int knock-out parasites were created in order to investigate the biological role of Pf-Int. Our data identify for the first time a malaria parasite gene with structural and functional features of recombinases. Pf-Int may bind to and alter DNA, either in a sequence specific or in a non-specific fashion, and may contribute to programmed or random DNA rearrangements. Pf-Int is the first molecular player identified with a potential role in genome plasticity in this pathogen. Finally, Pf-Int knock-out parasite is viable showing no detectable impact on blood stage development, which is compatible with such function.


Assessing bioterrorism preparedness and response of rural veterinarians: experiences and training needs.
Veterinarians play a unique role in emergency preparedness and response, and federal agencies and academic institutions therefore allocate considerable resources to provide training to enhance their readiness. However, the level of preparedness of veterinarians in many rural regions is yet to be improved. This article reports an assessment of the bioterrorism preparedness, specifically the experience and training needs, of rural veterinarians in North Texas. The study employed a cross-sectional design with a study population that included all veterinarians (N = 352) in the 37 counties within Texas Department of State Health Services Regions 2 and 3. Data on veterinarians practicing or residing in the target region were obtained from the Texas State Board of Veterinary Medical Examiners. The response rate was 35% (n = 121). Results indicate that chemical exposure was the condition most frequently seen and treated, followed by botulism and anthrax. The majority (80%) of respondents indicated that they had not previously participated in training related to bioterrorism preparedness, and many (41%) also indicated a willingness to participate in a state health department-initiated bioterrorism response plan. However, only 18% were confident in their ability to diagnose and treat bioterrorism cases. These results suggest that many North Texas veterinarians practicing in rural regions could benefit from additional training in bioterrorism preparedness and response. An area in particular need of further training is the diagnosis and treatment of Category A agents. Federal, state, and local health agencies are urged to increase training opportunities and to make additional efforts to involve veterinarians in bioterrorism preparedness and response.


[Mortality and length of stay in a surgical intensive care unit.].
Outcome in intensive care can be categorized as mortality related or morbidity related. Mortality is an insufficient measure of ICU outcome when measured alone and length of stay may be seen as an indirect measure of morbidity related outcome. The aim of the present study was to estimate the incidence and predictive factors for intrahospitalar outcome measured by mortality and LOS in patients admitted to a surgical ICU. In this prospective study all 185 patients, who underwent scheduled or emergency surgery admitted to a surgical ICU in a large tertiary university medical center performed during April and July 2004, were eligible to the study. The following variables were recorded: age, sex, body weight and height, core temperature (Tc), ASA physical status, emergency or scheduled surgery, magnitude of surgical procedure, anesthesia technique, amount of fluids during anesthesia, use of temperature monitoring and warming techniques, duration of the anesthesia, length of stay in ICU and in the hospital and SAPS II score. The mean length of stay in the ICU was 4.09 +/- 10.23 days. Significant risk factors for staying longer in ICU were SAPS II, ASA physical status, amount of colloids, fresh frozen plasma units and packed erythrocytes units used during surgery. Fourteen (7.60%) patients died in ICU and 29 (15.70%) died during their hospitalization. Statistically significant independent risk factors for mortality were emergency surgery, major surgery, high SAPS II scores, longer stay in ICU and in the hospital. Statistically significant protective factors against the probability of dying in the hospital were low body weight and low BMI. In conclusion, prolonged ICU stay is more frequent in more severely ill patients at admission and it is associated with higher hospital mortality. Hospital mortality is also more frequent in patients submitted to emergent and major surgery.


Characterization of New Leprosy Cases in Northeast of Iran within the Last 15 Years.
Leprosy is a neglected disease. The insidious onset of leprosy results in its late diagnosis and therefore the spread of the disease. Characterization of leprosy in areas with higher risk and collection of enough information about these spots to adopt more effective controlling measures are of great importance. In the present study, data for every patient who either referred to the health care center for leprosy or had had similar leprous symptoms between 2002 and 2016 were collected. Forty-two new cases of leprosy were identified with 28 of them being Iranian and 14 from Afghanistan. All patients were older than 15. 26.2% of the patients were women and 73.8% were men. According to World Health Organization (WHO) protocol, 36 patients (85.7%) were diagnosed to have been affected by the Multi Bacillary form; and among those patients, 61.9%, 19.05%, and 19.05% suffered from grade 1, 0, and 2 of the disease, respectively. There was a significant relationship between disability grading and sex (P=0.032), with grade 1 disability happening more often in men. Another significant relationship was also observed between Multi Bacillary form and nationality (P=0.011) indicating that Multi Bacillary form is more common among Iranians. With 0.02 leprosy cases in 10000 people, Iran is at elimination phase of the disease; however, identification of new cases in our region demands constant controlling programs and establishment of strict policies. Fortunately, the few numbers of patients diagnosed with leprosy in Northeast of Iran shows successful implementation of such policies under the scrutiny of the public health authorities.