Alterations in endocannabinoid tone following chemotherapy-induced peripheral neuropathy: effects of endocannabinoid deactivation inhibitors targeting fatty-acid amide hydrolase and monoacylglycerol lipase in comparison to reference analgesics following cisplatin treatment.
Cisplatin, a platinum-derived chemotherapeutic agent, produces mechanical and coldallodynia reminiscent of chemotherapy-induced neuropathy in humans. The endocannabinoid system represents a novel target for analgesic drug development. The endocannabinoid signaling system consists of endocannabinoids (e.g. anandamide (AEA) and 2-arachidonoylglycerol (2-AG)), cannabinoid receptors (e.g. CB(1) and CB(2)) and the enzymes controlling endocannabinoid synthesis and degradation. AEA is hydrolyzed by fatty-acid amide hydrolase (FAAH) whereas 2-AG is hydrolyzed primarily by monoacylglycerol lipase (MGL). We compared effects of brain permeant (URB597) and impermeant (URB937) inhibitors of FAAH with an irreversible inhibitor of MGL (JZL184) on cisplatin-evoked behavioral hypersensitivities. Endocannabinoid modulators were compared with agents used clinically to treat neuropathy (i.e. the opioid analgesic morphine, the anticonvulsant gabapentin and the tricyclic antidepressant amitriptyline). Cisplatin produced robust mechanical and cold allodynia but did not alter responsiveness to heat. After neuropathy was fully established, groups received acute intraperitoneal (i.p.) injections of vehicle, amitriptyline (30 mg/kg), gabapentin (100 mg/kg), morphine (6 mg/kg), URB597 (0.1 or 1 mg/kg), URB937 (0.1 or 1 mg/kg) or JZL184 (1, 3 or 8 mg/kg). Pharmacological specificity was assessed by coadministering each endocannabinoid modulator with either a CB(1) (AM251 3 mg/kg), CB(2) (AM630 3 mg/kg), TRPV1 (AMG9810 3 mg/kg) or TRPA1 (HC030031 8 mg/kg) antagonist. Effects of cisplatin on endocannabinoid levels and transcription of receptors (CB(1), CB(2), TRPV1, TRPA1) and enzymes (FAAH, MGL) linked to the endocannabinoid system were also assessed. URB597, URB937, JZL184 and morphine reversed cisplatin-evoked mechanical and cold allodynia to pre-cisplatin levels. By contrast, gabapentin only partially reversed the observed allodynia while amitriptyline, administered acutely, was ineffective. CB(1) or CB(2) antagonists completely blocked the anti-allodynic effects of both FAAH (URB597, URB937) and MGL (JZL184) inhibitors to mechanical and cold stimulation. By contrast, the TRPV1 antagonist AMG9810 blocked the anti-allodynic efficacy of both FAAH inhibitors, but not the MGL inhibitor. By contrast, the TRPA1 antagonist HC30031 did not attenuate anti-allodynic efficacy of any endocannabinoid modulator. When the levels of endocannabinoids were examined, cisplatin increased both anandamide (AEA) and 2-arachidonoylglycerol (2-AG) levels in the lumbar spinal cord and decreased 2-AG levels (but not AEA) in dorsal hind paw skin. RT-PCR showed that mRNA for FAAH, but not other markers, was upregulated by cisplatin treatment in lumbar spinal cord. The present studies demonstrate that cisplatin alters endocannabinoid tone and that inhibition of endocannabinoid hydrolysis alleviates chemotherapy-induced mechanical and cold allodynia. The anti-allodynic effects of FAAH and MGL inhibitors are mediated by CB(1) and CB(2) cannabinoid receptors, whereas TRPV1, but not TRPA1, -dependent mechanisms contribute to the anti-allodynic efficacy of FAAH (but not MGL) inhibitors. Strikingly, endocannabinoid modulators potently suppressed cisplatin-evoked allodynia with a rapid onset and showed efficacy that equaled or exceeded that of major classes of anti-neuropathic pain medications used clinically. Thus, inhibition of endocannabinoid hydrolysis, via FAAH or MGL inhibitors, represents an efficacious pharmacological approach for suppressing chemotherapy-induced neuropathic pain.


Resilience and Healing Among Cambodian Survivors of the Khmer Rouge Regime.
In this article the author presents a qualitative study about resilience and healing among Cambodian survivors of the communist Khmer Rouge regime. The database of the Documentation Center of Cambodia (DC-Cam) was used to analyze 30 stories of people who survived but lost family members during the Khmer Rouge regime. The participants acted as civil parties in the Cambodian tribunal involving a trial of "Duch," the head of Tuol Sleng prison or (s21), where survivors' relatives were interrogated, tortured, and killed. Participation in the DC-Cam investigations and in the trial were seen as healing, resiliency factors. Resilience is a person-environment concept that addresses how people and societies overcome/recover from adverse or traumatic events. Resilience was revealed here through people's narratives of critical events that occurred at the personal, interpersonal, sociocultural, and societal levels. Thus, the participants' stories allow us to hear the "truth" of these experiences, how they have made meaning of them, and how they mustered their personal and environmental resources to deal with overwhelming demands (Gutheil & Congress, 2000). Findings suggest that participants attained closure and a sense of justice as a result of their interacting with DC-Cam staff and giving testimony to the tribunal.


Evolution of floral diversity: genomics, genes and gamma.
A salient feature of flowering plant diversification is the emergence of a novel suite of floral features coinciding with the origin of the most species-rich lineage, Pentapetalae. Advances in phylogenetics, developmental genetics and genomics, including new analyses presented here, are helping to reconstruct the specific evolutionary steps involved in the evolution of this clade. The enormous floral diversity among Pentapetalae appears to be built on a highly conserved ground plan of five-parted (pentamerous) flowers with whorled phyllotaxis. By contrast, lability in the number and arrangement of component parts of the flower characterize the early-diverging eudicot lineages subtending Pentapetalae. The diversification of Pentapetalae also coincides closely with ancient hexaploidy, referred to as the gamma whole-genome triplication, for which the phylogenetic timing, mechanistic details and molecular evolutionary consequences are as yet not fully resolved. Transcription factors regulating floral development often persist in duplicate or triplicate in gamma-derived genomes, and both individual genes and whole transcriptional programmes exhibit a shift from broadly overlapping to tightly defined expression domains in Pentapetalae flowers. Investigations of these changes associated with the origin of Pentapetalae can lead to a more comprehensive understanding of what is arguably one of the most important evolutionary diversification events within terrestrial plants.This article is part of the themed issue 'Evo-devo in the genomics era, and the origins of morphological diversity'.


Evaluation of the presence of myofibroblasts and matrix metalloproteinase 1 expression in the stroma of oral verrucous hyperplasia and verrucous carcinoma.
Oral verrucous carcinoma is a low-grade subtype of oral squamous cell carcinoma that should be differentiated from oral verrucous hyperplasia, a premalignant lesion. Stromal activated myofibroblasts known as cancer-associated fibroblasts have an active role in the initiation and progression of the cancers via secretion of different molecules including matrix metalloproteinases. This study is designed to understand the differences in the presence of myofibroblasts and expression of matrix metalloproteinase-1 in the adjacent stroma of verrucous carcinoma and oral verrucous hyperplasia (OVH). Cross-sectional study. Twenty-seven OVH, 19 oral verrucous carcinoma (OVC), and 8 cutaneous verrucous carcinoma (CVC) specimens were analyzed for immunohistochemical (IHC) expression of α-smooth muscle actin (αSMA) and MMP-1. IHC studies for αSMA expression in nonvascular stromal cells of the adjacent stroma revealed mild or no expression in 81.4%, 73.7%, and 62.5% of the cases of OVH, OVC, and CVC groups, respectively. No significant difference was seen in αSMA expression index between OVH and OVC groups (Adj. Sig. = 0.220) and between OVC and CVC groups (Adj. Sig. = 1.00). Pairwise analysis revealed a significant difference in MMP-1 expression index between the groups. No significant correlation was observed between MMP-1 expression index and αSMA expression index in OVH (pv = 0.358) and OVC (pv = 0.388) groups. The differences in MMP-1 expression between OVH and OVC can be used as an adjunctive aid in challenging cases including disoriented or inadequate samples.


Outcomes assessment of case-based writing exercises in a veterinary clinical pathology course.
Our second-year core clinical pathology course uses free-response case-based learning exercises in an otherwise traditional lecture or laboratory course format to augment the development of skills in application of knowledge and critical thinking and clinical reasoning. We previously reported increased learner confidence accompanied by perceived improvements in understanding and ability to apply information, along with enhanced feelings of preparedness for examinations that students attributed to the case-based exercises. The current study prospectively follows a cohort of students to determine the ability of traditional multiple-choice versus free-response case-based assessments to predict future academic performance and to determine if the perceived value of the case-based exercises persists through the curriculum. Our data show that after holding multiple-choice scores constant, better performance on case-based free-response exercises led to higher GPA and better class rank in the second and third years and better class rank in the fourth year. Students in clinical rotations reported that the case-based approach was superior to traditional lecture or multiple-choice exam format for learning clinical reasoning, retaining factual information, organizing information, communicating medical information clearly to colleagues in clinical situations, and preparing high quality medical records. In summary, this longitudinal study shows that case-based free-response writing assignments are efficacious above and beyond standard measures in determining students' GPAs and class rank and in students' acquisition of knowledge, skills, and clinical reasoning. Students value these assignments and overwhelmingly find them an efficient use of their time, and these opinions are maintained even two years following the course.


Use of multiple genetic markers in prediction of breeding values.
Genotypes at a marker locus give information on transmission of genes from parents to offspring and that information can be used in predicting the individuals' additive genetic value at a linked quantitative trait locus (MQTL). In this paper a recursive method is presented to build the gametic relationship matrix for an autosomal MQTL which requires knowledge on recombination rate between the marker locus and the MQTL linked to it. A method is also presented to obtain the inverse of the gametic relationship matrix. This information can be used in a mixed linear model for simultaneous evaluation of fixed effects, gametic effects at the MQTL and additive genetic effects due to quantitative trait loci unlinked to the marker locus (polygenes). An equivalent model can be written at the animal level using the numerator relationship matrix for the MQTL and a method for obtaining the inverse of this matrix is presented. Information on several unlinked marker loci, each of them linked to a different locus affecting the trait of interest, can be used by including an effect for each MQTL. The number of equations per animal in this case is 2m + 1 where m is the number of MQTL. A method is presented to reduce the number of equations per animal to one by combining information on all MQTL and polygenes into one numerator relationship matrix. It is illustrated how the method can accommodate individuals with partial or no marker information. Numerical examples are given to illustrate the methods presented. Opportunities to use the presented model in constructing genetic maps are discussed.


Special feature for the Olympics: effects of exercise on the immune system: neuropeptides and their interaction with exercise and immune function.
It is known today that the immune system is influenced by various types of psychological and physiological stressors, including physical activity. It is well known that physical activity can influence neuropeptide levels both in the central nervous system as well as in peripheral blood. The reported changes of immune function in response to exercise have been suggested to be partly regulated by the activation of different neuropeptides and the identification of receptors for neuropeptides and steroid hormones on cells of the immune system has created a new dimension in this endocrine-immune interaction. It has also been shown that immune cells are capable of producing neuropeptides, creating a bidirectional link between the nervous and immune systems. The most common neuropeptides mentioned in this context are the endogenous opioids. The activation of endogenous opioid peptides in response to physical exercise is well known in the literature, as well as the immunomodulation mediated by opioid peptides. The role of endogenous opioids in the exercise-induced modulation of immune function is less clear. The present paper will also discuss the role of other neuroendocrine factors, such as substance P, neuropeptide Y and vasoactive intestinal peptide, and pituitary hormones, including growth hormone, prolactin and adrenocorticotrophin, in exercise and their possible effects on immune function.


Green tea polyphenols produce antidepressant-like effects in adult mice.
Recent studies have shown that a higher consumption of green tea leads to a lower prevalence of depressive symptoms in elderly individuals. However, no studies have explored the antidepressant-like effect of green tea in preclinical models of depression. The aim of this study was to investigate the antidepressant-like effects and the possible mechanism of action of green tea in widely used mouse models of depression. Mice were orally administered green tea polyphenols (GTP; 5, 10 and 20mg/kg) for 7days and assessed in the forced swimming test (FST) and tail suspension test (TST) 60min after the last GTP administration. Serum corticosterone and adrenocorticotrophic hormone (ACTH) levels were also determined immediately after the FST. Green tea polyphenols significantly reduced immobility in both the FST and TST but did not alter locomotor activity in the open field test, suggesting that GTP has antidepressant-like effects, and this action did not induce nonspecific motor changes in mice. Green tea polyphenols also reduced serum corticosterone and ACTH levels in mice exposed to the FST. The present study demonstrated that GTP exerts antidepressant-like effects in a mouse behavioral models of depression, and the mechanism may involve inhibition of the hypothalamic-pituitary-adrenal axis.


Efficacy and safety of pyridoxal 5'-phosphate (MC-1) in high-risk patients undergoing coronary artery bypass graft surgery: the MEND-CABG II randomized clinical trial.
Coronary artery bypass graft (CABG) surgery is frequently performed and effective; however, perioperative complications related to ischemia-reperfusion injury, including myocardial infarction (MI), remain common and result in significant morbidity and mortality. MC-1, a naturally occurring pyridoxine metabolite and purinergic receptor antagonist, prevents cellular calcium overload and may reduce ischemia-reperfusion injury. Phase 2 trial data suggest that MC-1 may reduce death or MI in high-risk patients undergoing CABG surgery. To assess the efficacy and safety of MC-1 administered immediately before and for 30 days after surgery in patients undergoing CABG surgery. The MC-1 to Eliminate Necrosis and Damage in Coronary Artery Bypass Graft Surgery II Trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial, with 3023 intermediate- to high-risk patients undergoing CABG surgery with cardiopulmonary bypass enrolled between October 2006 and September 2007 at 130 sites in Canada, the United States, and Germany. Patients received either MC-1, 250 mg/d (n = 1519), or matching placebo (n = 1504) immediately before and for 30 days after CABG surgery. The primary efficacy outcome was cardiovascular death or nonfatal MI, defined as a creatine kinase (CK) MB fraction of at least 100 ng/mL or new Q waves through postoperative day 30. The primary efficacy outcome occurred in 140 of 1510 patients (9.3%) in the MC-1 group and 133 of 1486 patients (9.0%) in the placebo group (risk ratio, 1.04; 95% confidence interval, 0.83-1.30; P = .76). All-cause mortality was higher among patients assigned to MC-1 than placebo at 4 days (1.0% vs 0.3%; P = .03) but was similar at 30 days (1.9% vs 1.5%; P = .44). There was no difference in the 8- to 24-hour CK-MB area under the curve between the MC-1 and placebo groups (median, 270 [interquartile range, 175-492] vs 268 [interquartile range, 170-456] hours x ng/mL; P = .11). In this population of intermediate- to high-risk patients undergoing CABG surgery, MC-1 did not reduce the composite of cardiovascular death or nonfatal MI. clinicaltrials.gov Identifier: NCT00402506


Neural-Fly enables rapid learning for agile flight in strong winds.
Executing safe and precise flight maneuvers in dynamic high-speed winds is important for the ongoing commoditization of uninhabited aerial vehicles (UAVs). However, because the relationship between various wind conditions and its effect on aircraft maneuverability is not well understood, it is challenging to design effective robot controllers using traditional control design methods. We present Neural-Fly, a learning-based approach that allows rapid online adaptation by incorporating pretrained representations through deep learning. Neural-Fly builds on two key observations that aerodynamics in different wind conditions share a common representation and that the wind-specific part lies in a low-dimensional space. To that end, Neural-Fly uses a proposed learning algorithm, domain adversarially invariant meta-learning (DAIML), to learn the shared representation, only using 12 minutes of flight data. With the learned representation as a basis, Neural-Fly then uses a composite adaptation law to update a set of linear coefficients for mixing the basis elements. When evaluated under challenging wind conditions generated with the Caltech Real Weather Wind Tunnel, with wind speeds up to 43.6 kilometers/hour (12.1 meters/second), Neural-Fly achieves precise flight control with substantially smaller tracking error than stateof-the-art nonlinear and adaptive controllers. In addition to strong empirical performance, the exponential stability of Neural-Fly results in robustness guarantees. Last, our control design extrapolates to unseen wind conditions, is shown to be effective for outdoor flights with only onboard sensors, and can transfer across drones with minimal performance degradation.


MIBiG 2.0: a repository for biosynthetic gene clusters of known function.
Fueled by the explosion of (meta)genomic data, genome mining of specialized metabolites has become a major technology for drug discovery and studying microbiome ecology. In these efforts, computational tools like antiSMASH have played a central role through the analysis of Biosynthetic Gene Clusters (BGCs). Thousands of candidate BGCs from microbial genomes have been identified and stored in public databases. Interpreting the function and novelty of these predicted BGCs requires comparison with a well-documented set of BGCs of known function. The MIBiG (Minimum Information about a Biosynthetic Gene Cluster) Data Standard and Repository was established in 2015 to enable curation and storage of known BGCs. Here, we present MIBiG 2.0, which encompasses major updates to the schema, the data, and the online repository itself. Over the past five years, 851 new BGCs have been added. Additionally, we performed extensive manual data curation of all entries to improve the annotation quality of our repository. We also redesigned the data schema to ensure the compliance of future annotations. Finally, we improved the user experience by adding new features such as query searches and a statistics page, and enabled direct link-outs to chemical structure databases. The repository is accessible online at https://mibig.secondarymetabolites.org/.


(1)H NMR-based metabolomics exploring biomarkers in rat cerebrospinal fluid after cerebral ischemia/reperfusion.
In our study, metabolomics was used to investigate biochemical changes in the early stages of rats focal cerebral ischemia/reperfusion (I/R) injury. Cerebrospinal fluid (CSF) samples at 0, 0.5, 1, 3, and 6 h of reperfusion (n = 10), based on (1)H NMR spectroscopy and multivariate data analyses, were tested to analyze the changing of metabolites during the early disease process. Partial least squares-discriminant analysis scores plots of the (1)H NMR data revealed clear differences among the experiment groups. Combining the results of the loading plot and t-test, we found that twenty-seven metabolites were changed significantly (p < 0.05) in the CSF samples among the different groups. Among that, the potential biomarkers in CSF of ischemic rats were: acetic acid, 3-hydroxyisovaleric acid, 3-hydroxybutyric acid, choline, l-alanine, creatine, creatinine, glycine, pyruvic acid, glycerol, glutamic acid, d-fructose, l-lactic acid and acetone. These findings help us understand the biochemical metabolite changes in CSF of I/R rats in early stages. What's more, metabolomics may, therefore, have the potential to be developed into a clinically useful diagnostic tool of ischemic brain injury.


Evidence supporting a link between dental amalgams and chronic illness, fatigue, depression, anxiety, and suicide.
The purpose of this review is to examine the evidence for a relationship between mercury (Hg) exposure from dental amalgams and certain idiopathic chronic illnesses--chronic fatigue syndrome (CFS), fibromyalgia (FM), depression, anxiety, and suicide. Dental amalgam is a commonly used dental restorative material that contains approximately 50% elemental mercury (Hg0) by weight and releases Hg0 vapor. Studies have shown that chronic Hg exposure from various sources including dental amalgams is associated with numerous health complaints, including fatigue, anxiety, and depression--and these are among the main symptoms that are associated with CFS and FM. In addition, several studies have shown that the removal of amalgams is associated with improvement in these symptoms. Although the issue of amalgam safety is still under debate, the preponderance of evidence suggests that Hg exposure from dental amalgams may cause or contribute to many chronic conditions. Thus, consideration of Hg toxicity may be central to the effective clinical investigation of many chronic illnesses, particularly those involving fatigue and depression.


Evidence for a novel cytoplasmic tRNA-protein complex containing the KH-multidomain protein vigilin.
Vigilin, a protein found predominantly in cells and tissues with a high biosynthetic capacity, was isolated in its native form from human HEp-2 cells (A.T.C.C. CCL23) by immunoaffinity chromatography. Vigilin forms part of a novel ribonucleoprotein complex that also contains additional, as yet uncharacterized, proteins. Experimental evidence suggests that the nucleic acids entrapped in this complex are protected from RNase and belong to the tRNA family. Using either a pool of total human RNA or radioactively labelled tRNA (tRNA (Asp**)) in rebinding experiments, we could show that tRNA is selectively recaptured by the RNA-depleted vigilin-containing complex.


Total 25-hydroxyvitamin D determination by an entry level triple quadrupole instrument: comparison between two commercial kits.
25-hydroxyvitamin D2/D3 (25-OHD2/D3) determination is a reliable biomarker for vitamin D status. Liquid chromatography-tandem mass spectrometry was recently proposed as a reference method for vitamin D status evaluation. The aim of this work is to compare two commercial kits (Chromsystems and PerkinElmer) for 25-OHD2/D3 determination by our entry level LC-MS/MS. Chromsystems kit adds an online trap column to an HPLC column and provides atmospheric pressure chemical ionization, isotopically labeled internal standard, and 4 calibrator points. PerkinElmer kit uses a solvent extraction and protein precipitation method. This kit can be used with or without derivatization with, respectively, electrospray and atmospheric pressure chemical ionization. For each analyte, there are isotopically labeled internal standards and 7 deuterated calibrator points. Performance characteristics are acceptable for both methods. Mean bias between methods calculated on 70 samples was 1.9 ng/mL. Linear regression analysis gave an R (2) of 0.94. 25-OHD2 is detectable only with PerkinElmer kit in derivatized assay option. Both methods are suitable for routine. Chromsystems kit minimizes manual sample preparation, requiring only protein precipitation, but, with our system, 25-OHD2 is not detectable. PerkinElmer kit without derivatization does not guarantee acceptable performance with our LC-MS/MS system, as sample is not purified online. Derivatization provides sufficient sensitivity for 25-OHD2 detection.


Energy Conservation Model Based on Genomic and Experimental Analyses of a Carbon Monoxide-Utilizing, Butyrate-Forming Acetogen, Eubacterium limosum KIST612.
Eubacterium limosum KIST612 is one of the few acetogens that can produce butyrate from carbon monoxide. We have used a genome-guided analysis to delineate the path of butyrate formation, the enzymes involved, and the potential coupling to ATP synthesis. Oxidation of CO is catalyzed by the acetyl-coenzyme A (CoA) synthase/CO dehydrogenase and coupled to the reduction of ferredoxin. Oxidation of reduced ferredoxin is catalyzed by the Rnf complex and Na(+) dependent. Consistent with the finding of a Na(+)-dependent Rnf complex is the presence of a conserved Na(+)-binding motif in the c subunit of the ATP synthase. Butyrate formation is from acetyl-CoA via acetoacetyl-CoA, hydroxybutyryl-CoA, crotonyl-CoA, and butyryl-CoA and is consistent with the finding of a gene cluster that encodes the enzymes for this pathway. The activity of the butyryl-CoA dehydrogenase was demonstrated. Reduction of crotonyl-CoA to butyryl-CoA with NADH as the reductant was coupled to reduction of ferredoxin. We postulate that the butyryl-CoA dehydrogenase uses flavin-based electron bifurcation to reduce ferredoxin, which is consistent with the finding of etfA and etfB genes next to it. The overall ATP yield was calculated and is significantly higher than the one obtained with H2 + CO2. The energetic benefit may be one reason that butyrate is formed only from CO but not from H2 + CO2.


Molecular characterization of methanogenic N(5)-methyl-tetrahydromethanopterin: Coenzyme M methyltransferase.
Methanogenic archaea share one ion gradient forming reaction in their energy metabolism catalyzed by the membrane-spanning multisubunit complex N(5)-methyl-tetrahydromethanopterin: coenzyme M methyltransferase (MtrABCDEFGH or simply Mtr). In this reaction the methyl group transfer from methyl-tetrahydromethanopterin to coenzyme M mediated by cobalamin is coupled with the vectorial translocation of Na(+) across the cytoplasmic membrane. No detailed structural and mechanistic data are reported about this process. In the present work we describe a procedure to provide a highly pure and homogenous Mtr complex on the basis of a selective removal of the only soluble subunit MtrH with the membrane perturbing agent dimethyl maleic anhydride and a subsequent two-step chromatographic purification. A molecular mass determination of the Mtr complex by laser induced liquid bead ion desorption mass spectrometry (LILBID-MS) and size exclusion chromatography coupled with multi-angle light scattering (SEC-MALS) resulted in a (MtrABCDEFG)3 heterotrimeric complex of ca. 430kDa with both techniques. Taking into account that the membrane protein complex contains various firmly bound small molecules, predominantly detergent molecules, the stoichiometry of the subunits is most likely 1:1. A schematic model for the subunit arrangement within the MtrABCDEFG protomer was deduced from the mass of Mtr subcomplexes obtained by harsh IR-laser LILBID-MS.


Endolymphatic hydrops and blood-labyrinth barrier in Ménière's disease.
The blood-labyrinth barrier is impaired in association with the hydrops grade in Ménière's disease. To investigate the relationship between endolymphatic hydrops and the clinical characteristics of patients with Ménière's disease revealed by 3 T magnetic resonance imaging (MRI). A double dose of gadoteridol (Gd; 0.2 mmol/kg) was injected intravenously in 12 patients with Ménière's disease. We performed three-dimensional fluid attenuated inversion recovery MRI and three-dimensional real inversion recovery MRI 4 h later using a 3 T MRI unit. Ten patients had unilateral and two had bilateral Ménière's disease. Fourteen ears with Ménière's disease showed intense Gd contrast on MRI compared with that in the 10 asymptomatic contralateral ears of patients with unilateral Ménière's disease (1.12 ± 0.36 vs 0.82 ± 0.15). The hydrops grade was correlated significantly with the contrast effect. The 14 ears with Ménière's disease had endolymphatic hydrops. Of the 10 contralateral ears of patients with unilateral Ménière's disease, 2 had endolymphatic hydrops in the cochlea and 6 had endolymphatic hydrops in the vestibule.


O2 uptake kinetics, pyruvate dehydrogenase activity, and muscle deoxygenation in young and older adults during the transition to moderate-intensity exercise.
The adaptation of pulmonary O(2) uptake (Vo(2)(p)) kinetics is slowed in older compared with young adults during the transition to moderate-intensity exercise. In this study, we examined the relationship between Vo(2)(p) kinetics and mitochondrial pyruvate dehydrogenase (PDH) activity in young (n = 7) and older (n = 6) adults. Subjects performed cycle exercise to a work rate corresponding to approximately 90% of estimated lactate threshold. Phase 2 Vo(2)(p) kinetics were slower (P < 0.05) in older (tau = 40 +/- 17 s) compared with young (tau = 21 +/- 6 s) adults. Relative phosphocreatine (PCr) breakdown was greater (P < 0.05) at 30 s in older compared with young adults. Absolute PCr breakdown at 6 min was greater (P < 0.05) in older compared with young adults. In young adults, PDH activity increased (P < 0.05) from baseline to 30 s, with no further change observed at 6 min. In older adults, PDH activity during baseline exercise was similar to that seen in young adults. During the exercise transition, PDH activity did not increase (P > 0.05) at 30 s of exercise but was elevated (P < 0.05) after 6 min. The change in deoxyhemoglobin (HHb) was greater for a given Vo(2)(p) in older adults, and there was a similar time course of HHb accompanying the slower Vo(2)(p) kinetics in the older adults, suggesting a slower adaptation of bulk O(2) delivery in older adults. In conclusion, the slower adaptation of Vo(2)(p) in older adults is likely a result of both an increased metabolic inertia and lower O(2) availability.


Common Dorsal Stream Substrates for the Mapping of Surface Texture to Object Parts and Visual Spatial Processing.
Everyday objects are often composed of multiple parts, each with a unique surface texture. The neural substrates mediating the integration of surface features on different object parts are not fully understood, and potential contributions by both the ventral and dorsal visual pathways are possible. To explore these substrates, we collected fMRI data while human participants performed a difference detection task on two objects with textured parts. The objects could either differ in the assignment of the same texture to different object parts ("texture-location") or the types of texture ("texture-type"). In the ventral stream, comparable BOLD activation levels were observed in response to texture-location and texture-type differences. In contrast, in a priori localized spatial processing regions of the dorsal stream, activation was greater for texture-location than texture-type differences, and the magnitude of the activation correlated with behavioral performance. We confirmed the reliance of surface texture to object part mapping on spatial processing mechanisms in subsequent psychophysical experiments, in which participants detected a difference in the spatial distance of an object relative to a reference line. In this task, distracter objects occasionally appeared, which differed in either texture-location or texture-type. Distracter texture-location differences slowed detection of spatial distance differences, but texture-type differences did not. More importantly, the distracter effects were only observed when texture-location differences were presented within whole shapes and not between separated shape parts at distinct spatial locations. We conclude that both the mapping of texture features to object parts and the representation of object spatial position are mediated by common neural substrates within the dorsal visual pathway.


Role of homeostasis in learning sparse representations.
Neurons in the input layer of primary visual cortex in primates develop edge-like receptive fields. One approach to understanding the emergence of this response is to state that neural activity has to efficiently represent sensory data with respect to the statistics of natural scenes. Furthermore, it is believed that such an efficient coding is achieved using a competition across neurons so as to generate a sparse representation, that is, where a relatively small number of neurons are simultaneously active. Indeed, different models of sparse coding, coupled with Hebbian learning and homeostasis, have been proposed that successfully match the observed emergent response. However, the specific role of homeostasis in learning such sparse representations is still largely unknown. By quantitatively assessing the efficiency of the neural representation during learning, we derive a cooperative homeostasis mechanism that optimally tunes the competition between neurons within the sparse coding algorithm. We apply this homeostasis while learning small patches taken from natural images and compare its efficiency with state-of-the-art algorithms. Results show that while different sparse coding algorithms give similar coding results, the homeostasis provides an optimal balance for the representation of natural images within the population of neurons. Competition in sparse coding is optimized when it is fair. By contributing to optimizing statistical competition across neurons, homeostasis is crucial in providing a more efficient solution to the emergence of independent components.


Automated Cross-Sectional Measurement Method of Intracranial Dural Venous Sinuses.
MRV is an important blood vessel imaging and diagnostic tool for the evaluation of stenosis, occlusions, or aneurysms. However, an accurate image-processing tool for vessel comparison is unavailable. The purpose of this study was to develop and test an automated technique for vessel cross-sectional analysis. An algorithm for vessel cross-sectional analysis was developed that included 7 main steps: 1) image registration, 2) masking, 3) segmentation, 4) skeletonization, 5) cross-sectional planes, 6) clustering, and 7) cross-sectional analysis. Phantom models were used to validate the technique. The method was also tested on a control subject and a patient with idiopathic intracranial hypertension (4 large sinuses tested: right and left transverse sinuses, superior sagittal sinus, and straight sinus). The cross-sectional area and shape measurements were evaluated before and after lumbar puncture in patients with idiopathic intracranial hypertension. The vessel-analysis algorithm had a high degree of stability with <3% of cross-sections manually corrected. All investigated principal cranial blood sinuses had a significant cross-sectional area increase after lumbar puncture (P ≤ .05). The average triangularity of the transverse sinuses was increased, and the mean circularity of the sinuses was decreased by 6% ± 12% after lumbar puncture. Comparison of phantom and real data showed that all computed errors were <1 voxel unit, which confirmed that the method provided a very accurate solution. In this article, we present a novel automated imaging method for cross-sectional vessels analysis. The method can provide an efficient quantitative detection of abnormalities in the dural sinuses.


Local topological order inhibits thermal stability in 2D.
We study the robustness of quantum information stored in the degenerate ground space of a local, frustration-free Hamiltonian with commuting terms on a 2D spin lattice. On one hand, a macroscopic energy barrier separating the distinct ground states under local transformations would protect the information from thermal fluctuations. On the other hand, local topological order would shield the ground space from static perturbations. Here we demonstrate that local topological order implies a constant energy barrier, thus inhibiting thermal stability.


Decoding natural signals from the peripheral retina.
Ganglion cells in the peripheral retina have lower density and larger receptive fields than in the fovea. Consequently, the visual signals relayed from the periphery have substantially lower resolution than those relayed by the fovea. The information contained in peripheral ganglion cell responses can be quantified by how well they predict the foveal ganglion cell responses to the same stimulus. We constructed a model of human ganglion cell outputs by combining existing measurements of the optical transfer function with the receptive field properties and sampling densities of midget (P) ganglion cells. We then simulated a spatial population of P-cell responses to image patches sampled from a large collection of luminance-calibrated natural images. Finally, we characterized the population response to each image patch, at each eccentricity, with two parameters of the spatial power spectrum of the responses: the average response contrast (standard deviation of the response patch) and the falloff in power with spatial frequency. The primary finding is that the optimal estimate of response contrast in the fovea is dependent on both the response contrast and the steepness of the falloff observed in the periphery. Humans could exploit this information when decoding peripheral signals to estimate contrasts, estimate blur levels, or select the most informative locations for saccadic eye movements.


Expression of specific sheath cell proteins during peripheral nerve growth and regeneration in mammals.
Protein synthesis in the nerve sheath of injured as well as intact mature and developing sciatic nerves from rat and rabbit was investigated by incubating segments of nerve with [35S]methionine in vitro. The composition of labeled proteins under the different conditions of nerve growth was analyzed by two-dimensional gel electrophoresis and fluorography. The expression of six secreted proteins in rat sciatic nerve with the apparent molecular weights of 70,000 (70 kD), 54,000 (54 kD), 51,000 (51 kD), 39,000 (39 kD), 37,000 (37 kD), and 30,000 (30 kD) was of particular interest because of the correlation of their synthesis and secretion with aspects of nerve growth and regeneration. The synthesis of the 37-kD protein was significantly stimulated during both sciatic nerve development as well as regeneration but not in the intact mature nerve. The expression of this protein appears to be regulated by signal(s) from the axon but not the target. The 70-kD protein was exclusively synthesized in response to axotomy, thus confining its role to some aspect(s) of nerve repair. In contrast, the 54- and 51-kD proteins were expressed in the intact mature nerve sheath. Their synthesis and release was rapidly inhibited upon axotomy but returned to normal or higher levels towards the end of sciatic nerve regeneration, suggesting a role in the maintenance of the integrity of the mature (nongrowing) rat nerve. The 39- and 30-kD proteins were only transiently synthesized within the first week after axotomy. Two proteins with the apparent molecular masses of 70 and 37 kD were synthesized in denervated rabbit sciatic nerve. The similar molecular weights, net charges, and time-courses of induction suggest a homology between these proteins in rabbit and rat, indicating common molecular responses of peripheral nerve sheath cells to axon injury in both mammalian species.


Issues and practices in the use of effects data from FREDERICA in the ERICA Integrated Approach.
The ERICA Integrated Approach requires that a risk assessment screening dose rate is defined for the risk characterisation within Tiers 1 and 2. At Tier 3, no numerical screening dose rate is used, and the risk characterisation is driven by methods that can evaluate the possible effects of ionising radiation on reproduction, mortality and morbidity. Species sensitivity distribution has been used to derive the ERICA risk assessment predicted no-effect dose rate (PNEDR). The method used was based on the mathematical processing of data from FRED (FASSET radiation effects database merged with the EPIC database to form FREDERICA) and resulted in a PNEDR of 10 microGy/h. This rate was assumed to ascribe sufficient protection of all ecosystems from detrimental effects on structure and function under chronic exposure. The value was weighed against a number of points of comparison: (i) PNEDR values obtained by application of the safety factor method, (ii) background levels, (iii) dose rates triggering effects on radioactively contaminated sites and (iv) former guidelines from literature reviews. In Tier 3, the effects analysis must be driven by the problem formulation and is thus highly case specific. Instead of specific recommendations on numeric values, guidance on the sorts of methods that may be applied for refined effect analysis is provided and illustrated.


The toxicology of climate change: environmental contaminants in a warming world.
Climate change induced by anthropogenic warming of the earth's atmosphere is a daunting problem. This review examines one of the consequences of climate change that has only recently attracted attention: namely, the effects of climate change on the environmental distribution and toxicity of chemical pollutants. A review was undertaken of the scientific literature (original research articles, reviews, government and intergovernmental reports) focusing on the interactions of toxicants with the environmental parameters, temperature, precipitation, and salinity, as altered by climate change. Three broad classes of chemical toxicants of global significance were the focus: air pollutants, persistent organic pollutants (POPs), including some organochlorine pesticides, and other classes of pesticides. Generally, increases in temperature will enhance the toxicity of contaminants and increase concentrations of tropospheric ozone regionally, but will also likely increase rates of chemical degradation. While further research is needed, climate change coupled with air pollutant exposures may have potentially serious adverse consequences for human health in urban and polluted regions. Climate change producing alterations in: food webs, lipid dynamics, ice and snow melt, and organic carbon cycling could result in increased POP levels in water, soil, and biota. There is also compelling evidence that increasing temperatures could be deleterious to pollutant-exposed wildlife. For example, elevated water temperatures may alter the biotransformation of contaminants to more bioactive metabolites and impair homeostasis. The complex interactions between climate change and pollutants may be particularly problematic for species living at the edge of their physiological tolerance range where acclimation capacity may be limited. In addition to temperature increases, regional precipitation patterns are projected to be altered with climate change. Regions subject to decreases in precipitation may experience enhanced volatilization of POPs and pesticides to the atmosphere. Reduced precipitation will also increase air pollution in urbanized regions resulting in negative health effects, which may be exacerbated by temperature increases. Regions subject to increased precipitation will have lower levels of air pollution, but will likely experience enhanced surface deposition of airborne POPs and increased run-off of pesticides. Moreover, increases in the intensity and frequency of storm events linked to climate change could lead to more severe episodes of chemical contamination of water bodies and surrounding watersheds. Changes in salinity may affect aquatic organisms as an independent stressor as well as by altering the bioavailability and in some instances increasing the toxicity of chemicals. A paramount issue will be to identify species and populations especially vulnerable to climate-pollutant interactions, in the context of the many other physical, chemical, and biological stressors that will be altered with climate change. Moreover, it will be important to predict tipping points that might trigger or accelerate synergistic interactions between climate change and contaminant exposures.


Home oxygen therapy for COPD: practical aspects.
Numerous studies have indicated that home oxygen therapy is safe and practical. In advanced chronic obstructive pulmonary disease (COPD), continuous oxygen therapy results in a higher survival rate than does administration of oxygen 12 hr/day. Practical oxygen systems are available. Thus, oxygen therapy is now established care for selected patients with advanced COPD. Further studies are needed to evaluate the effectiveness of oxygen therapy to combat the possible effects of transient hypoxemia in patients with COPD during sleep or exercise. COPD necessitates a preventive approach, including behavioral change if possible. Early identification by simple office spirometry and aggressive treatment designed to prevent or forestall complications of advanced disease are the next logical steps in developing a systematic, comprehensive approach aimed at the ultimate conquest of COPD in the next decade.


Predictors and mediators of trait anger across the psychosis continuum: The role of attachment style, paranoia and social cognition.
Anger in the context of psychosis has a significant impact on treatment outcomes and serious implications for risk management. Understanding mechanisms underlying anger will improve interventions and inform strategies for prevention. This study is the first to examine the relationships between anger and key theoretical drivers across different phases of the psychosis continuum. A battery including measures of theory of mind, attachment, hostile attribution bias, paranoia and anger was administered to 174 participants (14 ultra-high risk, 20 first-episode, 20 established psychosis, 120 non-clinical participants). We tested the model that insecure attachment, paranoia, impaired theory of mind and hostile attribution bias would predict trait anger using multiple regression. Attachment avoidance, paranoia and hostile attribution bias were significantly associated with anger but attachment anxiety and theory of mind were not. Mediation analysis showed that paranoia partially mediated the relationship between avoidant attachment and anger but hostile attribution bias did not. Findings emphasise the importance of interventions targeting paranoia to reduce anger and the potential of preventive strategies focused on attachment relationships in early life or adulthood to reduce adult paranoia and anger.


Chirp-Evoked Otoacoustic Emissions and Middle Ear Absorbance for Monitoring Ototoxicity in Cystic Fibrosis Patients.
The goal of this study was to investigate the use of transient-evoked otoacoustic emissions (TEOAEs) and middle ear absorbance measurements to monitor auditory function in patients with cystic fibrosis (CF) receiving ototoxic medications. TEOAEs were elicited with a chirp stimulus using an extended bandwidth (0.71 to 8 kHz) to measure cochlear function at higher frequencies than traditional TEOAEs. Absorbance over a wide bandwidth (0.25 to 8 kHz) provides information on middle ear function. The combination of these time-efficient measurements has the potential to identify early signs of ototoxic hearing loss. A longitudinal study design was used to monitor the hearing of 91 patients with CF (median age = 25 years; age range = 15 to 63 years) who received known ototoxic medications (e.g., tobramycin) to prevent or treat bacterial lung infections. Results were compared to 37 normally hearing young adults (median age = 32.5 years; age range = 18 to 65 years) without a history of CF or similar treatments. Clinical testing included 226-Hz tympanometry, pure-tone air-conduction threshold testing from 0.25 to 16 kHz and bone conduction from 0.25 to 4 kHz. Experimental testing included wideband absorbance at ambient and tympanometric peak pressure and TEOAEs in three stimulus conditions: at ambient pressure and at tympanometric peak pressure using a chirp stimulus with constant incident pressure level across frequency and at ambient pressure using a chirp stimulus with constant absorbed sound power across frequency. At the initial visit, behavioral audiometric results indicated that 76 of the 157 ears (48%) from patients with CF had normal hearing, whereas 81 of these ears (52%) had sensorineural hearing loss for at least one frequency. Seven ears from four patients had a confirmed behavioral change in hearing threshold for ≥3 visits during study participation. Receiver operating characteristic curve analyses demonstrated that all three TEOAE conditions were useful for distinguishing CF ears with normal hearing from ears with sensorineural hearing loss, with an area under the receiver operating characteristic curve values ranging from 0.78 to 0.92 across methods for frequency bands from 2.8 to 8 kHz. Case studies are presented to illustrate the relationship between changes in audiometric thresholds, TEOAEs, and absorbance across study visits. Absorbance measures permitted identification of potential middle ear dysfunction at 5.7 kHz in an ear that exhibited a temporary hearing loss. The joint use of TEOAEs and absorbance has the potential to explain fluctuations in audiometric thresholds due to changes in cochlear function, middle ear function, or both. These findings are encouraging for the joint use of TEOAE and wideband absorbance objective tests for monitoring ototoxicity, particularly, in patients who may be too ill for behavioral hearing tests. Additional longitudinal studies are needed in a larger number of CF patients receiving ototoxic drugs to further evaluate the clinical utility of these measures in an ototoxic monitoring program.


Society for immunotherapy of cancer (SITC) statement on the proposed changes to the common rule.
The Common Rule is a set of ethical principles that provide guidance on the management of human subjects taking part in biomedical and behavioral research in the United States. The elements of the Common Rule were initially developed in 1981 following a revision of the Declaration of Helsinki in 1975. Most academic facilities follow the Common Rule in the regulation of clinical trials research. Recently, the government has suggested a revision of the Common Rule to include more contemporary and streamlined oversight of clinical research. In this commentary, the leadership of the Society for Immunotherapy of Cancer (SITC) provides their opinion on this plan. While the Society recognizes the considerable contribution of clinical research in supporting progress in tumor immunotherapy and supports the need for revisions to the Common Rule, there is also some concern over certain elements which may restrict access to biospecimens and clinical data at a time when high throughput technologies, computational biology and assay standardization is allowing major advances in understanding cancer biology and providing potential predictive biomarkers of immunotherapy response. The Society values its professional commitment to patients for improving clinical outcomes with tumor immunotherapy and supports continued discussion with all stakeholders before implementing changes to the Common Rule in order to ensure maximal patient protections while promoting continued clinical research at this historic time in cancer research.


Immobilized dimers of N-cadherin-Fc chimera mimic cadherin-mediated cell contact formation: contribution of both outside-in and inside-out signals.
Cell adhesion receptors of the cadherin family are involved in various developmental processes, affecting cell adhesion and migration, and also cell proliferation and differentiation. In order to dissect the molecular mechanisms of cadherin-based cell-cell adhesion and subsequent signal transduction to the cytoskeleton and/or cytoplasm leading to adapted cell responses, we developed an approach allowing us to mimic and control cadherin activation. We produced a dimeric N-cadherin-Fc chimera (Ncad-Fc) which retains structural and functional properties of cadherins, including glycosylation, Ca(2+)-dependent trypsin sensitivity and the ability to mediate Ca(2+)-dependent self-aggregation of covered microbeads. Beads covered with either Ncad-Fc or anti-N-cadherin antibodies specifically bound to N-cadherin expressing cells. Both types of beads induced the recruitment of N-cadherin, beta-catenin, alpha-catenin and p120, by lateral mobilization of preexisting cell membrane complexes. Furthermore, cadherin clustering elicited by Ncad-Fc beads triggered local accumulations of tyrosine phosphorylated proteins, a recruitment and redistribution of actin filaments, as well as local membrane remodeling. These results support a model where the adhesion of cadherin ectodomains is followed by clustering of cadherin/catenin complexes allowing signal transduction affecting both cytoskeletal reorganization and cytoplasmic signal mobilization (outside-in signaling). Interestingly, bead-cell binding was altered by agents promoting microfilament and microtubule depolymerization or tyrosine phosphorylation, indicating a possible regulation of the adhesive properties of the extracellular domain of N-cadherin by intracellular factors (inside-out signaling).


Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine.
A single oral inoculation to mice of the live attenuated Yersinia pseudotuberculosis VTnF1 strain producing an F1 pseudocapsule protects against bubonic and pneumonic plague. However oral vaccination can fail in humans exposed to frequent intestinal infections. We evaluated in mice the efficacy of subcutaneous vaccine injection as an alternative way to induce protective immunity, while reducing the dose and avoiding strain release in nature. A single subcutaneous dose of up to 108 CFU induced dose-dependent antibody production. At the dose of 107 CFU, i.e. 10 times less than via the oral route, it caused a modest skin reaction and protected 100% against bubonic and 80% against pneumonic plague, caused by high doses of Yersinia pestis. Bacteria migrating to lymph nodes and spleen, but not feces, were rapidly eliminated. Thus, subcutaneous injection of VTnF1 would represent a good alternative when dissemination in nature and human intestinal responsiveness are limitations.


Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes.
Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.


Treating a transgender patient: overview of the guidelines.
Transgenderism and gender dysphoria are becoming more prevalent diagnoses and the patient population is increasing. Primary care practitioners, endocrinologists, and mental health professionals are all part of the medical care team that treats these patients, but family and internal medicine physicians continue to deliver the care in the long term. Transgender medicine is not a strong part of the medical curriculum, and recent studies have shown there is anxiety in new physicians in taking care of these patients. There are many aspects to transgender care that involve different specialities, including, but not limited to, mental health, primary care, endocrinology, surgery, and obstetrics and gynecology. This article gives an overview of the current guidelines for standards of care of transgender patients as delineated by the World Professional Association for Transgender Health and the Endocrine Society.


Utilizing Human Genetics to Develop Chemoprevention for Cancer-Too Good an Opportunity to be Missed.
Large-scale genetic studies are reliably identifying many risk factors for disease in the general population. Several of these genetic risk factors encode potential drug targets, and genetics has already helped to introduce targeted agents for some diseases, an example being lipid-lowering drugs to reduce the incidence of cardiovascular disease. Multiple drugs have been developed to treat cancers based on somatic mutations and genomics, but in stark contrast, there seems to be a reluctance to use germline genetic data to develop drugs to prevent malignancy, despite the large numbers of people who could benefit, the potential for lowering cancer rates, and the widespread current use of non-pharmaceutical measures to reduce cancer risk factors such as tobacco, alcohol, and infectious diseases. We argue that concerted efforts for cancer prevention based on genetics, including genes influenced by common polymorphisms that modulate cancer risk, are urgently needed. There are enormous, yet underutilized, opportunities to develop novel targeted agents for chemoprevention of cancer based on human germline genetics. Such efforts are likely to require the support of a dedicated funding program by national and international agencies. See related commentary by Winham and Sherman, p. 13.


A meta-analysis of nutritional supplementation for management of hospitalized alcoholic hepatitis.
Alcoholic liver disease (ALD) is associated with a high risk of morbidity and mortality. Malnutrition accompanies this condition and may be both a consequence of and contributor to the pathology. Many trials have investigated the benefits of providing supplemental nutrition in the management of patients with ALD. The present study is a meta-analysis of the available evidence. A meta-analysis of randomized controlled studies comparing nutritional supplementation plus a normal hospital diet versus diet alone. Seven randomized controlled studies including 262 patients with ALD were identified. Pooled analysis revealed no statistical difference in mortality between groups given special nutritional therapy versus a normal balanced diet (OR 0.80 [95% CI 0.42 to 1.52]). In addition, nutrition did not significantly improve ascites (OR 1.29 [95% CI 0.52 to 3.20]) or any biochemical parameters. However, encephalopathy showed a significant improvement or resolution (OR 0.24 [95% CI 0.06 to 0.93]). Nutritional supplementation provided no mortality benefit in patients with ALD, and neither ascites nor biochemical parameters significantly improved. However, encephalopathy was significantly ameliorated and, therefore, nutritional supplementation should be encouraged in that setting.


The knowns and unknowns of phosphorus loading into grains, and implications for phosphorus efficiency in cropping systems.
Inefficient use of phosphorus (P) in agriculture adds to production costs, increases the risk of eutrophication of waterways, and contributes to the rapid depletion of the world's non-renewable rock phosphate supplies. The removal of large quantities of P from fields in harvested grains is a major driver in the global P cycle, but opportunities exist to reduce the amount of P in harvested grains through plant breeding. Using rice (Oryza sativa L.) as a model crop, we examine our current understanding of the process of P loading into grain and its regulation by genetic and environmental factors. We expose a dearth of knowledge on the physiological processes involved in loading P into grains, poor resolution of the genes and networks involved in P mobilization from vegetative tissues to grains, and limited understanding of genetic versus environmental contributions to variation in grain P concentrations observed among genotypes. We discuss potential breeding strategies and highlight key research gaps that should be addressed to facilitate these breeding approaches. Given the strong economic and environmental incentives for a low grain P trait, we suggest that some of the investment and resources currently directed to determining the molecular regulation of P starvation responses in model plant species should be diverted to resolving the physiology, genetics, and molecular regulation of P loading into cereal grains.


In their own words: investigating the preparedness of final year dental students in the UK for independent general dental practice.
There is relatively little data on the preparedness of UK dental graduates for independent general dental practice. Two recent studies have indicated that graduates appear well prepared, but although quantifying the level of preparedness, they provide limited understanding of the underlying factors contributing to preparedness. This study aims to more deeply understand the contributing factors leading to assertions of graduate preparedness using focus groups of final year dental students, and semi-structured interviews of senior faculty members. Three UK dental schools were visited in order to conduct both study elements. Focus groups and semi-structured interviews were audio recorded and fully transcribed. Thematic analysis of the transcripts resulted in the production of a thematic matrix. The major categories of the thematic matrix were classified as extrinsic; including the role of educators and features of the course, and intrinsic; relating to fear of the unknown, the development of adult learning abilities and less easily identifiable attributes in the development of competence, which became known as 'bricks and mortar'. Students felt that the most important factor affecting their preparation was clinical exposure. Outreach placements were felt to be particularly useful, the simulation of general dental practice being highly valued by final year students. The interaction with educators was also felt to be a key influence on preparedness, with the involvement of general practitioners in dental school teaching felt to be helpful, perhaps giving students an extended exposure to general practice. It is hoped that the rich data derived from this study may allow an invaluable insight into factors contributing to preparedness of new dental graduates, which may then be considered in the light of any proposed changes in the curricula or syllabi.


Immune therapeutic potential of stem cells from human supernumerary teeth.
Discoveries of immunomodulatory functions in mesenchymal stem cells (MSCs) have suggested that they might have therapeutic utility in treating immune diseases. Recently, a novel MSC population was identified from dental pulp of human supernumerary teeth, and its multipotency characterized. Herein, we first examined the in vitro and in vivo immunomodulatory functions of human supernumerary tooth-derived stem cells (SNTSCs). SNTSCs suppressed not only the viability of T-cells, but also the differentiation of interleukin 17 (IL-17)-secreting helper T (Th17)-cells in in vitro co-culture experiments. In addition, systemic SNTSC transplantation ameliorated the shortened lifespan and elevated serum autoantibodies and nephritis-like renal dysfunction in systemic lupus erythematosus (SLE) model MRL/lpr mice. SNTSC transplantation also suppressed in vivo increased levels of peripheral Th17 cells and IL-17, as well as ex vivo differentiation of Th17 cells in MRL/lpr mice. Adoptive transfer experiments demonstrated that SNTSC-transplanted MRL/lpr mouse-derived T-cell-adopted immunocompromised mice showed a longer lifespan in comparison with non-transplanted MRL/lpr mouse-derived T-cell-adopted immunocompromised mice, indicating that SNTSC transplantation suppresses the hyper-immune condition of MRL/lpr mice through suppressing T-cells. Analysis of these data suggests that SNTSCs are a promising MSC source for cell-based therapy for immune diseases such as SLE.


Strengths-based positive psychology interventions: a randomized placebo-controlled online trial on long-term effects for a signature strengths- vs. a lesser strengths-intervention.
Recent years have seen an increasing interest in research in positive psychology interventions. There is broad evidence for their effectiveness in increasing well-being and ameliorating depression. Intentional activities that focus on those character strengths, which are most typical for a person (i.e., signature strengths, SS) and encourage their usage in a new way have been identified as highly effective. The current study aims at comparing an intervention aimed at using SS with one on using individual low scoring (or lesser) strengths in a randomized placebo-controlled trial. A total of 375 adults were randomly assigned to one of the two intervention conditions [i.e., using five signature vs. five lesser strengths (LS) in a new way] or a placebo control condition (i.e., early memories). We measured happiness and depressive symptoms at five time points (i.e., pre- and post-test, 1-, 3-, and 6-months follow-ups) and character strengths at pre-test. The main findings are that (1) there were increases in happiness for up to 3 months and decreases in depressive symptoms in the short term in both intervention conditions; (2) participants found working with strengths equally rewarding (enjoyment and benefit) in both conditions; (3) those participants that reported generally higher levels of strengths benefitted more from working on LS rather than SS and those with comparatively lower levels of strengths tended to benefit more from working on SS; and (4) deviations from an average profile derived from a large sample of German-speakers completing the Values-in-Action Inventory of Strengths were associated with greater benefit from the interventions in the SS-condition. We conclude that working on character strengths is effective for increasing happiness and discuss how these interventions could be tailored to the individual for promoting their effectiveness.


Primary Care Provider Management of Congenital Hypothyroidism Identified Through Newborn Screening.
To assess Primary Congenital Hypothyroidism (CH) management patterns and feasibility of providing long-term care for patients with CH identified through newborn screening by Primary Care Providers (PCPs) in California and Hawaii. A survey was mailed to all physicians (N=823) listed as the referral doctor for confirmed patients with CH identified through newborn screening programs in both states between 01/01/2009-12/31/2013. Information was collected on CH management patterns, barriers to providing care, and knowledge on CH treatment. Descriptive statistics and bivariate logistic regression results were reported. 206 PCPs completed the survey. Among these, 78% currently have patients with CH and 91% indicated willingness to provide long-term care to new patients with CH. Among PCPs currently caring for patients with CH, 17% managed CH by themselves with limited assistance from endocrinologists; 63% were involved in managing CH but endocrinologists played a larger role than PCPs; 19% were not involved in CH care. Only 49% of PCPs correctly answered questions regarding recommended follow-up frequencies and 23% knew the correct age for a trial off levothyroxine for suspected transient CH. Top two perceived barriers to providing long-term care included "need guidance or support from endocrinologists" (61%) and "not familiar with CH treatment guidelines" (28%). The majority of PCPs surveyed are willing to provide long-term care to patients with CH, but need support from endocrinologists and increased knowledge about current treatment guidelines.


Levels of felt stigma among a group of people with HIV in Puerto Rico.
HIV felt stigma is a major problem needing to be addressed because of its association with poor treatment adherence, decreases in help-seeking behaviors, high-risk sexual conduct, emotional discomfort, and the reduction of well-being in people with HIV/AIDS (PWHA). The aim of this study was to identify the frequency of felt stigma among PWHA in Puerto Rico. A cross-sectional study was conducted with 249 subjects (59% men, 41% women). Participants completed the Puerto Rico Comprehensive Center for HIV Disparities (PR-CCHD) Sociodemographic Questionnaire and the HIV Felt Sigma Scale. 80% of the subjects showed some level of felt stigma. Women showed significantly higher levels of HIV-related felt stigma than did men. Disclosure, negative self-image, and public attitude scores were also higher in women than in men. Sociodemographic variables such as age, marital status, employment status, income, and educational level showed significant associations with felt stigma and its dimensions. Results of this study evidence the need to develop culturally sensitive intervention models to reduce the felt-stigma burden in PWHA.


Sociodemographic correlates of eye care provider visits in the 2006-2009 Behavioral Risk Factor Surveillance Survey.
Research has suggested that adults 40 years old and over are not following eye care visit recommendations. In the United States, the proportion of older adults is expected to increase drastically in the coming years. This has important implications for population ocular disease burden, given the relationship between older age and the development of many ocular diseases and conditions. Understanding individual level determinants of vision health could support the development of tailored vision health campaigns and interventions among our growing older population. Thus, we assessed correlates of eye care visits among participants of the Behavior Risk Factor Surveillance System (BRFSS) survey. We pooled and analyzed 2006-2009 BRFSS data from 16 States (N = 118,075). We assessed for the proportion of survey respondents 40 years of age and older reporting having visited an eye care provider within the past two years, two or more years ago, or never by socio-demographic characteristics. Nearly 80% of respondents reported an eye care visit within the previous two years. Using the 'never visits' as the referent category, the groups with greater odds of having an ocular visit within the past two years included those: greater than 70 years of age (OR = 6.8 [95% confidence interval = 3.7-12.6]), with college degree (5.2[3.0-8.8]), reporting an eye disease, (4.74[1.1-21.2]), diagnosed with diabetes (3.5[1.7-7.5]), of female gender (2.9[2.1-3.9]), with general health insurance (2.7[1.8-3.9]), with eye provider insurance coverage (2.1[1.5-3.0]), with high blood pressure (1.5[1.1-2.2]), and with moderate to extreme near vision difficulties (1.42[1.11-2.08]). We found significant variation by socio-demographic characteristics and some variation in state-level estimates in this study. The present findings suggest that there remains compliance gaps of screening guidelines among select socio-demographic sub-groups, as well as provide evidence and support to the CDC's Vision Health Initiative. This data further suggests that there remains a need for ocular educational campaigns in select socio-demographic subgroups and possibly policy changes to enhance insurance coverage.


Completion pneumonectomy: Indications and outcomes in non-small cell lung cancer.
This retrospective single-center study aims to review the indications and outcomes of completion pneumonectomy after primary resection due to non-small cell lung cancer. Of a total of 452 patients who underwent pneumonectomy between January 2004 and August 2017 for non-small cell lung cancer, 29 (24 males, 5 females; mean age 59.9±7.1 years; range, 45 to 72 years) were performed completion pneumonectomy. Patients" indications, factors affecting early and late-term outcomes, operative mortality and survival rates were analyzed. Operative mortality rate was 24.1%, including two intraoperative and five postoperative deaths. Complication rate was 44.8% and the most frequent complication was bronchopleural fistula with 24.1%. Study population was divided into two groups. While elective completion pneumonectomy group (n=19) consisted of recurrent malignant tumor patients, rescue completion pneumonectomy group (n=10) consisted of patients performed urgent pneumonectomy due to a bronchopulmonary complication developing after an anatomic lung resection. The morbidity and mortality rates for elective completion pneumonectomy and rescue completion pneumonectomy were 26.3% and 21.1%; and 70% and 30%, respectively. The morbidity for rescue completion pneumonectomy was significantly higher than elective completion pneumonectomy (p=0.016). Advanced age and presence of any preoperative risk (comorbidity and neoadjuvant treatment) were related to higher operative mortality (p=0.019 and p=0.049, respectively). The median survival after completion pneumonectomy was 19.5 months (95% confidence interval 17.2 to 21.9 months). The morbidity and mortality rates of completion pneumonectomy are higher than standard pneumonectomy. Rescue completion pneumonectomy is related to higher postoperative risk, but has better survival. The most significant complication after completion pneumonectomy is bronchopleural fistula. Advanced age and presence of any preoperative risk are related to statistically significantly higher mortality in completion pneumonectomy. Nevertheless, completion pneumonectomy is still a significant treatment option in selected patients.


Widespread use and frequent detection of neonicotinoid insecticides in wetlands of Canada's Prairie Pothole Region.
Neonicotinoids currently dominate the insecticide market as seed treatments on Canada's major Prairie crops (e.g., canola). The potential impact to ecologically significant wetlands in this dominantly agro-environment has largely been overlooked while the distribution of use, incidence and level of contamination remains unreported. We modelled the spatial distribution of neonicotinoid use across the three Prairie Provinces in combination with temporal assessments of water and sediment concentrations in wetlands to measure four active ingredients (clothianidin, thiamethoxam, imidacloprid and acetamiprid). From 2009 to 2012, neonicotinoid use was increasing; by 2012, applications covered an estimated ∼11 million hectares (44% of Prairie cropland) with >216,000 kg of active ingredients. Thiamethoxam, followed by clothianidin, were the dominant seed treatments by mass and area. Areas of high neonicotinoid use were identified as high density canola or soybean production. Water sampled four times from 136 wetlands (spring, summer, fall 2012 and spring 2013) across four rural municipalities in Saskatchewan similarly revealed clothianidin and thiamethoxam in the majority of samples. In spring 2012 prior to seeding, 36% of wetlands contained at least one neonicotinoid. Detections increased to 62% in summer 2012, declined to 16% in fall, and increased to 91% the following spring 2013 after ice-off. Peak concentrations were recorded during summer 2012 for both thiamethoxam (range: <LOQ--1490 ng/L, canola) and clothianidin (range: <LOQ--3110 ng/L, canola). Sediment samples collected during the same period rarely (6%) contained neonicotinoid concentrations (which did not exceed 20 ng/L). Wetlands situated in barley, canola and oat fields consistently contained higher mean concentrations of neonicotinoids than in grasslands, but no individual crop singularly influenced overall detections or concentrations. Distribution maps indicate neonicotinoid use is increasing and becoming more widespread with concerns for environmental loading, while frequently detected neonicotinoid concentrations in Prairie wetlands suggest high persistence and transport into wetlands.


Mutant screen distinguishes between residues necessary for light-signal perception and signal transfer by phytochrome B.
The phytochromes (phyA to phyE) are a major plant photoreceptor family that regulate a diversity of developmental processes in response to light. The N-terminal 651-amino acid domain of phyB (N651), which binds an open tetrapyrrole chromophore, acts to perceive and transduce regulatory light signals in the cell nucleus. The N651 domain comprises several subdomains: the N-terminal extension, the Per/Arnt/Sim (PAS)-like subdomain (PLD), the cGMP phosphodiesterase/adenyl cyclase/FhlA (GAF) subdomain, and the phytochrome (PHY) subdomain. To define functional roles for these subdomains, we mutagenized an Arabidopsis thaliana line expressing N651 fused in tandem to green fluorescent protein, beta-glucuronidase, and a nuclear localization signal. A large-scale screen for long hypocotyl mutants identified 14 novel intragenic missense mutations in the N651 moiety. These new mutations, along with eight previously identified mutations, were distributed throughout N651, indicating that each subdomain has an important function. In vitro analysis of the spectral properties of these mutants enabled them to be classified into two principal classes: light-signal perception mutants (those with defective spectral activity), and signaling mutants (those normal in light perception but defective in intracellular signal transfer). Most spectral mutants were found in the GAF and PHY subdomains. On the other hand, the signaling mutants tend to be located in the N-terminal extension and PLD. These observations indicate that the N-terminal extension and PLD are mainly involved in signal transfer, but that the C-terminal GAF and PHY subdomains are responsible for light perception. Among the signaling mutants, R110Q, G111D, G112D, and R325K were particularly interesting. Alignment with the recently described three-dimensional structure of the PAS-GAF domain of a bacterial phytochrome suggests that these four mutations reside in the vicinity of the phytochrome light-sensing knot.


Detecting marker-QTL linkage and estimating QTL gene effect and map location using a saturated genetic map.
A simulation study was carried out on a backcross population in order to determine the effect of marker spacing, gene effect and population size on the power of marker-quantitative trait loci (QTL) linkage experiments and on the standard error of maximum likelihood estimates (MLE) of QTL gene effect and map location. Power of detecting a QTL was virtually the same for a marker spacing of 10 cM as for an infinite number of markers and was only slightly decreased for marker spacing of 20 or even 50 cM. The advantage of using interval mapping as compared to single-marker analysis was slight. "Resolving power" of a marker-QTL linkage experiment was defined as the 95% confidence interval for the QTL map location that would be obtained when scoring an infinite number of markers. It was found that reducing marker spacing below the resolving power did not add appreciably to narrowing the confidence interval. Thus, the 95% confidence interval with infinite markers sets the useful marker spacing for estimating QTL map location for a given population size and estimated gene effect.


Effects of embryonic exposure to polychlorinated biphenyls on zebrafish skeletal development.
Polychlorinated biphenyls (PCBs) are persistent organic pollutants that affect embryonic development. The purpose of this study was to examine the effects of embryonic exposure to PCBs on early skeletal development in zebrafish (Danio rerio). Zebrafish embryos were immediately exposed to various concentrations (0, 0.125, 0.25, 0.5 and 1.0 mg/l) of PCBs (Aroclor 1254) after fertilization. Embryos were assessed at 24, 48, 72, 96 and 120 h post-fertilization (hpf) for changes in embryonic survival and malformation rates. Calcium content and vitamin D receptor (VDR), parathyroid hormone (PTH) and TRVP6 mRNA expressions were assessed at 120 hpf. The results showed that PCBs exposure decreased the survival rate of the embryos in a time-and dose-dependent manner. The embryos exposed to the higher concentrations of PCBs (0.5 and 1.0 mg/l) displayed obvious skeletal morphological deformities. At 120 hpf, the calcium content of the zebrafish was downregulated in all the PCB-treated groups. VDR, PTH and TRVP6 mRNA expressions were all affected by PCBs. By 120 hpf, the mRNA expressions of VDR, PTH and TRVP6 from the PCB-treated larvae were all upregulated. The expressions of PTH and TRVP6 positively correlated with the level of PCBs to which the embryos were exposed. These results suggest that embryonic exposure to PCBs induces developmental deficits in the zebrafish skeleton.


Atosiban versus fenoterol as a uterine relaxant for external cephalic version: randomised controlled trial.
To compare the effectiveness of the oxytocin receptor antagonist atosiban with the beta mimetic fenoterol as uterine relaxants in women undergoing external cephalic version (ECV) for breech presentation. Multicentre, open label, randomised controlled trial. Eight hospitals in the Netherlands, August 2009 to May 2014. 830 women with a singleton fetus in breech presentation and a gestational age of more than 34 weeks were randomly allocated in a 1:1 ratio to either 6.75 mg atosiban (n=416) or 40 μg fenoterol (n=414) intravenously for uterine relaxation before ECV. The primary outcome measures were a fetus in cephalic position 30 minutes after the procedure and cephalic presentation at delivery. Secondary outcome measures were mode of delivery, incidence of fetal and maternal complications, and drug related adverse events. All analyses were done on an intention-to-treat basis. Cephalic position 30 minutes after ECV occurred significantly less in the atosiban group than in the fenoterol group (34% v 40%, relative risk 0.73, 95% confidence interval 0.55 to 0.93). Presentation at birth was cephalic in 35% (n=139) of the atosiban group and 40% (n=166) of the fenoterol group (0.86, 0.72 to 1.03), and caesarean delivery was performed in 60% (n=240) of women in the atosiban group and 55% (n=218) in the fenoterol group (1.09, 0.96 to 1.20). No significant differences were found in neonatal outcomes or drug related adverse events. In women undergoing ECV for breech presentation, uterine relaxation with fenoterol increases the rate of cephalic presentation 30 minutes after the procedure. No statistically significant difference was found for cephalic presentation at delivery. Dutch Trial Register, NTR 1877.


Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women.
The rates of colon cancer in various countries are strongly correlated with the per capita consumption of red meat and animal fat and, to a lesser degree, inversely associated with the consumption of fiber. We conducted a prospective study among 88,751 women 34 to 59 years old and without a history of cancer, inflammatory bowel disease, or familial polyposis who completed a dietary questionnaire in 1980. By 1986, during 512,488 person-years of follow-up, 150 incident cases of colon cancer had been documented. After adjustment for total energy intake, animal fat was positively associated with the risk of colon cancer (P for trend = 0.01); the relative risk for the highest as compared with the lowest quintile was 1.89 (95 percent confidence interval, 1.13 to 3.15). No association was found for vegetable fat. The relative risk of colon cancer in women who ate beef, pork, or lamb as a main dish every day was 2.49 (95 percent confidence interval, 1.24 to 5.03), as compared with those reporting consumption less than once a month. Processed meats and liver were also significantly associated with increased risk, whereas fish and chicken without skin were related to decreased risk. The ratio of the intake of red meat to the intake of chicken and fish was particularly strongly associated with an increased incidence of colon cancer (P for trend = 0.0005); the relative risk for women in the highest quintile of this ratio as compared with those in the lowest quintile was 2.49 (95 percent confidence interval, 1.50 to 4.13). A low intake of fiber from fruits appeared to contribute to the risk of colon cancer, but this relation was not statistically independent of meat intake. These prospective data provide evidence for the hypothesis that a high intake of animal fat increases the risk of colon cancer, and they support existing recommendations to substitute fish and chicken for meats high in fat.


Time constants in thermal laser medicine.
Temperature rise of laser-irradiated tissue due to direct absorption of laser light is related to laser parameters (power, spot size, irradiation time, and repetition rate) and tissue parameters (absorption and scattering coefficients, density, heat capacity, and thermal conductivity). Solutions to the bio-heat equation are approximated by introducing axial (z) and radial (r) time constants for heat conduction that represent two parallel channels for heat conduction. These axial (tau z) and radial (tau r) time constants are found proportional to squared distances (z02, r02) that represent the extent of axial and radial temperatures respectively. For convenience, z0 and r0 are approximated to the axial and radial extent of laser light in the tissue. The resulting solution of the bio-heat equation, expressed as temperature rise as function of time and position, is obviously exact for irradiation times short compared to ta z, tau r (adiabatic heating), but is also a quite reasonable approximation up to irradiation times three times the overall time constant. Comparison with (exact) numerical computations show that this holds for all ratios of (light) penetration depth to laser-beam radius; for strongly scattering materials, smaller laser beams give better predictions than do larger laser beams. Several examples of clinical relevance are discussed, such as multiple-laser-pulse irradiation of high- and low-absorbing tissues and laser treatment of port-wine stains, with some unexpected results that also show potential clinical relevance.


Brief Strategic Therapy for Bulimia Nervosa and Binge Eating Disorder: A Clinical and Research Protocol.
Background: Although cognitive behavioral therapy is the gold standard treatments for bulimia nervosa (BN) and binge eating disorder (BED), evidence for its long-term efficacy is weak. Empirical research support the efficacy of brief strategic therapy (BST) in treating BN and BED symptoms, but its statistical significance still need to be investigated. Objective: To statistically test the long-term efficacy of the BST treatment protocols for BN and BED through one-year post-treatment. Methods: A two-group longitudinal study will be conducted. Participants will be sequentially recruited for inclusion in a state-funded community psychotherapy clinic. Multilevel growth curve modeling will be used to estimate the average growth trajectories from baseline to one year after treatment termination for the severity of the BN and BED features as measured by the Eating Disorder Examination Questionnaire. Discussion: Findings from this study will clarify the impact of BST in treating BN and BED symptoms. Conclusion: Translating research into practice may inform how to ensure high-quality patient care.


Diagnostics for Statistical Variable Selection Methods for Prediction of Peptic Ulcer Disease in Helicobacter pylori Infection.
The development of accurate classification models depends upon the methods used to identify the most relevant variables. The aim of this article is to evaluate variable selection methods to identify important variables in predicting a binary response using nonlinear statistical models. Our goals in model selection include producing non-overfitting stable models that are interpretable, that generate accurate predictions and have minimum bias. This work was motivated by data on clinical and laboratory features of Helicobacter pylori infections obtained from 60 individuals enrolled in a prospective observational study. We carried out a comprehensive performance comparison of several nonlinear classification models over the H. pylori data set. We compared variable selection results by Multivariate Adaptive Regression Splines (MARS), Logistic Regression with regularization, Generalized Additive Models (GAMs) and Bayesian Variable Selection in GAMs. We found that the MARS model approach has the highest predictive power because the nonlinearity assumptions of candidate predictors are strongly satisfied, a finding demonstrated via deviance chi-square testing procedures in GAMs. Our results suggest that the physiological free amino acids citrulline, histidine, lysine and arginine are the major features for predicting H. pylori peptic ulcer disease on the basis of amino acid profiling.


Fine structure in the solution state 13C-NMR spectrum of C60 and its endofullerene derivatives.
The 13C NMR spectrum of fullerene C60 in solution displays two small "side peaks" on the shielding side of the main 13C peak, with integrated intensities of 1.63% and 0.81% of the main peak. The two side peaks are shifted by -12.6 ppb and -20.0 ppb with respect to the main peak. The side peaks are also observed in the 13C NMR spectra of endofullerenes, but with slightly different shifts relative to the main peak. We ascribe the small additional peaks to minor isotopomers of C60 containing two adjacent 13C nuclei. The shifts of the additional peaks are due to a secondary isotope shift of the 13C resonance caused by the substitution of a 12C neighbour by 13C. Two peaks are observed since the C60 structure contains two different classes of carbon-carbon bonds with different vibrational characteristics. The 2 : 1 ratio of the side peak intensities is consistent with the known structure of C60. The origin and intensities of the 13C side peaks are discussed, together with an analysis of the 13C solution NMR spectrum of a 13C-enriched sample of C60, which displays a relatively broad 13C NMR peak due to a statistical distribution of 13C isotopes. The spectrum of 13C-enriched C60 is analyzed by a Monte Carlo simulation technique, using a theorem for the second moment of the NMR spectrum generated by J-coupled spin clusters.


Therapeutic Potential of Thymoquinone and Its Nanoformulations in Pulmonary Injury: A Comprehensive Review.
As a crucial organ, the lung is exposed to various harmful agents that may induce inflammation and oxidative stress, which may cause chronic or acute lung injury. Nigella sativa, also known as black seed, has been widely used to treat various diseases and is one of the most extensively researched medicinal plants. Thymoquinone (TQ) is the main component of black seed volatile oil and has been proven to have antioxidant, anti-inflammatory, and antineoplastic properties. The potential therapeutic properties of TQ against various pulmonary disorders have been studied in both in vitro and in vivo studies. Furthermore, the application of nanotechnology may increase drug solubility, cellular absorption, drug release (sustained or control), and drug delivery to lung tissue target sites. As a result, fabricating TQ as nanoparticles (NPs) is a potential therapeutic approach against a variety of lung diseases. In this current review, we summarize recent findings on the efficacy of TQ and its nanotypes in lung disorders caused by immunocompromised conditions such as cancer, diabetes, gastric ulcers, and other neurodegenerative diseases. It is concluded that TQ nanoparticles with anti-inflammatory, antioxidant, antiasthma, and antitumor activity may be safely applied to treat lung disorders. However, more research is required before TQ nanoparticles can be used as pharmaceutical preparations in human studies.


Genotoxicity and reactive oxygen species production induced by magnetite nanoparticles in mammalian cells.
We examined the genotoxicity of magnetite nanoparticles (primary particle size: 10 nm) on human A549 and Chinese hamster ovary (CHO) AA8 cells. Six hours' treatment with the particles dose-dependently increased the frequency of micronuclei (MN) in the A549 and CHO AA8 cells up to 5.2% and 5.0% at a dose of 200 µg/ml (34 µg/cm²), respectively. In A549 cells, treatment with the nano-particles (2 µg/ml) for 1 hr induced H2AX phosphorylation, which is suggestive of DNA double strand breaks (DSB). Treating CHO AA8 cells with 2 µg/ml (0.34 µg/cm²) magnetite for 1 hour resulted in a five times higher frequency of sister chromatid exchange (SCE) than the control level. We detected reactive oxygen species (ROS) in CHO cells treated with the particles. These findings indicate that magnetite nano-particles induce ROS in mammalian cells, leading to the direct or indirect induction of DSB, followed by clastogenic events including MN and SCE.


Determining professional nurses' knowledge on the performance management and development system in Tshwane.
The implementation of the Performance Management and Development System (PMDS) is seen as being vital to the quality of care, resource management and inter-professional work. However, there is evidence that, at present, professional nurses lack the knowledge to implement such a system. The aim of this study was to explore and describe professional nurses' knowledge regarding the implementation of the PMDS in selected primary healthcare clinics in Tshwane. A quantitative, descriptive, exploratory design was used and convenience sampling was used to recruit respondents. A self-administered structured questionnaire was used to collect data from 39 professional nurses who were involved in managing the work performance of employees. The data were analysed quantitatively with Statistical Analysis System version 8.2 software. The respondents had limited knowledge about the implementation of the performance management and development system. There is a need for educational initiatives before, during and after the implementation of the PMDS, such as quarterly PMDS workshops and routine catch-up training. These would address the lack of knowledge of respondents as seen from the results.


Contraceptive Use over Five Years After Receipt Or Denial of Abortion Services.
Nonuse and inconsistent use of contraceptives contribute to a high incidence of unintended pregnancy and abortion among U.S. women. Little is known, however, about how these outcomes shape women's subsequent contraceptive use and unintended pregnancy risk. Contraceptive use was examined among 880 participants in the Turnaway Study, a five-year longitudinal study of women who sought abortions at 30 U.S. facilities in 2008-2010. Multivariable mixed-effects logistic and multinomial regression models assessed differences in use by whether women received the abortion; results were used to calculate predicted percentages of women using each method. The main groups of interest were 415 women who had an abortion at a gestation near their facility's limit and 160 who were denied abortion because they were beyond the limit, and who consequently gave birth. During each of the approximately five years of follow-up, the predicted percentage using any contraceptive method was 86% among women who had the abortion and 81% among those denied it. Over the entire period, the former women were more likely than the latter to use any method (odds ratio, 1.8). However, they were less likely to rely on female sterilization, rather than no method (risk ratio, 0.5), and more likely to use barrier methods (1.7) or short-acting reversible contraceptives (2.6). Women's elevated risk of unintended pregnancy after abortion is likely due at least partly to reliance on methods with relatively low effectiveness. Factors affecting contraceptive access postabortion, as well as individual characteristics such as fecundability, require research attention.