Balancing cognitive diversity and mutual understanding in multidisciplinary teams.
Interprofessional health care teams are increasingly utilized in health care organizations. Although there is support for their capacity to solve complex problems, there is also evidence that such teams are not always successful. In an effort to understand the capacity of interprofessional teams to innovate successfully, we investigate the role of cognitive diversity to establish whether and how knowledge differences lead to innovation. The aim of this study was to construct and investigate a model of team innovation predicted by cognitive diversity. In addition to investigating the direct impact of cognitive diversity in interprofessional health care teams, we develop a model incorporating mediated and moderated effects. In this study, we explore the role of debate as a mediating factor capable of explaining the impact of cognitive diversity on innovation. We further propose that the link between cognitive diversity and innovation through debate is contingent upon trans-specialist knowledge, knowledge shared by health care professionals, spanning specialist divides and enabling mutual understanding. The hypotheses were investigated using a cross-sectional, correlational design. Survey data received from 75 interprofessional teams employed in an acute care setting, representing a 36% response rate, were used to investigate our model. Analysis supports a significant relationship between cognitive diversity and debate, which is stronger when teams rate highly for trans-specialist knowledge. Results also support a positive relationship between debate and innovation and our full moderated mediated pathway. A range of strategies are indicated by our results to increase innovation in interprofessional teams. In particular, interventions such as interprofessional education and training, which have been shown to facilitate the development of shared language and meaning, are recommended by our findings.


Direct access to CD4+ T cells specific for defined antigens according to CD154 expression.
The direct assessment of T helper (T(H))-cell responses specific for antigens is essential to evaluate pathogenic and protective immunity. Presently, analysis and isolation of antigen-specific T(H) cells is restricted to cells that produce cytokines, or can be performed only with a rare selection of specific peptide major histocompatibility complex class II (MHC II) multimers. Here we report a new method that enables the assessment and isolation of T(H) cells specific for a defined antigen according to CD154 expression induced after stimulation in vitro. We show that antigen-induced CD154 expression is highly sensitive and specific for human and mouse antigen-specific T(H) cells. Moreover, the isolation of antigen-specific CD154(+) T(H) cells necessitates only surface staining with antibodies, thereby enabling the fast generation of antigen-specific T(H) cell lines. Our approach allows assessment of T(H) cells with a defined specificity for the combined quantitative and qualitative analysis of T(H)-cell immunity as well as for the isolation of specific T(H) cells for targeted cellular immunotherapies.


High-resolution mtDNA evidence for the late-glacial resettlement of Europe from an Iberian refugium.
The advent of complete mitochondrial DNA (mtDNA) sequence data has ushered in a new phase of human evolutionary studies. Even quite limited volumes of complete mtDNA sequence data can now be used to identify the critical polymorphisms that define sub-clades within an mtDNA haplogroup, providing a springboard for large-scale high-resolution screening of human mtDNAs. This strategy has in the past been applied to mtDNA haplogroup V, which represents <5% of European mtDNAs. Here we adopted a similar approach to haplogroup H, by far the most common European haplogroup, which at lower resolution displayed a rather uninformative frequency distribution within Europe. Using polymorphism information derived from the growing complete mtDNA sequence database, we sequenced 1580 base pairs of targeted coding-region segments of the mtDNA genome in 649 individuals harboring mtDNA haplogroup H from populations throughout Europe, the Caucasus, and the Near East. The enhanced genealogical resolution clearly shows that sub-clades of haplogroup H have highly distinctive geographical distributions. The patterns of frequency and diversity suggest that haplogroup H entered Europe from the Near East approximately 20,000-25,000 years ago, around the time of the Last Glacial Maximum (LGM), and some sub-clades re-expanded from an Iberian refugium when the glaciers retreated approximately 15,000 years ago. This shows that a large fraction of the maternal ancestry of modern Europeans traces back to the expansion of hunter-gatherer populations at the end of the last Ice Age.


Autosomal Dominant Retinal Dystrophy With Electronegative Waveform Associated With a Novel RAX2 Mutation.
The patients evaluated in this study, to our knowledge, represent the first complete clinical description of a family with an autosomal dominant inheritance pattern of retinal dystrophy associated with a novel mutation in RAX2. To clinically evaluate 4 patients and 5 unaffected family members, characterize the disease phenotype over time, and identify the associated genetic mutation. A prospective, longitudinal, observational, case-series analysis of 9 members of an affected family at the Casey Eye Institute, Oregon Health and Science University, Portland. The dates of the study were from July 31, 1992, to August 11, 2014. Clinical evaluations included eye examination, color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography, kinetic visual field testing, and electroretinography. Genetic mutation screening was performed with next-generation sequencing, and identified mutations were confirmed with Sanger sequencing. Clinical diagnosis and longitudinal characterization of retinal dystrophy and identification of genetic mutation. Six members of the family were identified as having retinal dystrophy (4 were examined, and 3 were genetically tested). Five unaffected family members were clinically evaluated (2 were genetically tested). The age at onset of retinal dystrophy was variable. All affected individuals presented with declining visual acuity, central scotomas, waxy disc pallor, attenuated vasculature, small yellow macular deposits and/or macular pigment mottling, and abnormal electroretinograms demonstrating mixed cone and rod dysfunction and a scotopic electronegative response to bright flashes. There were no other causes of an electronegative electroretinogram identified in any of the affected patients. Genetic testing revealed, to our knowledge, a novel frameshift heterozygous mutation in RAX2 in the patients with retinal dystrophy. A frameshift heterozygous mutation in RAX2 inherited in an autosomal dominant fashion was associated with mixed cone and rod dysfunction. Among the patients, there was variability in the age at onset and in the specific pattern of photoreceptor dysfunction, but the clinical course was nevertheless slowly progressive. Screening for RAX2 mutation could provide prognostic value for patients and families with scotopic electronegative responses to bright flashes.


IFNγ Induces DNA Methylation-Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer.
Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress proinflammatory diseases. GPR109A is the receptor for short-chain fatty acids. The functions of GPR109A have been the subject of extensive studies; however, the molecular mechanisms underlying GPR109A expression is largely unknown. We show that GPR109A is highly expressed in normal human colon tissues, but is silenced in human colon carcinoma cells. The GPR109A promoter DNA is methylated in human colon carcinoma. Strikingly, we observed that IFNγ, a cytokine secreted by activated T cells, activates GPR109A transcription without altering its promoter DNA methylation. Colon carcinoma grows significantly faster in IFNγ-deficient mice than in wild-type mice in an orthotopic colon cancer mouse model. A positive correlation was observed between GPR109A protein level and tumor-infiltrating T cells in human colon carcinoma specimens, and IFNγ expression level is higher in human colon carcinoma tissues than in normal colon tissues. We further demonstrated that IFNγ rapidly activates pSTAT1 that binds to the promoter of p300 to activate its transcription. p300 then binds to the GPR109A promoter to induce H3K18 hyperacetylation, resulting in chromatin remodeling in the methylated GPR109A promoter. The IFNγ-activated pSTAT1 then directly binds to the methylated but hyperacetylated GPR109 promoter to activate its transcription. Overall, our data indicate that GPR109A acts as a tumor suppressor in colon cancer, and the host immune system might use IFNγ to counteract DNA methylation-mediated GPR109A silencing as a mechanism to suppress tumor development.


The natural history of complete spinal cord injury: a pooled analysis of 1162 patients and a meta-analysis of modern data.
OBJECTIVE The natural history of complete spinal cord injury (SCI) is poorly studied. The classically quoted rate of improvement or conversion for patients with American Spinal Injury Association (ASIA) grade A (ASIA A) injuries is 15%-20%; however, data supporting this rate are very limited. In this paper, the authors conducted a meta-analysis of modern data reporting on ASIA A patients and evaluated factors affecting the natural history of the disease. METHODS The authors conducted a systematic literature review of all randomized clinical trials (RCTs) and observational studies of patients with traumatic SCI. The Embase, MEDLINE, PubMed, Scopus, CINAHL, and Cochrane databases were reviewed for all studies reporting on SCI and published after 1992. A meta-analysis was conducted using the DerSimonian and Laird (random-effects) model with a summary odds ratio analysis. RESULTS Eleven RCTs and 9 observational studies were included in the final analysis. Overall, the 20 included studies reported on 1162 patients with ASIA A injuries. The overall conversion rate was 28.1%, with 327 of 1162 patients improving to at least ASIA B. The overall rate of conversion noted in cervical spine injuries was 33.3%, whereas that in thoracic injuries was 30.6%. Patients undergoing early surgery had a higher rate of conversion (46.1%) than patients undergoing late surgery (25%) (OR 2.31, 95% CI 1.08-4.96, p = 0.03). CONCLUSIONS The overall rate of conversion of ASIA A SCIs from pooled data of prospective trials and observational series is 28.1%. This rate of conversion is higher than what is reported in the literature. Early surgery is predictive of a higher conversion rate. However, there are not enough data to provide conclusions pertaining to the efficacy of biological and medical therapies.


Conductance and geometry of pyridine-linked single-molecule junctions.
We have measured the conductance and characterized molecule-electrode binding geometries of four pyridine-terminated molecules by elongating and then compressing gold point contacts in a solution of molecules. We have found that all pyridine-terminated molecules exhibit bistable conductance signatures, signifying that the nature of the pyridine-gold bond allows two distinct conductance states that are accessed as the gold-molecule-gold junction is elongated. We have identified the low-conductance state as corresponding to a molecule fully stretched out between the gold electrodes, where the distance between contacts correlates with the length of the molecule; the high-conductance state is due to a molecule bound at an angle. For all molecules, we have found that the distribution of junction elongations in the low-conductance state is the same, while in the high-conductance state, the most likely elongation length increases linearly with molecule length. The results of first-principles conductance calculations for the four molecules in the low-conductance geometry agree well with the experimental results and show that the dominant conducting channel in the conjugated pyridine-linked molecules is through the pi* orbital.


Microgametophyte population sizes and plant reproductive output in the insect-pollinated Prunella grandiflora (Lamiaceae).
Intraspecific variation in pollen deposition and number of pollen tubes per style is rarely quantified, but is essential for assessing the occurrence of pollen limitation and pollen competition and their evolutionary implications. Moreover, pollen deposition, pollen tube growth, and the fate of fertilized ovules are rarely distinguished in field studies. Here we present such a study in eight natural populations of Prunella grandiflora. We quantified microgametophyte population sizes and inferred pollen limitation when the number of fertilizable ovules exceeded pollen tubes, and assessed seed set and fate after open pollination. Two and three populations had on average significantly fewer pollen grains and pollen tubes per flower, respectively, than the fixed number of fertilizable ovules per fruit, while one population experienced significant pollen competition. Style length was positively correlated with the number of pollen tubes. While pollen availability was very variable, seed abortion was significantly less frequent in denser populations, and in one population the proportion of well-developed seeds was significantly, positively correlated with the number of pollen tubes in the style. Less pollen deposition, lower numbers of pollen tubes reaching the base of the style, lower pollen quality and therefore increased abortion of fertilized ovules can all reduce seed set in natural P. grandiflora stands. Substantial intraspecific variability implies that microgametophyte competition also occurs in this species. Finally, style morphology may affect pollen receipt.


Researchers have found that legal cynicism is a significant predictor of crime. Although legal cynicism developed as a form of anomie, it is also plausible that legal cynicism is itself a deviant rationalization to justify one's criminal behavior. As such, legal cynicism might be a derivative manifestation of other individual-level constructs that bear on criminal propensity. We test this possibility by controlling for temperament traits related to antisocial behavior and psychopathic personality features in a sample of residentially incarcerated youth (N = 253). Results from negative binomial models revealed that legal cynicism was significantly associated with self-reported delinquency (including violence), but not total arrests. The significant associations with general delinquency and violence held even when controlling for sociodemographic characteristics. However, the associations were rendered either non-significant or greatly attenuated when we included temperament and psychopathy measures in the models. Overall, findings are convergent with the notion that legal cynicism is a consequence or product of antisocial traits and criminal propensity.


The Western South Atlantic Ocean in a High-CO2 World: Current Measurement Capabilities and Perspectives.
An international multi-disciplinary group of 24 researchers met to discuss ocean acidification (OA) during the Brazilian OA Network/Surface Ocean-Lower Atmosphere Study (BrOA/SOLAS) Workshop. Fifteen members of the BrOA Network (www.broa.furg.br) authored this review. The group concluded that identifying and evaluating the regional effects of OA is impossible without understanding the natural variability of seawater carbonate systems in marine ecosystems through a series of long-term observations. Here, we show that the western South Atlantic Ocean (WSAO) lacks appropriate observations for determining regional OA effects, including the effects of OA on key sensitive Brazilian ecosystems in this area. The impacts of OA likely affect marine life in coastal and oceanic ecosystems, with further social and economic consequences for Brazil and neighboring countries. Thus, we present (i) the diversity of coastal and open ocean ecosystems in the WSAO and emphasize their roles in the marine carbon cycle and biodiversity and their vulnerabilities to OA effects; (ii) ongoing observational, experimental, and modeling efforts that investigate OA in the WSAO; and (iii) highlights of the knowledge gaps, infrastructure deficiencies, and OA-related issues in the WSAO. Finally, this review outlines long-term actions that should be taken to manage marine ecosystems in this vast and unexplored ocean region.


Nutritional quality of complementary food prepared from unmalted and malted maize fortified with cowpea using extrusion cooking.
The nutritional quality of extruded unmalted or malted maize fortified with cowpea as complementary food was assessed based on its proximate analysis, amino acid composition and results from rat feeding with the blends. Results indicated a slight decrease and increase in protein content due to malting and extrusion respectively. The changes in fat, crude fibre and ash content were not significant. The blends were a good source of energy, ranging from 1831 to 2045 kJ per 100 g. Extrusion significantly increased the amino acid content of the blends, while malting had a varied effect on each of the amino acids. There was no significant difference in the protein efficiency ratio (PER), net protein ratio (NPR) and weight gain of rats fed the blends when compared with the control (casein diet). The present study shows that malting improved the nutritional quality of the blends. Rats fed the casein diet had higher values for total digestibility (TD) and net protein utilisation (NPU). There was no significant difference (P > 0.05) in the internal organ weights of rats fed all blends except the protein-free diet. © 2000 Society of Chemical Industry.


Molecular mimicry regulates ABA signaling by SnRK2 kinases and PP2C phosphatases.
Abscisic acid (ABA) is an essential hormone for plants to survive environmental stresses. At the center of the ABA signaling network is a subfamily of type 2C protein phosphatases (PP2Cs), which form exclusive interactions with ABA receptors and subfamily 2 Snfl-related kinase (SnRK2s). Here, we report a SnRK2-PP2C complex structure, which reveals marked similarity in PP2C recognition by SnRK2 and ABA receptors. In the complex, the kinase activation loop docks into the active site of PP2C, while the conserved ABA-sensing tryptophan of PP2C inserts into the kinase catalytic cleft, thus mimicking receptor-PP2C interactions. These structural results provide a simple mechanism that directly couples ABA binding to SnRK2 kinase activation and highlight a new paradigm of kinase-phosphatase regulation through mutual packing of their catalytic sites.


Combining freshly isolated chondroprogenitor cells from the infrapatellar fat pad with a growth factor delivery hydrogel as a putative single stage therapy for articular cartilage repair.
Growth factor delivery systems incorporating chondroprogenitor cells are an attractive potential treatment option for damaged cartilage. The rapid isolation, processing, and implantation of therapeutically relevant numbers of autologous chondroprogenitor cells, all performed "in-theatre" during a single surgical procedure, would significantly accelerate the clinical translation of such tissue engineered implants by avoiding the time, financial and regulatory challenges associated with in vitro cell expansion, and differentiation. The first objective of this study was to explore if rapid adherence to a specific substrate could be used as a simple means to quickly identify a subpopulation of chondroprogenitor cells from freshly digested infrapatellar fat pad (IFP) tissue. Adhesion of cells to tissue culture plastic within 30 min was examined as a mechanism of isolating subpopulations of cells from the freshly digested IFP. CD90, a cell surface marker associated with cell adhesion, was found to be more highly expressed in rapidly adhering cells (termed "RA" cells) compared to those that did not adhere (termed "NA" cells) in this timeframe. The NA subpopulation contained a lower number of colony forming cells, but overall had a greater chondrogenic potential but a diminished osteogenic potential compared to the RA subpopulation and unmanipulated freshly isolated (FI) control cells. When cultured in agarose hydrogels, NA cells proliferated faster than RA cells, accumulating significantly higher amounts of total sGAG and collagen. Finally, we sought to determine if cartilage tissue could be engineered by seeding such FI cells into a transforming growth factor-β3 delivery hydrogel. In such a system, both RA and NA cell populations demonstrated an ability to proliferate and produced a matrix rich in sGAG (∼2% w/w) that stained positively for type II collagen; however, the tissues were comparable to that generated using FI cells. Therefore, while the results of these in vitro studies do not provide strong evidence to support the use of selective substrate adhesion as a means to isolate chondroprogenitor cells, the findings demonstrate the potential of combining a growth factor delivery hydrogel and FI IFP cells as a single stage therapy for cartilage defect repair.


Crystal structures of pheasant and guinea fowl egg-white lysozymes.
The crystal structures of pheasant and guinea fowl lysozymes have been determined by X-ray diffraction methods. Guinea fowl lysozyme crystallizes in space group P6(1)22 with cell dimensions a = 89.2 A and c = 61.7 A. The structure was refined to a final crystallographic R-factor of 17.0% for 8,854 observed reflections in the resolution range 6-1.9 A. Crystals of pheasant lysozyme are tetragonal, space group P4(3)2(1)2, with a = 98.9 A, c = 69.3 A and 2 molecules in the asymmetric unit. The final R-factor is 17.8% to 2.1 A resolution. The RMS deviation from ideality is 0.010 A for bond lengths and 2.5 degrees for bond angles in both models. Three amino acid positions beneath the active site are occupied by Thr 40, Ile 55, and Ser 91 in hen, pheasant, and other avian lysozymes, and by Ser 40, Val 55, and Thr 91 in guinea fowl and American quail lysozymes. In spite of their internal location, the structural changes associated with these substitutions are small. The pheasant enzyme has an additional N-terminal glycine residue, probably resulting from an evolutionary shift in the site of cleavage of prelysozyme. In the 3-dimensional structure, this amino acid partially fills a cleft on the surface of the molecule, close to the C alpha atom of Gly 41 and absent in lysozymes from other species (which have a large side-chain residue at position 41: Gln, His, Arg, or Lys). The overall structures are similar to those of other c-type lysozymes, with the largest deviations occurring in surface loops. Comparison of the unliganded and antibody-bound models of pheasant lysozyme suggests that surface complementarity of contacting surfaces in the antigen-antibody complex is the result of local, small rearrangements in the epitope. Structural evidence based upon this and other complexes supports the notion that antigenic variation in c-type lysozymes is primarily the result of amino acid substitutions, not of gross structural changes.


Comparing Biofeedback Types for Children With Residual /ɹ/ Errors in American English: A Single-Case Randomization Design.
Purpose Research comparing different biofeedback types could lead to individualized treatments for those with residual speech errors. This study examines within-treatment response to ultrasound and visual-acoustic biofeedback, as well as generalization to untrained words, for errors affecting the American English rhotic /ɹ/. We investigated whether some children demonstrated greater improvement in /ɹ/ during ultrasound or visual-acoustic biofeedback. Each participant received both biofeedback types. Individual predictors of treatment response (i.e., age, auditory-perceptual skill, oral somatosensory skill, and growth mindset) were also explored. Method Seven children ages 9-16 years with residual rhotic errors participated in 10 treatment visits. Each visit consisted of two conditions: 45 min of ultrasound biofeedback and 45 min of visual-acoustic biofeedback. The order of biofeedback conditions was randomized within a single-case experimental design. Acquisition of /ɹ/ was evaluated through acoustic measurements (normalized F3-F2 difference) of selected nonbiofeedback productions during practice. Generalization of /ɹ/ was evaluated through acoustic measurements and perceptual ratings of pretreatment/posttreatment probes. Results Five participants demonstrated acquisition of practiced words during the combined treatment package. Three participants demonstrated a clinically significant degree of generalization to untreated words on posttreatment probes. Randomization tests indicated one participant demonstrated a significant advantage for visual-acoustic over ultrasound biofeedback. Participants' auditory-perceptual acuity on an /ɹ/-/w/ identification task was identified as a possible correlate of generalization following treatment. Conclusions Most participants did not demonstrate a statistically significant difference in acoustic productions between the ultrasound and visual-acoustic conditions, but one participant showed greater improvement in /ɹ/ during visual-acoustic biofeedback. Supplemental Material https://doi.org/10.23641/asha.14881101.


Contribution of the NH2 terminus of Kv2.1 to channel activation.
Opening and closing of voltage-operated channels requires the interaction of diverse structural elements. One approach to the identification of channel domains that participate in gating is to locate the sites of action of modifiers. Covalent reaction of Kv2.1 channels with the neutral, sulfhydryl-specific methylmethanethiosulfonate (MMTS) caused a slowing of channel gating with a predominant effect on the kinetics of activation. These effects were also obtained after intracellular, but not extracellular, application of a charged MMTS analog. Single channel analysis revealed that MMTS acted primarily by prolonging the latency to first opening without substantially affecting gating transitions after the channel first opens and until it inactivates. To localize the channel cysteine(s) with which MMTS reacts, we generated NH2- and COOH-terminal deletion mutants and a construct in which all three cysteines in transmembrane regions were substituted. Only the NH2-terminal deletion construct gave rise to currents that activated slowly and displayed MMTS-insensitive kinetics. These results show that the NH2-terminal tail of Kv2.1 participates in transitions leading to activation through interactions involving reduced cysteine(s) that can be modulated from the cytoplasmic phase.


Drivers and strategies for avoiding overuse. A cross-sectional study to explore the experience of Spanish primary care providers handling uncertainty and patients' requests.
Identify the sources of overuse from the point of view of the Spanish primary care professionals, and analyse the frequency of overuse due to pressure from patients in addition to the responses when professionals face these demands. A cross-sectional study. Primary care in Spain. A non-randomised sample of 2201 providers (general practitioners, paediatricians and nurses) was recruited during the survey. The frequency, causes and responsibility for overuse, the frequency that patients demand unnecessary tests or procedures, the profile of the most demanding patients, and arguments for dissuading the patient. In all, 936 general practitioners, 682 paediatricians and 286 nurses replied (response rate 18.6%). Patient requests (67%) and defensive medicine (40%) were the most cited causes of overuse. Five hundred and twenty-two (27%) received requests from their patients almost every day for unnecessary tests or procedures, and 132 (7%) recognised granting the requests. The lack of time in consultation, and information about new medical advances and treatments that patients could find on printed and digital media, contributed to the professional's inability to adequately counter this pressure by patients. Clinical safety (49.9%) and evidence (39.4%) were the arguments that dissuaded patients from their requests the most. Cost savings was not a convincing argument (6.8%), above all for paediatricians (4.3%). General practitioners resisted more pressure from their patients (x2=88.8, P<0.001, percentage difference (PD)=17.0), while nurses admitted to carrying out more unnecessary procedures (x2=175.7, P<0.001, PD=12.3). Satisfying the patient and patient uncertainty about what should be done and defensive medicine practices explains some of the frequent causes of overuse. Safety arguments are useful to dissuade patients from their requests.


Dynamics of Onchocerca volvulus microfilarial densities after ivermectin treatment in an ivermectin-naïve and a multiply treated population from Cameroon.
Ivermectin has been the keystone of onchocerciasis control for the last 25 years. Sub-optimal responses to the drug have been reported in Ghanaian communities under long-term treatment. We assessed, in two Cameroonian foci, whether the microfilaricidal and/or embryostatic effects of ivermectin on Onchocerca volvulus have been altered after several years of drug pressure. We compared the dynamics of O. volvulus skin microfilarial densities after ivermectin treatment in two cohorts with contrasting exposure to this drug: one received repeated treatment for 13 years whereas the other had no history of large-scale treatments (referred to as controls). Microfilarial densities were assessed 15, 80 and 180 days after ivermectin in 122 multiply treated and 127 ivermectin-naïve individuals. Comparisons were adjusted for individual factors related to microfilarial density: age and number of nodules. Two weeks post ivermectin, microfilarial density dropped equally (98% reduction) in the ivermectin-naïve and multiply treated groups. Between 15 and 180 days post ivermectin, the proportion of individuals with skin microfilariae doubled (from 30.8% to 67.8%) in controls and quadrupled (from 19.8% to 76.9%) in multiply treated individuals but the mean densities remained low in both sites. In fact, between 15 and 80 days, the repopulation rate was significantly higher in the multiply treated individuals than in the controls but no such difference was demonstrated when extending the follow-up to 180 days. The repopulation rate by microfilariae was associated with host factors: negatively with age and positively with the number of nodules. These observations may indicate that the worms from the multi-treated area recover mf productivity earlier but would be less productive than the worms from the ivermectin-naïve area between 80 and 180 days after ivermectin. Moreover, they do not support the operation of a strong cumulative effect of repeated treatments on the fecundity of female worms as previously described.


Anthocyanins and Flavanones Are More Bioavailable than Previously Perceived: A Review of Recent Evidence.
This review considers recent investigations on the bioavailability of anthocyanins and flavanones. Both flavonoids are significant dietary components and are considered to be poorly bioavailable, as only low levels of phase II metabolites appear in the circulatory system and are excreted in urine. However, when lower molecular weight phenolic and aromatic ring-fission catabolites, produced primarily by the action of the colonic microbiota, are taken into account, it is evident that anthocyanins and flavanones are much more bioavailable than previously envisaged. The metabolic events to which these flavonoids are subjected as they pass along the gastrointestinal tract and are absorbed into the circulatory system prior to their rapid elimination by renal excretion are highlighted. Studies on the impact of other food components and the probiotic intake on flavonoid bioavailability are summarized, as is the bioactivity of metabolites and catabolites assayed using a variety of in vitro model systems.


Stimulation in hippocampal region CA1 in behaving rats yields long-term potentiation when delivered to the peak of theta and long-term depression when delivered to the trough.
Experimental evidence suggests that the hippocampal theta rhythm plays a critical role in learning. Previous studies have shown long-term potentiation (LTP) to be preferentially induced with stimulation on the peak of local theta rhythm in region CA1 in anesthetized rats and with stimulation of the perforant path at the peak of theta in both anesthetized and behaving animals. We set out to determine the effects of tetanic burst stimulation in stratum radiatum of region CA1 in awake behaving animals, delivered during either the peak or the trough of the theta rhythm in the EEG. Bursts delivered to the peak resulted in an increase of 17.9 +/- 0.94% in potential slope. When identical stimulation bursts were delivered to the trough of local theta waves, the potential slope decreased 12.9 +/- 1.03%. This is the first report of LTP being preferentially induced at the peak of local theta rhythm in behaving animals in region CA1 and that LTD was found in response to tetanic stimulation at the trough of the local theta wave. The results are discussed within the framework of a recent theory that proposes that the theta rhythm sets the dynamics for alternating phases of encoding and retrieval (Hasselmo et al., 20021).


A simple and robust method to extend the dynamic range of an aberrometer.
We present an algorithm to extend significantly the dynamic range of a Shack-Hartmann wavefront sensor. With this method, the recorded Shack-Hartmann spots are not constrained to stay in the field of view of their lenslet. The proposed algorithm is computationally effective, robust to a high level of noise on the measured centroid positions and also to missing centroid values. The principle is closely related to the description of wavefronts using Zernike polynomials, which makes optimization for a given sensor and application achievable thanks to numerical simulation. These features make it useful for the measurements of highly aberrated eyes.


Thrombotic Microangiopathy: An Under-Recognised Cause of Snake-bite-related Acute Kidney Injury.
Thrombotic microangiopathy (TMA) as a cause of snake-bite-induced acute kidney injury (AKI) is rarely reported. Very little is known about the clinical course, optimal management, and prognosis of this entity. We describe a series of snake-bite-induced TMA and compare their outcomes with those without TMA. This was a single-center retrospective study of patients with AKI following snake envenomation admitted between January 2012 and December 2017. Demographic profile, clinical parameters, and outcomes were studied. TMA was diagnosed based on presence of triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI, and groups with and without TMA were compared. Of 103 patients with AKI following snake bite, 19 (18.5%) had clinical evidence of TMA. All patients with TMA had advanced azotemia (mean peak serum creatinine 9.5 ± 3.0 mg/dL), with 18 (95%) requiring renal replacement therapy (RRT). Thirteen (68%) had either complete or partial recovery of renal functions, two (10%) progressed to end-stage renal disease, and one died (three patients were lost to follow-up). Age ≥50 years, presence of oliguria/anuria, anti-snake venom dose ≥10 vials, and urea ≥80 mg/dL at presentation were independently associated with TMA (P < 0.05). RRT requirement (95% vs. 57%), mean number of RRT sessions (18 vs. 4.5 sessions), and hospital stay ≥7 days (84% vs. 58%) were higher in patients with TMA (P < 0.05), but patient outcomes did not differ. In conclusion, TMA was seen in 18.5% of patients with snake-bite-related AKI in our study and was associated with almost universal need for RRT, longer duration on RRT, and hospital stay compared with patients without TMA.


Silica nanoparticles induce oxidative stress, inflammation, and endothelial dysfunction in vitro via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling.
Despite the widespread application of silica nanoparticles (SiNPs) in industrial, commercial, and biomedical fields, their response to human cells has not been fully elucidated. Overall, little is known about the toxicological effects of SiNPs on the cardiovascular system. In this study, SiNPs with a 58 nm diameter were used to study their interaction with human umbilical vein endothelial cells (HUVECs). Dose- and time-dependent decrease in cell viability and damage on cell plasma-membrane integrity showed the cytotoxic potential of the SiNPs. SiNPs were found to induce oxidative stress, as evidenced by the significant elevation of reactive oxygen species generation and malondialdehyde production and downregulated activity in glutathione peroxidase. SiNPs also stimulated release of cytoprotective nitric oxide (NO) and upregulated inducible nitric oxide synthase (NOS) messenger ribonucleic acid, while downregulating endothelial NOS and ET-1 messenger ribonucleic acid, suggesting that SiNPs disturbed the NO/NOS system. SiNP-induced oxidative stress and NO/NOS imbalance resulted in endothelial dysfunction. SiNPs induced inflammation characterized by the upregulation of key inflammatory mediators, including IL-1β, IL-6, IL-8, TNFα, ICAM-1, VCAM-1, and MCP-1. In addition, SiNPs triggered the activation of the Nrf2-mediated antioxidant system, as evidenced by the induction of nuclear factor-κB and MAPK pathway activation. Our findings demonstrated that SiNPs could induce oxidative stress, inflammation, and NO/NOS system imbalance, and eventually lead to endothelial dysfunction via activation of the MAPK/Nrf2 pathway and nuclear factor-κB signaling. This study indicated a potential deleterious effect of SiNPs on the vascular endothelium, which warrants more careful assessment of SiNPs before their application.


The Fabrication, Implantation, and Stability of Intraspinal Microwire Arrays in the Spinal Cord of Cat and Rat.
Intraspinal microstimulation (ISMS) is currently under investigation for its ability to restore function following spinal cord injury and aid in addressing basic investigations of the spinal cord in feline and murine (rat) models. In this report we describe the procedures for fabricating and implanting intraspinal microwires, with special emphasis on the rat model. We also report our results on targeting success and long-term stability and functionality of the implants. Early targeting with implants fabricated based on general "average" dimensions of the spinal cord was approximately 50% successful in reaching the proper targets within the ventral grey matter in cats. Improvements in insertion technique and the use of multiple contact electrodes have raised the targeting success to 100%. Furthermore, the manufacturing of ISMS arrays has been improved by the use of magnetic resonance imaging to create subject-specific implants for cats and track the location of the arrays post-implant. In the rat, our procedures have produced desirable targeting of all recovered microwires. We speculate this is due to the different targeting parameters and the shorter depth of insertion in the rat spinal cord. Although there is a heightened mechanical mismatch between the 30 μm -diameter microwires and the small rat spinal cord, chronic implantation and stimulation produce limited histological damage and do not compromise function. Furthermore, despite the increased difficulties of implanting into the smaller rat spinal cord, ISMS is effective in activating spinal cord networks in the lumbosacral enlargement in a manner that is safe, stable and reproducible.


Cost comparison of robot-assisted and laparoscopic pyeloplasty.
Laparoscopic repair of ureteropelvic junction obstruction is now the standard of care at many institutions. The objective of this study is to compare costs associated with robot-assisted pyeloplasty (RP) vs laparoscopic pyeloplasty (LP). A decision analysis model was developed to compare costs of each procedure based on hospital-related cost centers. A literature search was performed to identify nonoverlapping studies with outcomes for RP and LP. Weighted means were calculated for operative time and length of stay. Cost data were obtained from our institution. One- and two-way sensitivity analyses were performed to evaluate the effect of changing variables on the cost-effectiveness of RP. Eight studies were identified with 181 and 145 patients undergoing RP or LP, respectively. Operative times were 211 minutes for RP and 224 minutes for LP. Hospital stays were shorter for RP at 1.54 days compared with 1.98 days for LP. Mean direct costs were higher for RP at $10,635 vs $9,065 for LP. The largest difference was in fixed surgical supply costs per case at $1357 for RP and $406 for LP. One-way sensitivity analysis showed that RP would be cost effective if performed in less than 96 minutes. Even if RP was performed on an outpatient basis or more than 1000 cases/year, however, LP would still be cost superior. Two-way analyses showed areas where RP could be more cost-effective than LP. RP is associated with higher cost compared with LP, predominately because of the cost of the robot and surgical supply costs. Decreasing operative time and equipment costs may result in RP being more cost-effective than LP. Shorter hospital stay alone, however, is insufficient to allow RP to be cost-effective. One would need to demonstrate tangible advantages to the robot to justify the added costs.


Systematic review of the relation between smokeless tobacco and cancer in Europe and North America.
Interest is rising in smokeless tobacco as a safer alternative to smoking, but published reviews on smokeless tobacco and cancer are limited. We review North American and European studies and compare effects of smokeless tobacco and smoking. We obtained papers from MEDLINE searches, published reviews and secondary references describing epidemiological cohort and case-control studies relating any form of cancer to smokeless tobacco use. For each study, details were abstracted on design, smokeless tobacco exposure, cancers studied, analysis methods and adjustment for smoking and other factors. For each cancer, relative risks or odds ratios with 95% confidence intervals were tabulated. Overall, and also for USA and Scandinavia separately, meta-analyses were conducted using all available estimates, smoking-adjusted estimates, or estimates for never smokers. For seven cancers, smoking-attributable deaths in US men in 2005 were compared with deaths attributable to introducing smokeless tobacco into a population of never-smoking men. Eighty-nine studies were identified; 62 US and 18 Scandinavian. Forty-six (52%) controlled for smoking. Random-effects meta-analysis estimates for most sites showed little association. Smoking-adjusted estimates were only significant for oropharyngeal cancer (1.36, CI 1.04-1.77, n = 19) and prostate cancer (1.29, 1.07-1.55, n = 4). The oropharyngeal association disappeared for estimates published since 1990 (1.00, 0.83-1.20, n = 14), for Scandinavia (0.97, 0.68-1.37, n = 7), and for alcohol-adjusted estimates (1.07, 0.84-1.37, n = 10). Any effect of current US products or Scandinavian snuff seems very limited. The prostate cancer data are inadequate for a clear conclusion.Some meta-analyses suggest a possible effect for oesophagus, pancreas, larynx and kidney cancer, but other cancers show no effect of smokeless tobacco. Any possible effects are not evident in Scandinavia. Of 142,205 smoking-related male US cancer deaths in 2005, 104,737 are smoking-attributable. Smokeless tobacco-attributable deaths would be 1,102 (1.1%) if as many used smokeless tobacco as had smoked, and 2,081 (2.0%) if everyone used smokeless tobacco. An increased risk of oropharyngeal cancer is evident most clearly for past smokeless tobacco use in the USA, but not for Scandinavian snuff. Effects of smokeless tobacco use on other cancers are not clearly demonstrated. Risk from modern products is much less than for smoking.


Occult Talaromyces marneffei Infection Unveiled by the Novel Mp1p Antigen Detection Assay.
Talaromyces marneffei causes fatal invasive mycosis in Southeast Asia. Diagnosis by culture has limited sensitivity and can result in treatment delay. We describe the use of a novel Mp1p enzyme immunoassay (EIA) to identify blood culture-negative talaromycosis, subsequently confirmed by bone marrow cultures. This EIA has the potential to speed diagnosis, enabling early therapy initiation.


The Effect of Maternal Milk on Tolerance and Growth in Premature Infants: A Hypothesis-generating Study.
Early growth rates and feeding advancement rates of preterm infants are thought to influence later health. Feeding advancement is often difficult because of feeding intolerance. Exclusive human milk feeding improves tolerance, but can result in a lower weight gain rate. The addition of human milk fortifier has advantages for growth, but there are concerns that it may nullify the beneficial effect of human milk on tolerance. Therefore, the objective of the present study was to evaluate the relation between the amount of fortified human milk or formula and feeding tolerance and growth in preterm infants. Patients (n = 174) participating in the TOL trial and born with a gestational age 30 weeks or younger were divided into tertiles according to the amount of human milk received during feeding advancement. Data on feeding tolerance during the advancement phase of enteral nutrition and anthropometrics were analysed. The infants (n = 59) receiving the lowest percentage of their enteral intake as human milk (0%-57%) had the lowest amount of gastric residuals (P = 0.034) compared with the other 2 tertiles. Time to reach full enteral feeding and other tolerance parameters were not different among the groups. There was no dose response effect of the amount of human milk consumed on growth. In preterm infants, an association between type of feeding (human milk vs infant formula) and time to achieve full enteral feeding or short-term growth was not found. Future prospective trials are needed to verify our results and focus on means to improve tolerance further.


Running interference for hedgehog signaling.
The new technology of RNA interference (RNAi) is allowing high-throughput screening of cells to examine many biological processes. Michelson discusses one such system in which the Drosophila Hedgehog (Hh) pathway was analyzed by systematic genome-wide RNAi analysis. The results not only suggest unexpected overlap in the Hh and Wingless (Wg) pathways, but also provide proof of principle for the development of high-throughput assays using RNAi techniques.


The Cytokinin Complex Associated With Rhodococcus fascians: Which Compounds Are Critical for Virulence?
Virulent strains of Rhodococcus fascians cause a range of disease symptoms, many of which can be mimicked by application of cytokinin. Both virulent and avirulent strains produce a complex of cytokinins, most of which can be derived from tRNA degradation. To test the three current hypotheses regarding the involvement of cytokinins as virulence determinants, we used PCR to detect specific genes, previously associated with a linear virulence plasmid, including two methyl transferase genes (mt1 and mt2) and fas4 (dimethyl transferase), of multiple strains of R. fascians. We inoculated Pisum sativum (pea) seeds with virulent and avirulent strains of R. fascians, monitored the plants over time and compared these to mock-inoculated controls. We used RT-qPCR to monitor the expression of mt1, mt2, and fas4 in inoculated tissues and LC-MS/MS to obtain a comprehensive picture of the cytokinin complement of inoculated cotyledons, roots and shoots over time. The presence and expression of mt1 and mt2 was associated with those strains of R. fascians classed as virulent, and not those classed as avirulent. Expression of mt1, mt2, and fas4 peaked at 9 days post-inoculation (dpi) in cotyledons and at 15 dpi in shoots and roots developed from seeds inoculated with virulent strain 602. Pea plants inoculated with virulent and avirulent strains of R. fascians both contained cytokinins likely to have been derived from tRNA turnover including the 2-methylthio cytokinins and cis-zeatin-derivatives. Along with the isopentenyladenine-type cytokinins, the levels of these compounds did not correlate with virulence. Only the novel 1- and 2-methylated isopentenyladenine cytokinins were uniquely associated with infection by the virulent strains and are, therefore, the likely causative factors of the disease symptoms.


Genome-wide analysis of self-reported risk-taking behaviour and cross-disorder genetic correlations in the UK Biobank cohort.
Risk-taking behaviour is a key component of several psychiatric disorders and could influence lifestyle choices such as smoking, alcohol use, and diet. As a phenotype, risk-taking behaviour therefore fits within a Research Domain Criteria (RDoC) approach, whereby identifying genetic determinants of this trait has the potential to improve our understanding across different psychiatric disorders. Here we report a genome-wide association study in 116,255 UK Biobank participants who responded yes/no to the question "Would you consider yourself a risk taker?" Risk takers (compared with controls) were more likely to be men, smokers, and have a history of psychiatric disorder. Genetic loci associated with risk-taking behaviour were identified on chromosomes 3 (rs13084531) and 6 (rs9379971). The effects of both lead SNPs were comparable between men and women. The chromosome 3 locus highlights CADM2, previously implicated in cognitive and executive functions, but the chromosome 6 locus is challenging to interpret due to the complexity of the HLA region. Risk-taking behaviour shared significant genetic risk with schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, and post-traumatic stress disorder, as well as with smoking and total obesity. Despite being based on only a single question, this study furthers our understanding of the biology of risk-taking behaviour, a trait that has a major impact on a range of common physical and mental health disorders.


Poisson distribution of male mating success in laboratory populations of Drosophila melanogaster.
Variation among males and females in reproductive success is a major determinant of effective population size. Most studies of male mating success in Drosophila, however, have been done under conditions very different from those in typical cultures. We determined the distribution of male mating success in five laboratory populations of D. melanogaster maintained on a 14 d, discrete generation cycle fairly representative of standard Drosophila cultures. Mating success was measured as the number of matings a male could achieve under conditions closely approximating a regular culture vial of these populations. Preliminary studies determined that most mating in these populations occurred within 14 h of the flies attaining sexual maturity. Consequently, individual virgin males were marked with white paint on their thorax, put into vials with varying numbers of unmarked virgin flies of both sexes, and monitored continuously for matings over a period of up to 14 h. At various times during the assay, virgin males and females were added to these vials in proportions simulating the pattern of eclosion in culture vials. The observed variation in the number of matings per male in the five populations was, by and large, consistent with a Poisson distribution, suggesting that male mating success in short-generation-time, discrete-generation laboratory cultures of D. melanogaster may fulfil a fundamental assumption of the Wright-Fisher model of genetic drift in finite populations.


Prevalence, awareness, control and determinants of hypertension among primary health care professional nurses in Eastern Cape, South Africa.
Nurses in primary health care settings are key stakeholders in the diagnosis and management of hypertensive patients. Unfortunately, the working conditions of nurses predispose them to stress, long hours of work, shift duties and unhealthy diets, which are drivers of hypertension. Yet nurses are often overlooked in health screening exercises, primarily because they are assumed to be informed and 'healthy'. This study examined the prevalence, awareness, control and determinants of hypertension among professional primary health care nurses in the Eastern Cape Province of South Africa. This was a cross-sectional survey of 203 professional nurses working at 41 primary health care facilities of the Eastern Cape Province. A modified WHO STEPwise questionnaire was used for data collection during face-to-face interviews. The information obtained included demographic information, behavioural lifestyles, anthropometric and blood pressure (BP) measurements. Hypertension is defined as an average of two BP ≥ 140/90 mmHg or self-reported history of antihypertensive medication use. The prevalence of hypertension was 52%. Of this, 41% were unaware of their hypertension status. Of those who were aware and on treatment, only 38.1% had a controlled blood pressure. After adjusting for confounders (for physical activity, dietary practices, parity, income and alcohol use), only age and duration of practice were independent predictors of hypertension among the study population. There is a high prevalence of hypertension among the study participants. There is an unexpected low rate of awareness and suboptimal control of blood pressure among the participants. Age is the significant predictor of hypertension among professional nurses in Eastern Cape Province, South Africa. There is an urgent need for the implementation of an effective workplace health programme for nurses in the province.


Effects of intranasal and peripheral oxytocin or gastrin-releasing peptide administration on social interaction and corticosterone levels in rats.
The intranasal route of drug administration has gained increased popularity as it is thought to allow large molecules, such as peptide hormones, more direct access to the brain, while limiting systemic exposure. Several studies have investigated the effects of intranasal oxytocin administration in humans as this peptide is associated with prosocial behavior. There are, however, few preclinical studies investigating the effects of intranasal oxytocin administration in rodents. Oxytocin modulates hypothalamic-pituitary-adrenal (HPA) axis functioning and it has been suggested that oxytocin's ability to increase sociability may occur through a reduction in stress reactivity. Another peptide that appears to influence both social behavior and HPA axis activity is gastrin-releasing peptide (GRP), but it is not known if these GRP-induced effects are related. With this in mind, in the present study, we assessed the effects of intranasal and intraperitoneal oxytocin and GRP administration on social interaction and release of corticosterone in rats. Intranasal and intraperitoneal administration of 20, but not 5 μg, of oxytocin significantly increased social interaction, whereas intranasal and peripheral administration of GRP (20 but not 5 μg) significantly decreased levels of social interaction. In addition, while intranasal oxytocin (20 μg) had no effect on blood corticosterone levels, a marked increase in blood corticosterone levels was observed following intraperitoneal oxytocin administration. With GRP, intranasal (20 μg) but not peripheral administration increased corticosterone levels. These findings provide further evidence that intranasal peptide delivery can induce behavioral alterations in rodents which is consistent with findings from human studies. In addition, the peptide-induced changes in social interaction were not linked to fluctuations in corticosterone levels.


Immunoperoxidase staining for identification of Aspergillus species in routinely processed tissue sections.
To evaluate the performance of an immunoperoxidase stain using the monoclonal antibody EB-A1 to detect Aspergillus species in formalin fixed, paraffin wax embedded tissue. The monoclonal antibody EB-A1 directed against galactomannan was used to detect Aspergillus species in 23 patients with suspected or confirmed invasive aspergillosis. Immunostaining was performed on formalin fixed, paraffin wax embedded tissue using the streptavidin-biotin method and compared with conventional haematoxylin and eosin, periodic acid-Schiff, and Gomori-Grocott stains. Results of immunostaining were semiquantitatively analysed with regard to both intensity of staining and number of positively staining micro-organisms. Tissue sections from 16 patients with confirmed invasive mycoses due to Candida species, Apophysomyces elegans, Rhizopus oryzae, Pseudallescheria boydii and Histoplasma capsulatum were used as controls. In 19 (83%) of 23 cases invasive aspergillosis was confirmed by both histological examination and culture (18 Aspergillus fumigatus and one A flavus). Immunoperoxidase stains were positive in 17 (89%) of 19 cases including one case of disseminated infection due to A flavus. Furthermore, the immunoperoxidase stain was positive in a culture negative tissue section with histological evidence of mycelial development, indicating the presence of Aspergillus species. Some cross-reactivity was observed with the highly related fungus P boydii, although the number of mycelial elements that stained was low. Immunoperoxidase staining using the monoclonal antibody EB-A1 performs well on routinely processed tissue sections and permits detection and generic identification of Aspergillus species, although it was no better than conventional histopathology in identifying the presence of an infection. An additional advantage is that the immunostain may help to provide an aetiological diagnosis when cultures remain negative.


Leveraging a matrix of stakeholders to facilitate access to chemotherapy for women's cancers in the Democratic Republic of the Congo.
Cancer incidence is increasing worldwide. Over the next 20 years, the growing proportion of cases in low- and middle-income countries (LMICs) will account for an estimated 70% of all cancers diagnosed. The vast majority of cancer patients in LMICs will require chemotherapy, due to the advanced stage of their disease at the time of initial presentation. Unfortunately, the availability of cancer drugs in these environments is sparse, resulting in premature death and years of life lost. In an effort to lay a foundation for women's cancer control in the Democratic Republic of the Congo (DRC), we implemented a programme which combined workforce development, infrastructure creation and cancer drug access. This manuscript reports on our experience with the latter. A private sector healthcare facility was selected as the programme implementation site. Workforce capacity was developed through a south-south partnership with an African national cancer centre. Cancer drugs were procured through a global cancer medicine access initiative. A new chemotherapy infusion unit was successfully established at the Biamba Marie Mutombo Hospital in Kinshasa, DRC. A team of Congolese healthcare providers was trained at the Cancer Disease Hospital in Zambia to safely and effectively administer chemotherapy for breast and cervical cancer. Over 100 breast and cervical cancer patients have been treated with 337 courses of chemotherapy, without any serious adverse events. Common barriers to cancer drug access and its administration can be eliminated using regional educational resources to build oncologic workforce capacity, private sector healthcare facilities for infrastructure support and pharmaceutical consortiums to procure low-cost cancer medicines. By leveraging a matrix of global, regional and local stakeholders, the prevailing status quo of very limited access to chemotherapy for women's cancers was creatively disrupted in DRC, Africa's largest fragile, conflict and violence-affected country.


alpha 2-Macroglobulin remains as important as antithrombin III for thrombin regulation in cord plasma in the presence of endothelial cell surfaces.
Infants and children rarely develop thrombotic complications compared with adults, suggesting that there are protective mechanisms in place for the young. Because endothelial cell surfaces regulate thrombin formation and inhibition, we compared thrombin regulation by human umbilical vein endothelial cell surfaces exposed to defibrinated cord and adult plasmas. After activation by either 10% activated partial thromboplastin reagent (strong activator) or coagulant phospholipids (weak activator) the following were measured: free thrombin, thrombin bound to antithrombin III (ATIII), heparin cofactor II, alpha 2-macroglobulin (alpha 2M), and prothrombin concentration. Free thrombin activity was expressed as remaining activity, after subtraction of thrombin-alpha 2M activity. After 10% activated partial thromboplastin reagent, 100% of prothrombin was consumed and significant amounts of thrombin generated by 2 min. Cord plasma generated significantly less thrombin than adult plasma, reflecting the lower initial plasma concentration of prothrombin. correspondingly, concentrations of thrombin inhibitor complexes were significantly greater in adult plasma than in cord plasma. After coagulant phospholipids, 50% of prothrombin was consumed and negligible thrombin activity measured for both adult and cord plasma. Similar amounts of thrombin inhibitor complexes were formed. ATIII was the predominant inhibitor of thrombin in adult plasma, whereas alpha 2M was as important as ATIII in cord plasma for both activators. When cord plasma concentrations of ATIII were increased to adult values, the proportion complexed to alpha 2M decreased. We conclude that on human umbilical vein endothelial cells, the capacity to generate thrombin is decreased in adult and cord plasmas.(ABSTRACT TRUNCATED AT 250 WORDS)


Timing of the Diagnosis of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.
Symptoms of inattention, hyperactivity, and impulsivity are core features of attention-deficit/hyperactivity disorder (ADHD). However, children with autism spectrum disorder (ASD) often present with similar symptoms and may receive a diagnosis of ADHD first. We investigated the relationship between the timing of ADHD diagnosis in children with ASD and the age at ASD diagnosis. Data were drawn from the 2011-2012 National Survey of Children's Health, which asked parents to provide the age(s) at which their child received a diagnosis of ADHD and/or ASD. Using weighted prevalence estimates, we examined the association between a previous diagnosis of ADHD and the age at ASD diagnosis, while controlling for factors known to influence the timing of ASD diagnosis. Our study consisted of 1496 children with a current diagnosis of ASD as reported by parents of children ages 2 to 17 years. Approximately 20% of these children had initially been diagnosed with ADHD. Children diagnosed with ADHD before ASD were diagnosed with ASD ∼3 years (95% confidence interval 2.3-3.5) after children in whom ADHD was diagnosed at the same time or after ASD. The children with ADHD diagnosed first were nearly 30 times more likely to receive their ASD diagnosis after age 6 (95% confidence interval 11.2-77.8). The delay in ASD diagnosis was consistent across childhood and independent of ASD severity. To avoid potential delays in ASD diagnosis, clinicians should consider ASD in young children presenting with ADHD symptoms.


Molecular structures of various alkyldichlorosilanes in the solid state.
A series of organodichlorosilanes RR'SiCl2 (R,R' = (CH2)3; (CH2)4; (CH2)5; Me,Me; Me,H; Me,Cl) was studied by single-crystal X-ray diffraction analyses. At ambient temperature liquid chlorosilanes (melting points in the range of 180-220 K) were transferred into glass capillaries and crystallized in situ on a diffractometer. In the solid state structure these chlorosilanes are monomeric, even in the case of the sterically less demanding 1,1-dichlorosilacyclobutane (CH2)3SiCl2. Interestingly, regardless the steric demand of the alkyl substituents, the dialkyldichlorosilanes exhibit essentially the same Cl-Si-Cl angle (for (CH2)3SiCl2, (CH2)4SiCl2, (CH2)5SiCl2, Me2SiCl2: 106.08(3)°, 106.07(4)°/105.86(4)°, 106.91(2)° and 105.59(6)°, respectively). Replacement of one alkyl group by hydrogen has only a marginal influence on the Cl-Si-Cl angle (MeHSiCl2 106.31(3)°), whereas in MeSiCl3 slightly wider Cl-Si-Cl angles are found (ranging between 107.04(11)° and 107.86(11)°), in accordance with VSEPR. Computational analyses, i.e., potential energy surface scans of the Cl-Si-Cl angle variation, of (CH2)3SiCl2, Me2SiCl2, MeHSiCl2 and H2SiCl2 reveal essentially identical energy profiles for the Cl-Si-Cl deformation in these four dichlorosilanes with basically superimposed curves for (CH2)3SiCl2 and Me2SiCl2, whereas with increasing H-substitution the energetic minimum is shifted to a slightly wider Cl-Si-Cl angle. In the crystal packing only MeHSiCl2 exhibits weak intermolecular SiCl van der Waals contacts, whereas the Si-Cl moieties of the other five chlorosilanes engage in intermolecular ClH and (for (CH2)3SiCl2, (CH2)4SiCl2 and MeSiCl3) ClCl contacts.


Notch1 Activation or Loss Promotes HPV-Induced Oral Tumorigenesis.
Viral oncogene expression is insufficient for neoplastic transformation of human cells, so human papillomavirus (HPV)-associated cancers will also rely upon mutations in cellular oncogenes and tumor suppressors. However, it has been difficult so far to distinguish incidental mutations without phenotypic impact from causal mutations that drive the development of HPV-associated cancers. In this study, we addressed this issue by conducting a functional screen for genes that facilitate the formation of HPV E6/E7-induced squamous cell cancers in mice using a transposon-mediated insertional mutagenesis protocol. Overall, we identified 39 candidate driver genes, including Notch1, which unexpectedly was scored by gain- or loss-of-function mutations that were capable of promoting squamous cell carcinogenesis. Autochthonous HPV-positive oral tumors possessing an activated Notch1 allele exhibited high rates of cell proliferation and tumor growth. Conversely, Notch1 loss could accelerate the growth of invasive tumors in a manner associated with increased expression of matrix metalloproteinases and other proinvasive genes. HPV oncogenes clearly cooperated with loss of Notch1, insofar as its haploinsufficiency accelerated tumor growth only in HPV-positive tumors. In clinical specimens of various human cancers, there was a consistent pattern of NOTCH1 expression that correlated with invasive character, in support of our observations in mice. Although Notch1 acts as a tumor suppressor in mouse skin, we found that oncogenes enabling any perturbation in Notch1 expression promoted tumor growth, albeit via distinct pathways. Our findings suggest caution in interpreting the meaning of putative driver gene mutations in cancer, and therefore therapeutic efforts to target them, given the significant contextual differences in which such mutations may arise, including in virus-associated tumors.


Differential Gene Expression Patterns of Yersinia pestis and Yersinia pseudotuberculosis during Infection and Biofilm Formation in the Flea Digestive Tract.
Yersinia pestis, the etiologic agent of plague, emerged as a fleaborne pathogen only within the last 6,000 years. Just five simple genetic changes in the Yersinia pseudotuberculosis progenitor, which served to eliminate toxicity to fleas and to enhance survival and biofilm formation in the flea digestive tract, were key to the transition to the arthropodborne transmission route. To gain a deeper understanding of the genetic basis for the development of a transmissible biofilm infection in the flea foregut, we evaluated additional gene differences and performed in vivo transcriptional profiling of Y. pestis, a Y. pseudotuberculosis wild-type strain (unable to form biofilm in the flea foregut), and a Y. pseudotuberculosis mutant strain (able to produce foregut-blocking biofilm in fleas) recovered from fleas 1 day and 14 days after an infectious blood meal. Surprisingly, the Y. pseudotuberculosis mutations that increased c-di-GMP levels and enabled biofilm development in the flea did not change the expression levels of the hms genes responsible for the synthesis and export of the extracellular polysaccharide matrix required for mature biofilm formation. The Y. pseudotuberculosis mutant uniquely expressed much higher levels of Yersinia type VI secretion system 4 (T6SS-4) in the flea, and this locus was required for flea blockage by Y. pseudotuberculosis but not for blockage by Y. pestis. Significant differences between the two species in expression of several metabolism genes, the Psa fimbrial genes, quorum sensing-related genes, transcription regulation genes, and stress response genes were evident during flea infection. IMPORTANCE Y. pestis emerged as a highly virulent, arthropod-transmitted pathogen on the basis of relatively few and discrete genetic changes from Y. pseudotuberculosis. Parallel comparisons of the in vitro and in vivo transcriptomes of Y. pestis and two Y. pseudotuberculosis variants that produce a nontransmissible infection and a transmissible infection of the flea vector, respectively, provided insights into how Y. pestis has adapted to life in its flea vector and point to evolutionary changes in the regulation of metabolic and biofilm development pathways in these two closely related species.


A potential role for reactive oxygen species and the HIF-1alpha-VEGF pathway in hypoxia-induced pulmonary vascular leak.
Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS-HIF-1-VEGF pathway in pulmonary vascular leak has not been defined. We hypothesized that the ROS-HIF-1-VEGF pathway has an important role in producing hypoxia-induced pulmonary vascular leak. Human pulmonary artery endothelial cell (HPAEC) monolayers were exposed to either normoxia (21% O(2)) or acute hypoxia (3% O(2)) for 24 h and monolayer permeability and H(2)O(2), nuclear HIF-1alpha, and cytosolic VEGF levels were determined. HPAEC were treated with antioxidant cocktail (AO; ascorbate, glutathione, and alpha-tocopherol), HIF-1 siRNA, or the VEGF soluble binding protein fms-like tyrosine kinase-1 (sFlt-1) to delineate the role of the ROS-HIF-1-VEGF pathway in hypoxia-induced HPAEC leak. Additionally, mice exposed to hypobaric hypoxia (18,000 ft, 10% O(2)) were treated with the same antioxidant to determine if in vitro responses corresponded to in vivo hypoxia stress. Hypoxia increased albumin permeativity, H(2)O(2) production, and nuclear HIF-1alpha and cytosolic VEGF concentration. Treatment with an AO lowered the hypoxia-induced HPAEC monolayer permeability as well as the elevation of HIF-1alpha and VEGF. Treatment of hypoxia-induced HPAEC with either an siRNA designed against HIF-1alpha or the VEGF antagonist sFlt-1 decreased monolayer permeability. Mice treated with AO and exposed to hypobaric hypoxia (18,000 ft, 10% O(2)) had less pulmonary vascular leak than those that were untreated. Our data suggest that hypoxia-induced permeability is due, in part, to the ROS-HIF-1alpha-VEGF pathway.


Dual-energy x-ray absorptiometry to measure the effects of a thirteen-week moderate to vigorous aquatic exercise and nutritional education intervention on percent body fat in adults with intellectual disabilities from group home settings.
People with intellectual disability are more likely to be obese and extremely obese than people without intellectual disability with rates remaining elevated among adults, women and individuals living in community settings. Dual-energy X-ray absorptiometry measured the effects of a 13-week aquatic exercise and nutrition intervention on percent body fat in eight adults with intellectual disabilities (aged 41.0 ± 13.7 yrs) of varying fat levels (15%-39%) from two group homes. A moderate to vigorous aquatic exercise program lasted for the duration of 13 weeks with three, one-hour sessions held at a 25m pool each week. Nutritional assistants educated participants as to the importance of food choice and portion size. A two-tailed Wilcoxon matched-pairs signed-ranks test determined the impact of the combined intervention on body fat percentage and BMI at pre and post test. Median body fat percentage (0.8 %) and BMI (0.3 kg/m(2)) decreased following the exercise intervention, but neither were statistically significant, p = .11 and p = .55, respectively. The combined intervention was ineffective at reducing percent body fat in adults with intellectual disability according to dual-energy X-ray absorptiometry. These results are in agreement with findings from exercise alone interventions and suggest that more stringent nutritional guidelines are needed for this population and especially for individuals living in group home settings. The study did show that adults with intellectual disability may participate in moderate to vigorous physical activity when given the opportunity.


Re-emergence of Vibrio tubiashii in bivalve shellfish aquaculture: severity, environmental drivers, geographic extent and management.
During 2006 and 2007, we documented the re-emergence of severe episodes of vibriosis caused by Vibrio tubiashii in shellfish hatcheries on the west coast of North America. Lost larval and juvenile production included 3 previously undescribed hosts, Pacific (Crassostrea gigas) and Kumamoto (C. sikamea) oysters and geoduck clams Panope abrupta, with a 2007 decline in larval oyster production of approximately 59% in one hatchery. Losses of larval and juvenile bivalves were linked to V. tubiashii blooms in the coastal environment, which were associated with the apparent mixing of unusually warm surface seawater and intermittently upwelled cooler, nutrient- and Vibrio spp.- enriched seawater. The ocean temperature elevation anomaly in 2007 was not clearly linked to an El Niño event, as was a similar episode in 1998. Concentrations of the dominant shellfish-pathogenic vibrios were as high as 1.6 x 10(5) cfu ml(-1) in the cold, upwelled water. The bacteria possessed the genes coding for a protease and hemolysin described for V. tubiashii, and pathogenic isolates secreted these peptides. Lesions resulting from a classic invasive disease and a toxigenic noninvasive disease occurred in oyster and geoduck clam larvae. Management and prevention require reduction of incoming concentrations of the bacteria, reduction of contamination in water and air supplies and in stock chemical solutions, removal of bacterial toxins, and interruption of the cycle of bacterial amplification in the hatchery and in microalgal food supplies.


Fruit and vegetable consumption and self-reported functional health in men and women in the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk): a population-based cross-sectional study.
To investigate the association between fruit and vegetable consumption and self-reported physical and mental functional health measured by an anglicised short-form 36-item questionnaire (UK SF-36). Population-based cross-sectional study. General community in Norfolk, UK. A total of 16,792 men and women aged 40-79 years recruited from general practice population registers as part of the European Prospective Investigation into Cancer (EPIC)-Norfolk study, who completed food-frequency questionnaires in 1993-1997 and Health and Life Experiences Questionnaires 18 months later, were enrolled in the study. Mean SF-36 physical component summary scores increased significantly with increasing total fruit and vegetable consumption in both men and women (P < 0.0001 for trend). Men and women in the top quartile of consumption compared with the bottom quartile had a significantly higher likelihood of reporting good physical health (defined as a score > or = 55); odds ratio (OR) 1.30, 95% confidence interval (CI) 1.11-1.53 for men and OR 1.28, 95% CI 1.11-1.48 for women, after controlling for age, body mass index, smoking, education, social class, prevalent illness and total energy intake. Exclusion of current smokers and people with prevalent illness did not alter the associations. Higher fruit and vegetable consumption is associated with better self-reported physical functional health within a general population. Increasing daily intake by two portions of fruit and vegetables was associated with an 11% higher likelihood of good functional health. Since the current average consumption of fruit and vegetables in the UK is about three portions, the recommended 'five a day' strategy may have additional benefit for functional as well as other health outcomes in the population.


Implementation of a 2-for-1 Price Incentive for Fruits and Vegetables in a Grocery Retail Setting.
There is growing interest in expanding healthy eating interventions in the retail setting. The purpose of this study was to evaluate the implementation of a successful 2-for-1 price incentive for fruits and vegetables (F&V), including frozen and canned, that took place in partnership with a large chain grocery retailer in Maine. Intervention Approach. A randomized controlled trial (RCT) pilot study was conducted in 2015-2016, followed by a larger RCT in 2016-2017, to assess whether a supermarket double-dollar F&V incentive increased purchases of these items. A convergent, parallel mixed-methods design was used to examine barriers and facilitators to implementing the interventions, using six implementation outcomes: acceptability, adoption, appropriateness, feasibility, implementation fidelity, and perceived cost. The intervention was deemed highly acceptable, appropriate, and feasible by shoppers, retailers, and researchers. The F&V discount had a high rate of initial adoption. There was a moderate degree of fidelity, which improved over time based on lessons learned from the pilot and applied to the subsequent RCT. Specific costs associated with implementation from the research perspective are reported. Implications for Practice, Policy, and Research. Partnerships between academic researchers and retailers can be an effective model for improving healthful purchases among shoppers. These findings are relevant for investigators, public health advocates, and retailers interested in implementing similar grocery retail-based interventions.


Widespread increasing vegetation sensitivity to soil moisture.
Global vegetation and associated ecosystem services critically depend on soil moisture availability which has decreased in many regions during the last three decades. While spatial patterns of vegetation sensitivity to global soil water have been recently investigated, long-term changes in vegetation sensitivity to soil water availability are still unclear. Here we assess global vegetation sensitivity to soil moisture during 1982-2017 by applying explainable machine learning with observation-based leaf area index (LAI) and hydro-climate anomaly data. We show that LAI sensitivity to soil moisture significantly increases in many semi-arid and arid regions. LAI sensitivity trends are associated with multiple hydro-climate and ecological variables, and strongest increasing trends occur in the most water-sensitive regions which additionally experience declining precipitation. State-of-the-art land surface models do not reproduce this increasing sensitivity as they misrepresent water-sensitive regions and sensitivity strength. Our sensitivity results imply an increasing ecosystem vulnerability to water availability which can lead to exacerbated reductions in vegetation carbon uptake under future intensified drought, consequently amplifying climate change.


Large irradiation doses can improve the fast neutron/gamma discriminating capability of plastic scintillators.
When new materials appear as potential alternatives for radiation detection, several criteria have to be fulfilled. The one presented herein is the response variation to large irradiation doses of neutron/gamma discriminating plastic scintillators. Thus, several samples were exposed to high gamma doses reaching 10 kGy. They were characterized in terms of gamma spectrometry and fast neutron/gamma discrimination, prior to and after irradiation. Results show an unexpected increase of the figure of merit (FoM), which is the numerical value for n/γ discrimination performances. An in-depth investigation evaluates the physicochemical impact of such large doses within the material. The characterization includes photophysics, radiation/matter interaction and chemical analyses (EPR, 1H NMR, fluorescence spectroscopy and HRMS).


Effects of grass species on grazing steers: I. Diet composition and ingestive mastication.
In traditional grazing trials, per animal and per hectare productivity are determined, but pasture and animal measurements are generally inadequate to address reasons for different treatment responses. This 2-yr study examined the diet and diet characteristics of steers grazing tall fescue (Festuca arundinacea Schreb.), switchgrass (Panicum virgatum L.), flaccidgrass (Pennisetum flaccidum Griseb.), and bermudagrass (Cynodon dactylon [L.] Pers.) pastures. A randomized complete block design was used with two agronomic replicates. In vitro DM disappearance (IVDMD) of masticates from tall fescue (TF), switchgrass (SG), and flaccidgrass (FG) generally were similar; all exceeded 70% (70.3 to 79.9%), except for bermudagrass (BG), which was lowest (63.5 to 65.0%). Sieving the masticate DM showed BG to contain the highest proportion (20 to 29%) of particles passing a .5-mm sieve and the lowest proportion (6 to 8%) of particles retained on a 2.8-mm sieve. This resulted in BG having the smallest mean (1.29 mm) and median (1.08 mm) particle sizes in yr 1 and a mean (1.10 mm) and median (.91 mm) particle size smaller than SG in yr 2. Except for BG, the IVDMD of the masticate DM was lowest for small particles. Canopies showed BG and SG to have the highest proportion of stem (47 and 52%, respectively); the BG canopy was composed of fractions that were consistently lowest in IVDMD. In general, BG offered the grazing animal a canopy inferior in IVDMD concentration and had canopy characteristics that limited the animals' selection of a diet with quality as high as that of TF, SG, or FG.


CMT2N-causing aminoacylation domain mutants enable Nrp1 interaction with AlaRS.
Through dominant mutations, aminoacyl-tRNA synthetases constitute the largest protein family linked to Charcot-Marie-Tooth disease (CMT). An example is CMT subtype 2N (CMT2N), caused by individual mutations spread out in AlaRS, including three in the aminoacylation domain, thereby suggesting a role for a tRNA-charging defect. However, here we found that two are aminoacylation defective but that the most widely distributed R329H is normal as a purified protein in vitro and in unfractionated patient cell samples. Remarkably, in contrast to wild-type (WT) AlaRS, all three mutant proteins gained the ability to interact with neuropilin 1 (Nrp1), the receptor previously linked to CMT pathogenesis in GlyRS. The aberrant AlaRS-Nrp1 interaction is further confirmed in patient samples carrying the R329H mutation. However, CMT2N mutations outside the aminoacylation domain do not induce the Nrp1 interaction. Detailed biochemical and biophysical investigations, including X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange (HDX), switchSENSE hydrodynamic diameter determinations, and protease digestions reveal a mutation-induced structural loosening of the aminoacylation domain that correlates with the Nrp1 interaction. The b1b2 domains of Nrp1 are responsible for the interaction with R329H AlaRS. The results suggest Nrp1 is more broadly associated with CMT-associated members of the tRNA synthetase family. Moreover, we revealed a distinct structural loosening effect induced by a mutation in the editing domain and a lack of conformational impact with C-Ala domain mutations, indicating mutations in the same protein may cause neuropathy through different mechanisms. Our results show that, as with other CMT-associated tRNA synthetases, aminoacylation per se is not relevant to the pathology.


[Postnatal growth patterns in eight species of herons and egrets (Ciconiiformes: Ardeidae)].
Avian postnatal growth has received considerable attention and its ecological implications have been deeply analyzed. In this current paper, I describe the patterns of culmen and tarsus growth, as well as of weight gain patterns in eight species of herons and egrets (Aves: Ardeidae) found in the Birama Swamp in Eastern Cuba. Between 1998 and 2006,714 nestlings of the following species were measured every two days: Butorides virescens, Bubulcus ibis, Egretta thula, E. tricolor, E. caerulea, E. rufescens, Ardea alba and Nycticorax nycticorax. Logistic and Gompertz equations were adjusted to data using non-lineal regression models with adult values as the asymptote. For each species, the following were determined and recorded: growth rate, age at inflexion, instantaneous growth rates at each age interval, and time taken to reach 90% of adult size. Reported hatchling sizes were similar in other localities, with a variation coefficient ranging between 10-19%. At hatch, each species exhibited differing sizes relative to adult values. In all cases, Gompertz equations were best fitted to explain more variance and lesser residuals. Rates of weight change and tarsus growth were alometrically related to the log of adult weight. Two main growth processes were identified: a physical extension in dimensions of each measurement reflecting inter-specific morphometric differences, and a lineal increase of the growth period from Green Heron to Great Egret. The Black-crowned Night Heron, Cattle Egret and Reddish Egret exhibited some unique measurement characteristics in comparison to the remaining members of the family. All results support the hypothesis that hypermorphosis, as the main evolutionary process in the microevolution of Ardeidae, is caused by a delayed final moment of growth.


Abuse from in-laws during pregnancy and post-partum: qualitative and quantitative findings from low-income mothers of infants in Mumbai, India.
To examine experiences of perinatal (in pregnancy or post-partum) abuse from in-laws and to assess associations between such experiences and perinatal intimate partner violence (IPV) from husbands, as reported by Indian women residing in low-income communities in Mumbai. The present study includes both qualitative and quantitative research conducted across two phases of study. The qualitative phase involved face-to-face, semi-structured in-depth interviews (n = 32) with women seeking health care for their infants (6 months or younger) and self-reporting emotional or physical abuse from their husband. The quantitative arm involved survey data collection (n = 1,038) from mothers seeking immunization for their infants 6 months or younger at three large Urban Health Centers in Mumbai. Results of the qualitative study documented the occurrence of both non-physical and physical abuse from in-laws during pregnancy and post-partum. Non-physical forms of abuse included forced heavy domestic labor, food denial and efforts toward prevention of medical care acquisition. Quantitative results demonstrated that 26.3% of the sample reported perinatal abuse (non-physical and physical) from in-laws and that women experiencing perinatal sexual or physical IPV from husbands were significantly more likely to report perinatal abuse from in-laws (AOR = 5.33, 95% CI = 3.93-7.23). Perinatal abuse from in-laws is not uncommon among women in India and may be compromising maternal and child health in this context; such abuse is also linked to perinatal violence from husbands. Programs and interventions that screen and address IPV in pregnant and post-partum populations in India should be developed to include consideration of in-laws.


5-(4-Hydroxy-2,3,5-trimethylbenzylidene) thiazolidine-2,4-dione attenuates atherosclerosis possibly by reducing monocyte recruitment to the lesion.
A variety of benzylidenethiazole analogs have been demonstrated to inhibit 5-lipoxygenase (5-LOX). Here we report the anti-atherogenic potential of 5-(4-hydroxy- 2,3,5-trimethylbenzylidene) thiazolidin-2,4-dione (HMB-TZD), a benzylidenethiazole analog, and its potential mechanism of action in LDL receptor-deficient (Ldlr-/-) mice. HMB-TZD Treatment reduced leukotriene B4 (LTB4) production significantly in RAW264.7 macrophages and SVEC4-10 endothelial cells. Macrophages or endothelial cells pre-incubated with HMB-TZD for 2 h and then stimulated with lipopolysaccharide or tumor necrosis factor-alpha (TNF-α) displayed reduced cytokine production. Also, HMB-TZD reduced cell migration and adhesion in accordance with decreased proinflammatory molecule production in vitro and ex vivo. HMB-TZD treatment of 8-week-old male Ldlr-/- mice resulted in significantly reduced atherosclerotic lesions without a change to plasma lipid profiles. Moreover, aortic expression of pro-atherogenic molecules involved in the recruitment of monocytes to the aortic wall, including TNF-α , MCP-1, and VCAM-1, was downregulated. HMB-TZD also reduced macrophage infiltration into atherosclerotic lesions. In conclusion, HMB-TZD ameliorates atherosclerotic lesion formation possibly by reducing the expression of proinflammatory molecules and monocyte/macrophage recruitment to the lesion. These results suggest that HMB-TZD, and benzylidenethiazole analogs in general, may have therapeutic potential as treatments for atherosclerosis.


Renal fibrosis.
Tubulointerstitial renal fibrosis, characterized as a progressive detrimental connective tissue deposition on the kidney parenchyma, appears to be a harmful process leading inevitably to renal function deterioration, independently of the primary renal disease which causes the original kidney injury. Epithelial to Mesenchymal Transition (EMT) of tubular epithelial cells which are transformed to mesenchymal fibroblasts migrating to adjacent interstitial parenchyma constitutes the principal mechanism of renal fibrosis along with local and circulating cells. Proteinuria as well as hypoxia is included among the main mechanisms of EMT stimulation. TGFbeta-1 through the SMAD pathway is considered as the main modulator regulating the EMT molecular mechanism, probably in cooperation with hypoxia inducible factors. Hepatocyte Growth Factor (HGF) and Bone Morphogenetic Factor-7 (BMF-7) are inhibitory to EMT molecules which could prevent in experimental and clinical level the catastrophic process of interstitial fibrosis. Interesting data emerge indicating that HGF and BMF-7 administration prevents the peritoneal fibrosis of mesothelial cells.


Fourier-Bessel rotational invariant eigenimages.
We present an efficient and accurate algorithm for principal component analysis (PCA) of a large set of two-dimensional images and, for each image, the set of its uniform rotations in the plane and its reflection. The algorithm starts by expanding each image, originally given on a Cartesian grid, in the Fourier-Bessel basis for the disk. Because the images are essentially band limited in the Fourier domain, we use a sampling criterion to truncate the Fourier-Bessel expansion such that the maximum amount of information is preserved without the effect of aliasing. The constructed covariance matrix is invariant to rotation and reflection and has a special block diagonal structure. PCA is efficiently done for each block separately. This Fourier-Bessel-based PCA detects more meaningful eigenimages and has improved denoising capability compared to traditional PCA for a finite number of noisy images.


Gain modulation in the central nervous system: where behavior, neurophysiology, and computation meet.
Gain modulation is a nonlinear way in which neurons combine information from two (or more) sources, which may be of sensory, motor, or cognitive origin. Gain modulation is revealed when one input, the modulatory one, affects the gain or the sensitivity of the neuron to the other input, without modifying its selectivity or receptive field properties. This type of modulatory interaction is important for two reasons. First, it is an extremely widespread integration mechanism; it is found in a plethora of cortical areas and in some subcortical structures as well, and as a consequence it seems to play an important role in a striking variety of functions, including eye and limb movements, navigation, spatial perception, attentional processing, and object recognition. Second, there is a theoretical foundation indicating that gain-modulated neurons may serve as a basis for a general class of computations, namely, coordinate transformations and the generation of invariant responses, which indeed may underlie all the brain functions just mentioned. This article describes the relationships between computational models, the physiological properties of a variety of gain-modulated neurons, and some of the behavioral consequences of damage to gain-modulated neural representations.


Performance of the Xpert MTB/RIF assay in the diagnosis of tuberculosis in formalin-fixed, paraffin-embedded tissues.
Extrapulmonary tuberculosis (EPTB), which accounts for 10%-40% of the global burden of TB, with the highest incidence in Sub-Saharan Africa, is strongly associated with human immunodeficiency virus infection. Diagnosing EPTB is challenging, and recently, there has been a concerted effort to evaluate the latest molecular diagnostics for diagnosing TB in a range of specimen types. The Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) is one such technology, which simultaneously detects Mycobacterium tuberculosis and rifampicin resistance. Our objective was to evaluate the accuracy of the Xpert MTB/RIF assay for the diagnosis of EPTB and detection of rifampicin resistance in routinely processed formalin-fixed, paraffin-embedded (FFPE) tissues, compared with histological detection of TB as the gold standard. A convenience set of 100 biobanked FFPE tissues, including lymph nodes (n = 64), male genital tract tissue (n = 10), abdominal tissue (n = 8), female genital tissue (n = 5), breast tissue (n = 5), synovial tissue (n = 4), skin (n = 2), tongue tissue (n = 1), and thyroid (n = 1), from routine cases of clinically suspected EPTB admitted to the University Teaching Hospital, Lusaka, Zambia, were analyzed using the Xpert MTB/RIF assay and in-house polymerase chain reaction (PCR) assay targeting IS6110, in parallel with Ziehl-Neelsen (ZN) staining, against histology as the gold standard. Some 66% of specimens had histological evidence of TB infection. ZN staining was positive for TB in 8% of cases, and Xpert MTB/RIF was positive for TB in 25% of cases. Taking histology as the gold standard, the sensitivity and specificity were as follows: In lymph tissue the accuracy of the Xpert MTB/RIF assay was 41% (95%CI 27-57), not significantly better than ZN or the in-house PCR assay. In non-lymph tissue the sensitivity of the in-house PCR assay was 82% (95%CI: 56%-95%), significantly higher than the Xpert MTB/RIF assay (P = 0.004). The Xpert MTB/RIF assay indicated rifampicin resistance in just three cases. The Xpert MTB/RIF assay is potentially a useful tool for the diagnosis of TB in routine FFPE tissues.


Mitochondrial neuronal uncoupling proteins: a target for potential disease-modification in Parkinson's disease.
This review gives a brief insight into the role of mitochondrial dysfunction and oxidative stress in the converging pathogenic processes involved in Parkinson's disease (PD). Mitochondria provide cellular energy in the form of ATP via oxidative phosphorylation, but as an integral part of this process, superoxides and other reactive oxygen species are also produced. Excessive free radical production contributes to oxidative stress. Cells have evolved to handle such stress via various endogenous anti-oxidant proteins. One such family of proteins is the mitochondrial uncoupling proteins (UCPs), which are anion carriers located in the mitochondrial inner membrane. There are five known homologues (UCP1 to 5), of which UCP4 and 5 are predominantly expressed in neural cells. In a series of previous publications, we have shown how these neuronal UCPs respond to 1-methyl-4-phenylpyridinium (MPP+; toxic metabolite of MPTP) and dopamine-induced toxicity to alleviate neuronal cell death by preserving ATP levels and mitochondrial membrane potential, and reducing oxidative stress. We also showed how their expression can be influenced by nuclear factor kappa-B (NF-κB) signaling pathway specifically in UCP4. Furthermore, we previously reported an interesting link between PD and metabolic processes through the protective effects of leptin (hormone produced by adipocytes) acting via UCP2 against MPP+-induced toxicity. There is increasing evidence that these endogenous neuronal UCPs can play a vital role to protect neurons against various pathogenic stresses including those associated with PD. Their expression, which can be induced, may well be a potential therapeutic target for various drugs to alleviate the harmful effects of pathogenic processes in PD and hence modify the progression of this disease.