Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas.
Six men with either recurrent (n = 4) or unresectable (n = 2) squamous cell carcinoma of the penis (n = 5) and urethra (n = 1) received chemotherapy with cisplatin intravenously at a dose of 100 mg/m2. This was followed 24 hours later by a continuous intravenous infusion of 5-fluorouracil (5-FU) at a dose of 960 mg/m2/d for five days every 3 to 4 weeks. There was universal alopecia. The other toxicities were mild and consisted of mucositis, nausea, vomiting, reversible creatininemia, and transient azotemia. After chemotherapy, five patients had a clinical partial response and one had a complete response. Of the five patients with no metastases, three had residual unresectable tumors. These three patients received radiation and survived for 6, 8, and 20 months after the start of chemotherapy. The other two patients were rendered disease-free by surgery. The first patient, who was a partial responder to chemotherapy, survived for 26 months. The second patient, who was a clinical complete responder, had excision of microscopic disease and is disease-free at 32+ months after the start of chemotherapy. This is the first article to report that the combination of cisplatin and 5-FU is active in penile and urethral carcinomas. After chemotherapy, surgery may be useful in selected patients to accurately assess response and excise localized residual tumors. Patients rendered tumor-free may achieve long-term survival.


Tuneable Acidity in Fluorinated Al-SBA-15 Materials for the Esterification of Valeric Acid to Alkyl Valerates.
The acidity of Al-SBA-15 materials functionalized by ball milling with several niobium loadings (0. 25-1 wt.%) as well as with several fluorine loadings (by wet impregnation using NH4F as a precursor) was characterized and materials investigated in the esterification of valeric acid to alkyl valerates. The parent Al-SBA-15 support as well as the modified materials loaded with Nb and/or F have been catalysts synthesized characterized by X-ray diffraction (XRD), N2 physisorption measurements, and diffuse reflection infrared spectroscopy (DRIFT) among others. A special interest was paid on the acidity of the materials that was investigated by temperature-programmed desorption of pyridine. Interestingly, the characterization results for the materials containing fluorine showed up an increase in the acidity strength despite of a reduction in the number of acid sites. The catalytic performance of the as-prepared catalysts was investigated in the microwave-assisted esterification reaction of valeric acid to valerate esters. Thus, while the materials modified with niobium exhibited a lower catalytic activity as compared with the catalytic support (Al-SBA-15), the materials loaded with fluorine either onto Al-SBA-15 or on Nb1%/Al-SBA-15 materials presented enhanced conversion values of valeric acid. Therefore, it can be said that the new acid sites with enhanced strength formed by the incorporation of fluorine boost the esterification of valeric acid with alcohols to form the respective valerate ester.


Proficiency testing as a tool to assess the performance of visual TLC quantitation estimates.
The use of rapid and inexpensive nonlaboratory-based screening tests for drug quality assessments is recommended as a component of a drug quality assurance program in poor resource settings. We have established routine Minilab test procedures to screen product quality and a proficiency testing program to determine the competency of the inspectors and reliability of results. Samples for the proficiency testing were prepared by pulverizing a standard reference tablet of the appropriate drug and making serial dilutions with starch to obtain concentrations of 0, 40, and 100%. The samples, which were labeled only with the drug name and an identifying letter, were given to inspectors for quality screening using Minilab procedures. In round 1 of the proficiency test, only 3 of 28 substandard samples were correctly identified. Round 2 of the proficiency test, which was administered after a performance qualification test for the analytical method, showed much improvement: 19 of 27 substandard drugs were correctly identified, while 5 out of 9 inspectors made the correct inference on the quality of 45 samples. However, in both rounds, 2 inspectors failed to identify substandard samples, indicating that their technical competencies need to be improved for the reliability of the results. Although the thin-layer chromatography screening methods provide a rapid means for drug quality assessment, they need to be put in the hands of competent users. The inclusion of a proficiency test in the screening program provides a measure of determining competency of the personnel and reliability of the results.


A 360-degree evaluation of the communication and interpersonal skills of medicine resident physicians in Pakistan.
To provide high-quality patient care, effective communication and interpersonal skills are necessary for physicians. A 360-degree evaluation of residents in the department of medicine was conducted to assess their interpersonal and communication skills. The measurement properties and utility of the multi-source ratings were investigated. A cross-sectional assessment of a cohort of Internal Medicine residents was conducted at the Aga Khan Medical University in Pakistan. Every resident (n = 49) was evaluated by eight raters, including physicians, nurses and unit staff. Each resident also completed a self-evaluation. Evidence to support the validity of the ratings was gathered by exploring performance differences amongst more- and less-experienced providers. Analysis of variance (ANOVA) was employed to test for differences in mean scores, both for rater type and experience (residency year). Generalizability theory was employed to estimate the reliability of the ratings. We received 367/441 (83.2%) completed forms. There was a significant effect attributable to rater source (F = 5.2, P < 0.01). There were no significant differences in mean scores for residents at different levels of training. The mean resident self-assessment scores were significantly lower than those provided by faculty (P < 0.01). Based on eight raters, the reliability of the ratings was moderate (ρ2 = 0.39). The 360-degree evaluation technique can be used to measure the communication and interpersonal skills of residents. It can also provide important data to guide resident feedback. Health care providers and staff who interact with residents on regular basis can, as a group provide moderately consistent judgments of their abilities.


Results of a prospective trial of mantle irradiation alone for selected patients with early-stage Hodgkin's disease.
To determine the efficacy of mantle radiation therapy alone in selected patients with early-stage Hodgkin's disease. Between October 1988 and June 2000, 87 selected patients with pathologic stage (PS) IA to IIA or clinical stage (CS) IA Hodgkin's disease were entered onto a single-arm prospective trial of treatment with mantle irradiation alone. Eighty-three of 87 patients had > or = 1 year of follow-up after completion of mantle irradiation and were included for analysis in this study. Thirty-seven patients had PS IA, 40 had PS IIA, and six had CS IA disease. Histologic distribution was as follows: nodular sclerosis (n = 64), lymphocyte predominant (n = 15), mixed cellularity (n = 3), and unclassified (n = 1). Median follow-up time was 61 months. The 5-year actuarial rates of freedom from treatment failure (FFTF) and overall survival were 86% and 100%, respectively. Eleven of 83 patients relapsed at a median time of 27 months. Nine of the 11 relapses contained at least a component below the diaphragm. All 11 patients who developed recurrent disease were alive without evidence of Hodgkin's disease at the time of last follow-up. The 5-year FFTF in the 43 stage I patients was 92% compared with 78% in the 40 stage II patients (P =.04). Significant differences in FFTF were not seen by histology (P =.26) or by European Organization for Research and Treatment of Cancer H-5F eligibility (P =.25). Mantle irradiation alone in selected patients with early-stage Hodgkin's disease is associated with disease control rates comparable to those seen with extended field irradiation. The FFTF is especially favorable among stage I patients.


Dextromethorphan efficiently increases bactericidal activity, attenuates inflammatory responses, and prevents group a streptococcal sepsis.
Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antitussive drug, has recently been reported to possess anti-inflammatory properties. In this study, we investigated the potential protective effect of DM in GAS infection using an air pouch infection mouse model. Our results showed that DM treatment increased the survival rate of GAS-infected mice. Bacterial numbers in the air pouch were lower in mice treated with DM than in those infected with GAS alone. The bacterial elimination efficacy was associated with increased cell viability and bactericidal activity of air-pouch-infiltrating cells. Moreover, DM treatment prevented bacterial dissemination in the blood and reduced serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-1β and the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and RANTES. In addition, GAS-induced mouse liver injury was reduced by DM treatment. Taken together, DM can increase bacterial killing and reduce inflammatory responses to prevent sepsis in GAS infection. The consideration of DM as an adjunct treatment in combination with antibiotics against bacterial infection warrants further study.


Parenting behavior at 2 years predicts school-age performance at 7 years in very preterm children.
Parenting influences child development, but it is unclear whether early parenting behavior can influence school-age outcomes in very preterm (VPT) children, and/or if certain groups of VPT children may be more affected by early parenting behavior. These research questions were examined. Participants were 147 children born <30 weeks' gestation or birth weight <1250 g and their primary caregiver. At term corrected age (CA), magnetic resonance imaging (MRI) was used to determine presence and severity of brain abnormality and medical data collected. High medical risk was defined as the presence of at least one of sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, moderate to severe white matter abnormality on MRI, or postnatal corticosteroids. At 2 years CA, parent-child interaction was assessed, and at 7 years CA, general intelligence (IQ), language, executive function, academic skills, and social-emotional functioning were assessed. Higher levels of parent-child synchrony, and parent facilitation, sensitivity and positive affect at 2 years were associated with better child outcomes at 7 years, while higher levels of intrusiveness and negative affect were associated with poorer outcomes. Many of these relationships remained after controlling for early child cognitive development. Interactions between child medical risk (higher/lower) and parenting were limited to child reading, math, and executive functioning outcomes, with stronger relationships for lower medical risk children. The contribution of early parenting to VPT children's school-age performance is significant, with stronger effects for lower medical risk children in some outcomes. These findings support the premise that parenting strategies should be included in the NICU and early interventions programs for VPT infants.


Resource Partitioning in Food, Space and Time between Arctic Charr (Salvelinus alpinus), Brown Trout (Salmo trutta) and European Whitefish (Coregonus lavaretus) at the Southern Edge of Their Continuous Coexistence.
Arctic charr and European whitefish are considered to be strong competitors in lakes, with the latter usually being the superior species. However, high niche plasticity and lake morphometry may suggestively facilitate resource partitioning and coexistence between charr and whitefish. Here, we explore the trophic niche utilization (diet and habitat use) of charr and whitefish co-occurring with brown trout in the deep and oligotrophic Lake Fyresvatnet, southern Norway (59°05'N, 8°10'E). Using CPUE, stomach contents and stable isotope analyses, a distinct resource partitioning was revealed between brown trout and the other two species. Brown trout typically occupied the littoral zone, feeding on benthic invertebrates, surface insects and small-sized whitefish. In contrast, charr and whitefish were predominantly zooplanktivorous, but diverged somewhat in habitat utilization as charr shifted seasonally between the profundal and the littoral zone, whereas whitefish were found in the upper water layers (littoral and pelagic habitats). Accordingly, the stable isotope values of carbon (δ13C) reflected a pelagic orientated prey resource use for both charr and whitefish, whereas brown trout had elevated carbon and nitrogen (δ15N) signatures that reflected their benthivore and piscivore diet, respectively. The findings suggest that charr may not rely upon the profundal zone as a feeding habitat but as a refuge area, and may coexist with whitefish if a third competitive and predatory species like brown trout co-occur in the lake. The study indicates that a general high habitat plasticity of Arctic charr may be essential in the presently observed coexistence with a competitively superior fish species like whitefish, and that a third fish species like brown trout may facilitate this particular fish community structure.


Threonine-rich repeats increase fibronectin binding in the Candida albicans adhesin Als5p.
Commensal and pathogenic states of Candida albicans depend on cell surface-expressed adhesins, including those of the Als family. Mature Als proteins consist of a 300-residue N-terminal region predicted to have an immunoglobulin (Ig)-like fold, a 104-residue conserved Thr-rich region (T), a central domain of a variable number of tandem repeats (TR) of a 36-residue Thr-rich sequence, and a heavily glycosylated C-terminal Ser/Thr-rich stalk region, also of variable length (N. K. Gaur and S. A. Klotz, Infect. Immun. 65: 5289-5294, 1997). Domain deletions in ALS5 were expressed in Saccharomyces cerevisiae to excrete soluble protein and for surface display. Far UV circular dichroism indicated that soluble Ig-T showed a single negative peak at 212 nm, consistent with previous data indicating that this region has high beta-sheet content with very little alpha-helix. A truncation of Als5p with six tandem repeats (Ig-T-TR(6)) gave spectra with additional negative ellipticity at 200 nm and, at 227 to 240 nm, spectra characteristic of a structure with a similar fraction of beta-sheet but with additional structural elements as well. Soluble Als5p Ig-T and Ig-T-TR(6) fragments bound to fibronectin in vitro, but the inclusion of the TR region substantially increased affinity. Cellular adhesion assays with S. cerevisiae showed that the Ig-T domain mediated adherence to fibronectin and that TR repeats greatly increased cell-to-cell aggregation. Thus, the TR region of Als5p modulated the structure of the Ig-T region, augmented cell adhesion activity through increased binding to mammalian ligands, and simultaneously promoted fungal cell-cell interactions.


The status of central ethical reviewing and challenges regarding its introduction to non-interventional studies in Japan.
In 2018, we conducted a study on 121 ethics review committee offices in Japan to examine the state of "central review" in non-interventional studies and discern any challenges regarding its introduction. Of the 452 offices that were invited to participate, 121 responded (26.8% response rate), and 35 (28.9%) had records of furnishing contracting agreements with ethical reviews by other research institutions. The merits of central reviewing include easing the burden on ethics review committees, improving the quality level and consistency of ethical reviews, and enhancing the efficiency in conducting them. The demerits include increased administrative overheads and work for researchers, such as preparing application forms and checking institutional requirements, and a lack of clarity regarding who is responsible for conducting the research, which makes it is less desirable for institutions to have their own ethics review committees. This study revealed that the comprehensive introduction of central review in non-interventional studies continues to encounter many hurdles, and promoting central review requires overcoming these challenges one at a time. The Ethical Guidelines for Medical and Health Research Involving Human Subjects will be revised in 2021 to require central review as a part of ethical reviews for non-interventional studies. In the future, central reviews of non-interventional studies will need to be of high quality and conducted efficiently, and this will require research institutions to utilize relevant central review guidelines and checklists.


Two-dimensional PPLN for simultaneous laser Q-switching and optical parametric oscillation in a Nd:YVO4 laser.
We report on a tunable intracavity optical parametric oscillator (IOPO) achieved using a two-dimensional (2D) periodically poled lithium niobate (PPLN) as simultaneously an electro-optic (EO) Bragg Q-switch and an optical frequency mixer (OFM) in a diode-pumped Nd:YVO(4) laser. The 2D periodic domain inversion structure is designed to provide two orthogonal reciprocal vectors to respectively satisfy the phase-matching conditions required by the two quasi-phase-matching devices (i.e., the PPLN EO Bragg deflector and the PPLN OFM). At a ~140-V Q-switching voltage and a 1-kHz switching rate, we obtained a signal wave at 1550 nm with a pulse energy of 9.7 μJ (corresponding to a peak power of ~2.4 kW) from the IOPO at 9.1-W diode pump power. Simultaneously we also observed multi-wavelength generation from the system originating in the single-pass parametric conversions in the 2D nonlinear photonic crystal structure. Temperature tuning of the IOPO signal wavelength in the eye-safe region was also demonstrated.


Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum.
Rhythmic theta frequency (~5-12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of 'upstream' and 'downstream' cortico-cortical circuits involved in mnemonic functions.


Reducing drug and alcohol use and improving well-being for Indigenous and non-Indigenous Australians using the Community Reinforcement Approach: A feasibility and acceptability study.
There is a lack of evidence of effective and appropriate drug and alcohol treatment for Aboriginal and Torres Strait Islander peoples. This paper contributes to addressing the evidence gap by examining the feasibility and acceptability and conducting a pre/post-evaluation of the Aboriginal-adapted Community Reinforcement Approach (CRA) delivered in New South Wales, Australia. Aboriginal and non-Aboriginal clients (n = 55) received tailored CRA delivery between March and November 2013. Compared to the original US version, tailored CRA had reduced technical language, reduced number of treatment sessions, and the addition of group delivery option. An Australian training manual with local case studies was developed. Alcohol, Smoking and Substance Involvement Test (ASSIST), Kessler-5 (K-5) and the Growth Empowerment Measure were used. 58% of participants were followed-up at 3 months. Tailored CRA was feasible to deliver in a rural, community-based health setting, and rated by clients as highly effective and acceptable. CRA was associated with statistically significant reductions in the use of alcohol, tobacco, cannabis, amphetamine and over the counter medication, and levels of psychological distress, and an increase in levels of empowerment for Aboriginal and non-Aboriginal clients. This study provides evidence for the feasibility and acceptability of an Aboriginal-adapted psychological intervention addressing drug, alcohol and mental health outcomes.


Pharmacological effects of alpha-methyldopa, alpha-methylnorepinephrine, and octopamine on rat arteriolar, arterial, and terminal vascular smooth.
Experiments on rat mesenteric arterioles, metarterioles, and aortae demonstrate that although alpha-methylnorepinephrine is much less potent in inducing contraction than epinephrine on all three blood vessel types, it is either equivalent or only one and a half to two times less potent than the natural postganglionic neurotransmitter, norepinephrine, on these blood vessels. Furthermore, alpha-methylnorepinephrine is equivalent to norepinephrine in its ability to induce maximal contractile responses on rat arterioles, metarterioles, and aortae. Systemic administration of alpha-methyldopa to rats for 15 days shifted the log dose-response curves for all three catecholamines, but not vasopressin or potassium chloride, to the right of all three blood vessel types; the maximal contractile responses to these amines were, however, not affected by chronic treatment with alpha-methyldopa. In addition, acute, intra-arterial administration of 500 mg/kg of alpha-methyldopa was found not only to induce mesenteric arteriolar vasodilatation gradually but also to depress arteriolar reponsiveness to catecholamines. In view of these direct findings, it is difficult to accept the hypothesis that alpha-methyldopa induces hypotension via formation of a "false" postganglionic neurotransmitter substance, namely, alpha-methylnorepinephrine. The present findings suggest that alpha-methyldopa may exert some of its anti-hypertensive action, at least in the rat, by (1) depressing arteriolar responsiveness to circulating and released catecholamines and (2) some unknown direct action on peripheral vascular muscle. In addition, the present study indicates that octopamine is (1) between 60 and 15,000 times less potent than norepinephrine on rat arterioles and metarterioles and (2) incapable of eliciting more than a 40% occlusion of these terminal vessels. It is suggested that such data support the concept that octopamine, in contrast to alpha-methylnorepinephrine, could serve as a false adrenergic neurotransmitter agent and thus account for part or all of the hypotensive action of monoamine oxidase inhibitors like pargyline. The use of complete dose-response curves, several different adrenergic compounds (i.e., epinephrine, norepinephrine, alpha-methylnorepinephrine, octopamine, phenylephrine, and dopamine), and different rat blood vessels supports the concept that adrenergic molecules containing a catecholamine nucleus and a beta-hydroxyl group elicit the most potent constrictor responses from peripheral blood vessels. In addition, the data suggest that the structure-activity relationships for catecholamines and their analogs on terminal vascular smooth muscle are probably different from those for arterial smooth muscle.


Arrival of Paleo-Indians to the southern cone of South America: new clues from mitogenomes.
With analyses of entire mitogenomes, studies of Native American mitochondrial DNA (MTDNA) variation have entered the final phase of phylogenetic refinement: the dissection of the founding haplogroups into clades that arose in America during and after human arrival and spread. Ages and geographic distributions of these clades could provide novel clues on the colonization processes of the different regions of the double continent. As for the Southern Cone of South America, this approach has recently allowed the identification of two local clades (D1g and D1j) whose age estimates agree with the dating of the earliest archaeological sites in South America, indicating that Paleo-Indians might have reached that region from Beringia in less than 2000 years. In this study, we sequenced 46 mitogenomes belonging to two additional clades, termed B2i2 (former B2l) and C1b13, which were recently identified on the basis of mtDNA control-region data and whose geographical distributions appear to be restricted to Chile and Argentina. We confirm that their mutational motifs most likely arose in the Southern Cone region. However, the age estimate for B2i2 and C1b13 (11-13,000 years) appears to be younger than those of other local clades. The difference could reflect the different evolutionary origins of the distinct South American-specific sub-haplogroups, with some being already present, at different times and locations, at the very front of the expansion wave in South America, and others originating later in situ, when the tribalization process had already begun. A delayed origin of a few thousand years in one of the locally derived populations, possibly in the central part of Chile, would have limited the geographical and ethnic diffusion of B2i2 and explain the present-day occurrence that appears to be mainly confined to the Tehuelche and Araucanian-speaking groups.


Auguste Forel on ants and neurology.
Auguste Forel was born in 1848 in the French part of Switzerland. He developed a lifelong passion for myrmecology in his childhood, but chose medicine and neuropsychiatry to earn his living. He first undertook a comparative study of the thalamus under Theodor Meynert in Vienna and then, from 1872 to 1879, he worked as Assistant Physician to Bernhard von Gudden in Munich. This led in 1877 to his seminal work on the organization of the tegmental region in which he provides the first description of the zona incerta and the so-called H (Haubenfeld) fields that still bear his name. In 1879, Forel was appointed Professor of Psychiatry in Munich and Director of the Burghölzli cantonal asylum. He became interested in the therapeutic value of hypnotism, while continuing his work on brain anatomy and ants. His neuroanatomical studies with Gudden's method led him to formulate the neuron theory in 1887, four years before Wilhelm von Waldeyer, who received most of the credit for it. Forel then definitively turned his back on neuroscience. After his retirement from the Burghölzli asylum in 1898. and despite a stroke in 1911 that left him hemiplegic, Forel started to write extensively on various social issues, such as alcohol abstinence and sexual problems. Before his death in 1931 at the age of 83, Forel published a remarkable book on the social world of the ants in which he made insightful observations on the neural control of sensory and instinctive behavior common to both humans and insects.


Novel fabrication of an SnO(2) nanowire gas sensor with high sensitivity.
We fabricated a nanowire-based gas sensor using a simple method of growing SnO(2) nanowires bridging the gap between two pre-patterned Au catalysts, in which the electrical contacts to the nanowires are self-assembled during the synthesis of the nanowires. The gas sensing capability of this network-structured gas sensor was demonstrated using a diluted NO(2). The sensitivity, as a function of temperature, was highest at 200 °C and was determined to be 18 and 180 when the NO(2) concentration was 0.5 and 5 ppm, respectively. Our sensor showed higher sensitivity compared to different types of sensors including SnO(2) powder-based thin films, SnO(2) coating on carbon nanotubes or single/multiple SnO(2) nanobelts. The enhanced sensitivity was attributed to the additional modulation of the sensor resistance due to the potential barrier at nanowire/nanowire junctions as well as the surface depletion region of each nanowire.


Change in food intake frequency at five years after baseline in the JACC study.
In a cohort study, information on an individual is taken at baseline, after which it usually remains fixed. There is some risk that this will lead to misclassification and cause weakened or biased results. To prevent such distortion, following up of exposure is important, although it is still scarce in practice. In the Japan Collaborative Cohort Study for Evaluation of Cancer Risk (JACC Study) sponsored by Monbusho (Ministry of Education, Science, Sports and Culture of Japan), 37,838 (14,531 males and 23,307 females) subjects out of a cohort of 127,477 inhabitants answered an interim questionnaire on food intake frequency consisting of 33 items about five years after registration. The long-term reproducibility was assessed using Spearman's correlation coefficients and agreement. From data at two time points, longitudinal change, age effect, and secular trend were examined. Subjective changes in these items at the time of the interim survey were also compared to longitudinal changes. Spearman's correlation coefficients varied from 0.27 (fruit juice in males) to 0.55 (beef in females and milk in males), and agreement from 29.9% (fruit juice in males) to 61.4% (liver in females). Correlation was relatively stronger in meat and dairy products and weaker in vegetables and fruits. In both males and females, most increased food item was edible wild plants followed by confectioneries (males) and yogurt (females). Over five years, food intake was considerably changed. These interim data could be used for a long-term follow-up study to prevent the results becoming weakened or biased.


Don't Like RDF Reification? Making Statements about Statements Using Singleton Property.
Statements about RDF statements, or meta triples, provide additional information about individual triples, such as the source, the occurring time or place, or the certainty. Integrating such meta triples into semantic knowledge bases would enable the querying and reasoning mechanisms to be aware of provenance, time, location, or certainty of triples. However, an efficient RDF representation for such meta knowledge of triples remains challenging. The existing standard reification approach allows such meta knowledge of RDF triples to be expressed using RDF by two steps. The first step is representing the triple by a Statement instance which has subject, predicate, and object indicated separately in three different triples. The second step is creating assertions about that instance as if it is a statement. While reification is simple and intuitive, this approach does not have formal semantics and is not commonly used in practice as described in the RDF Primer. In this paper, we propose a novel approach called Singleton Property for representing statements about statements and provide a formal semantics for it. We explain how this singleton property approach fits well with the existing syntax and formal semantics of RDF, and the syntax of SPARQL query language. We also demonstrate the use of singleton property in the representation and querying of meta knowledge in two examples of Semantic Web knowledge bases: YAGO2 and BKR. Our experiments on the BKR show that the singleton property approach gives a decent performance in terms of number of triples, query length and query execution time compared to existing approaches. This approach, which is also simple and intuitive, can be easily adopted for representing and querying statements about statements in other knowledge bases.


B355252, A Novel Small Molecule, Confers Neuroprotection Against Cobalt Chloride Toxicity In Mouse Hippocampal Cells Through Altering Mitochondrial Dynamics And Limiting Autophagy Induction.
Cerebral hypoxia as often occurs in cases of stroke, hemorrhage, or other traumatic brain injuries, is one of the leading causes of death worldwide and a main driver of disabilities in the elderly. Using a chemical mimetic of hypoxia, cobalt chloride (CoCl2), we tested the ability of a novel small molecule, 4-chloro-N-(naphthalen-1-ylmethyl)-5-(3-(piperazin-1-yl)phenoxy)thiophene-2-sulfonamide (B355252), to alleviate CoCl2-induced damage in mouse hippocampal HT22 cells. A dose-dependent decrease in cell viability was observed during CoCl2 treatment along with increases in mitochondrial membrane potential and generation of reactive oxygen species (ROS). B355252 conferred protection against these changes. We further found that mitochondrial dynamics, the balance between mitochondrial fusion and fission, were perturbed by CoCl2 treatment. Mitochondrial fusion, which was assessed by measuring the expression of proteins optic atrophy protein 1 (OPA1) and mitofusin 2 (Mfn2), declined due to CoCl2 exposure, but B355252 addition was able to elevate Mfn2 expression while OPA1 expression was unchanged. Mitochondrial fission, measured by phosphorylated dynamin-related protein 1 (p-DRP1) and fission protein 1 (FIS1) expression, also decreased following CoCl2 exposure, and was stabilized by B355252 addition. Finally, autophagy was assessed by measuring the conversion of cytosolic microtubule-associated protein 1A/1B-light chain three-I (LC3-I) to autophagosome-bound microtubule-associated protein 1A/1B-light chain three-II (LC3-II) and was found to be increased by CoCl2. B355252 addition significantly reduced autophagy induction. Taken together, our results indicate B355252 has therapeutic potential to reduce the damaging effects caused by CoCl2 and should be further evaluated for applications in cerebral ischemia therapy.


Deletion of potD, encoding a putative spermidine-binding protein, results in a complex phenotype in Legionella pneumophila.
L. pneumophila is an intracellular pathogen that replicates in a membrane-bound compartment known as the Legionella-containing vacuole (LCV). We previously observed that the polyamine spermidine, produced by host cells or added exogenously, enhances the intracellular growth of L. pneumophila. To study this enhancing effect and determine whether polyamines are used as nutrients, we deleted potD from L. pneumophila strain JR32. The gene potD encodes a spermidine-binding protein that in other bacteria is essential for the function of the PotABCD polyamine transporter. Deletion of potD did not affect L. pneumophila growth in vitro in the presence or absence of spermidine and putrescine, suggesting that PotD plays a redundant or no role in polyamine uptake. However, deletion of potD resulted in a puzzlingly complex phenotype that included defects in L. pneumophila's ability to form filaments, tolerate Na(+), associate with macrophages and amoeba, recruit host vesicles to the LCV, and initiate intracellular growth. Moreover, the ΔpotD mutant was completely unable to grow in L929 cells treated with a pharmacological inhibitor of spermidine synthesis. These complex and disparate effects suggest that the L. pneumophila potD encodes either: (i) a multifunctional protein, (ii) a protein that interacts with, or regulates a, multifunctional protein, or (iii) a protein that contributes (directly or indirectly) to a regulatory network. Protein function studies with the L. pneumophila PotD protein are thus warranted.


Ontogeny of hepatic energy metabolism genes in mice as revealed by RNA-sequencing.
The liver plays a central role in metabolic homeostasis by coordinating synthesis, storage, breakdown, and redistribution of nutrients. Hepatic energy metabolism is dynamically regulated throughout different life stages due to different demands for energy during growth and development. However, changes in gene expression patterns throughout ontogeny for factors important in hepatic energy metabolism are not well understood. We performed detailed transcript analysis of energy metabolism genes during various stages of liver development in mice. Livers from male C57BL/6J mice were collected at twelve ages, including perinatal and postnatal time points (n = 3/age). The mRNA was quantified by RNA-Sequencing, with transcript abundance estimated by Cufflinks. One thousand sixty energy metabolism genes were examined; 794 were above detection, of which 627 were significantly changed during at least one developmental age compared to adult liver. Two-way hierarchical clustering revealed three major clusters dependent on age: GD17.5-Day 5 (perinatal-enriched), Day 10-Day 20 (pre-weaning-enriched), and Day 25-Day 60 (adolescence/adulthood-enriched). Clustering analysis of cumulative mRNA expression values for individual pathways of energy metabolism revealed three patterns of enrichment: glycolysis, ketogenesis, and glycogenesis were all perinatally-enriched; glycogenolysis was the only pathway enriched during pre-weaning ages; whereas lipid droplet metabolism, cholesterol and bile acid metabolism, gluconeogenesis, and lipid metabolism were all enriched in adolescence/adulthood. This study reveals novel findings such as the divergent expression of the fatty acid β-oxidation enzymes Acyl-CoA oxidase 1 and Carnitine palmitoyltransferase 1a, indicating a switch from mitochondrial to peroxisomal β-oxidation after weaning; as well as the dynamic ontogeny of genes implicated in obesity such as Stearoyl-CoA desaturase 1 and Elongation of very long chain fatty acids-like 3. These data shed new light on the ontogeny of homeostatic regulation of hepatic energy metabolism, which could ultimately provide new therapeutic targets for metabolic diseases.


Periosteal microcirculatory reactions in a zoledronate-induced osteonecrosis model of the jaw in rats.
Nitrogen-containing bisphosphonates induce osteonecrosis mostly in the jaw and less frequently in other bones. Because of the crucial role of periosteal perfusion in bone repair, we investigated zoledronate-induced microcirculatory reactions in the mandibular periosteum in comparison with those in the tibia in a clinically relevant model of bisphosphonate-induced medication-related osteonecrosis of the jaw (MRONJ). Sprague-Dawley rats were treated with zoledronate (ZOL; 80 i.v. μg/kg/week over 8 weeks) or saline vehicle. The first two right mandibular molar teeth were extracted after 3 weeks. Various systemic and local (periosteal) microcirculatory inflammatory parameters were examined by intravital videomicroscopy after 9 weeks. Gingival healing disorders (∼100%) and MRONJ developed in 70% of ZOL-treated cases but not after saline (shown by micro-CT). ZOL induced significantly higher degrees of periosteal leukocyte rolling and adhesion in the mandibular postcapillary venules (at both extraction and intact sites) than at the tibia. Leukocyte NADPH-oxidase activity was reduced; leukocyte CD11b and plasma TNF-alpha levels were unchanged. Chronic ZOL treatment causes a distinct microcirculatory inflammatory reaction in the mandibular periosteum but not in the tibia. The local reaction in the absence of augmented systemic leukocyte inflammatory activity suggests that topically different, endothelium-specific changes may play a critical role in the pathogenesis of MRONJ. This model permits for the first time to explore the microvascular processes in the mandibular periosteum after chronic ZOL treatment. This approach may contribute to a better understanding of the pathomechanism and the development of strategies to counteract bisphosphonate-induced side effects.


A theoretical analysis of bagging as a linear combination of classifiers.
We apply an analytical framework for the analysis of linearly combined classifiers to ensembles generated by bagging. This provides an analytical model of bagging misclassification probability as a function of the ensemble size, which is a novel result in the literature. Experimental results on real data sets confirm the theoretical predictions. This allows us to derive a novel and theoretically grounded guideline for choosing bagging ensemble size. Furthermore, our results are consistent with explanations of bagging in terms of classifier instability and variance reduction, support the optimality of the simple average over the weighted average combining rule for ensembles generated by bagging, and apply to other randomization-based methods for constructing classifier ensembles. Although our results do not allow to compare bagging misclassification probability with the one of an individual classifier trained on the original training set, we discuss how the considered theoretical framework could be exploited to this aim.


Dorsal-ventral patterning and differentiation of noggin-induced neural tissue in the absence of mesoderm.
In Xenopus development, dorsal mesoderm is thought to play a key role in both induction and patterning of the nervous system. Previously, we identified a secreted factor, noggin, which is expressed in dorsal mesoderm and which can mimic that tissue's neural-inducing activity, without inducing mesoderm. Here the neural tissue induced in ectodermal explants by noggin is further characterized using four neural-specific genes: two putative RNA-binding proteins, nrp-1 and etr-1; the synaptobrevin sybII; and the lipocalin cpl-1. First we determine the expression domain of each gene during embryogenesis. Then we analyze expression of these genes in noggin-treated explants. All markers, including the differentiated marker sybII, are expressed in noggin-induced neural tissue. Furthermore, cpl-1, a marker of dorsal brain, and etr-1, a marker absent in much of the dorsal forebrain, are expressed in non-overlapping territories within these explants. We conclude that the despite the absence of mesoderm, noggin-induced neural tissue shows considerable differentiation and organization, which may represent dorsal-ventral patterning of the forebrain.


Unusual surface and edge morphologies, sp2 to sp3 hybridized transformation and electronic damage after Ar+ ion irradiation of few-layer graphene surfaces.
Roughness and defects induced on few-layer graphene (FLG) irradiated by Ar+ ions at different energies were investigated using X-ray photoemission spectroscopy (XPS) and atomic force microscopy techniques. The results provide direct experimental evidence of ripple formation, sp2 to sp3 hybridized carbon transformation, electronic damage, Ar+ implantation, unusual defects and edge reconstructions in FLG, which depend on the irradiation energy. In addition, shadowing effects similar to those found in oblique-angle growth of thin films were seen. Reliable quantification of the transition from the sp2-bonding to sp3-hybridized state as a result of Ar+ ion irradiation is achieved from the deconvolution of the XPS C (1s) peak. Although the ion irradiation effect is demonstrated through the shape of the derivative of the Auger transition C KVV spectra, we show that the D parameter values obtained from these spectra which are normally used in the literature fail to account for the sp2 to sp3 hybridization transition. In contrast to what is known, it is revealed that using ion irradiation at large FLG sample tilt angles can lead to edge reconstructions. Furthermore, FLG irradiation by low energy of 0.25 keV can be a plausible way of peeling graphene layers without the need of Joule heating reported previously.


Removal of copper from an electroplating industrial effluent using the native and modified spirogyra.
In the present study, biosorption behavior of a green filamentous alga, spirogyra in its native and modified states was investigated for copper removal from an electroplating industrial effluent. For this, the effluent containing 194 mg·L-1 Cu2+ in sulfate medium was contacted with both forms of spirogyra, under the parametric variations of effluent pH, adsorbent dosage, contact time, and sorption temperature. The study revealed spirogyra as a prominent candidate for removing contaminant metal cation; however, at the same condition, biosorption capacity of modified biomass in gel form was higher than the native spirogyra. At the optimized condition with 6 g sorbent dosage treated to 100 mL effluent for 30 min at pH 6.0 and temperature 20 °C, the maximum 82.8% and 96.4% copper could be adsorbed by the native and modified spirogyra, respectively. The batch sorption data using native biomass followed pseudo-first-order kinetic; exhibiting the multilayer sorption mechanism via surface diffusion could be defined by the Freundlich model. In contrast, the sulfuric acid treated modified spirogyra followed pseudo-second-order kinetics and intra particle diffusion as the rate-limiting step.


Detection of inflammation- and neoplasia-associated alterations in human large intestine using plant/invertebrate lectins, galectin-1 and neoglycoproteins.
Commonly, plant and invertebrate lectins are accepted glycohistochemical tools for the analysis of normal and altered structures of glycans in histology and pathology. Mammalian lectins and neoglycoproteins are recent additions to this panel for the detection of lectin-reactive carbohydrate epitopes and glycoligand-binding sites. The binding profiles of these three types of probes were comparatively analyzed in normal, inflamed and neoplastic large intestine. In normal colonic mucosa the intracellular distribution of glycoconjugates and carbohydrate ligand-binding sites in enterocytes reveals a differential binding of lectins with different specificity and of neoglycoproteins to the Golgi apparatus, the rough and smooth endoplasmic reticulum and the apical cell surface. The accessible glycoligand-binding sites and the lectin-reactive carbohydrate epitopes detected by galectin-1 show the same pattern of intracellular location excluding the apical cell surface. Lectin-reactive carbohydrate epitopes detected by plant lectins of identical monosaccharide specificity as the endogenous lectin [Ricinus communis agglutinin-I (RCA-I), Viscum album agglutinin (VAA)], however, clearly differ with respect to their intracellular distribution. Maturation-associated differences and heterogeneity in glycohistochemical properties of epithelial cells and non-epithelial cells (macrophages, dendritic cells, lymphocytes) are found. Dissimilarities in the fine structural ligand recognition of lectins with nominal specificity to the same monosaccharide have been demonstrated for the galactoside-specific lectins RCA-I, VAA and galectin-1 as well as the N-acetylgalactosamine (GalNAc)-specific lectins Dolichos biflorus agglutinin (DBA), soybean agglutinin (SBA) and Helix pomatia agglutinin in normal mucosa and in acute appendicitis. Acute inflammation of the intestinal mucosa found in acute phlegmonous appendicitis is associated with selective changes of glycosylation of mucin in goblet cells mainly of lower and middle crypt segments resulting in an increase of DBA- and SBA-binding sites in the goblet cell population. Appendicitis causes no detectable alteration of neoglycoprotein binding. In contrast, tumorigenesis of colonic adenoma is characterized by increases in lectin-reactive galactose (Gal; Gal-beta1, 3-GalNAc), fucose and N-acetylglucosamine moieties and by enhanced presentation of respective carbohydrate ligand-binding capacity. This work reveals that endogenous lectins and neoglycoproteins are valuable glycohistochemical tools supplementing the well-known analytic capacities of plant lectins in the fields of gastrointestinal anatomy and gastroenteropathology.


Adipose tissue fatty acid patterns and changes in anthropometry: a cohort study.
Diets rich in n-3 long chain polyunsaturated fatty acids (LC-PUFA), but low in n-6 LC-PUFA and 18:1 trans-fatty acids (TFA), may lower the risk of overweight and obesity. These fatty acids have often been investigated individually. We explored associations between global patterns in adipose tissue fatty acids and changes in anthropometry. 34 fatty acid species from adipose tissue biopsies were determined in a random sample of 1100 men and women from a Danish cohort study. We used sex-specific principal component analysis and multiple linear regression to investigate the associations of adipose tissue fatty acid patterns with changes in weight, waist circumference (WC), and WC controlled for changes in body mass index (WC(BMI)), adjusting for confounders. 7 principal components were extracted for each sex, explaining 77.6% and 78.3% of fatty acid variation in men and women, respectively. Fatty acid patterns with high levels of TFA tended to be positively associated with changes in weight and WC for both sexes. Patterns with high levels of n-6 LC-PUFA tended to be negatively associated with changes in weight and WC in men, and positively associated in women. Associations with patterns with high levels of n-3 LC-PUFA were dependent on the context of the rest of the fatty acid pattern. Adipose tissue fatty acid patterns with high levels of TFA may be linked to weight gain, but patterns with high n-3 LC-PUFA did not appear to be linked to weight loss. Associations depended on characteristics of the rest of the pattern.


Electronic data capture for large scale typhoid surveillance, household contact tracing, and health utilisation survey: Strategic Typhoid Alliance across Africa and Asia.
Electronic data capture systems (EDCs) have the potential to achieve efficiency and quality in collection of multisite data. We quantify the volume, time, accuracy and costs of an EDC using large-scale census data from the STRATAA consortium, a comprehensive programme assessing population dynamics and epidemiology of typhoid fever in Malawi, Nepal and Bangladesh to inform vaccine and public health interventions. A census form was developed through a structured iterative process and implemented using Open Data Kit Collect running on Android-based tablets. Data were uploaded to Open Data Kit Aggregate, then auto-synced to MySQL-defined database nightly. Data were backed-up daily from three sites centrally, and auto-reported weekly. Pre-census materials' costs were estimated. Demographics of 308,348 individuals from 80,851 households were recorded within an average of 14.7 weeks range (13-16) using 65 fieldworkers. Overall, 21.7 errors (95% confidence interval: 21.4, 22.0) per 10,000 data points were found: 13.0 (95% confidence interval: 12.6, 13.5) and 24.5 (95% confidence interval: 24.1, 24.9) errors on numeric and text fields respectively. These values meet standard quality threshold of 50 errors per 10,000 data points. The EDC's total variable cost was estimated at US$13,791.82 per site. In conclusion, the EDC is robust, allowing for timely and high-volume accurate data collection, and could be adopted in similar epidemiological settings.


Hydrogen-Driven Cage Unzipping of C60 into Nano-Graphenes.
Annealing of C60 in hydrogen at temperatures above the stability limit of C-H bonds in C60H x (500-550 °C) is found to result in direct collapse of the cage structure, evaporation of light hydrocarbons, and formation of solid mixture composed of larger hydrocarbons and few-layered graphene sheets. Only a minor part of this mixture is soluble; this was analyzed using matrix-assisted laser desorption/ionization MS, Fourier transform infrared (FTIR), and nuclear magnetic resonance spectroscopy and found to be a rather complex mixture of hydrocarbon molecules composed of at least tens of different compounds. The sequence of most abundant peaks observed in MS, which corresponds to C2H2 mass difference, suggests a stepwise breakup of the fullerene cage into progressively smaller molecular fragments edge-terminated by hydrogen. A simple model of hydrogen-driven C60 unzipping is proposed to explain the observed sequence of fragmentation products. The insoluble part of the product mixture consists of large planar polycyclic aromatic hydrocarbons, as evidenced by FTIR and Raman spectroscopy, and some larger sheets composed of few-layered graphene, as observed by transmission electron microscopy. Hydrogen annealing of C60 thin films showed a thickness-dependent results with reaction products significantly different for the thinnest films compared to bulk powders. Hydrogen annealing of C60 films with the thickness below 10 nm was found to result in formation of nanosized islands with Raman spectra very similar to the spectra of coronene oligomers and conductivity typical for graphene.


[Prevalence of metabolic syndrome in a sample of Chilean children consulting in an obesity clinic].
In Chile between 1986 and 1998, the prevalence of obesity has increased from 4.6% to 24% in prepuberal and from 2.3% to 17% in puberal children. To assess the prevalence of metabolic syndrome (MS) in a sample of obese and overweight Chilean children. Descriptive study in 489 children (273 females), aged from 6 to 16 years, consulting in an obesity program. Body mass index, Tanner puberal development, waist circumference, blood pressure, fasting blood glucose, insulin and lipid levels were measured. Insulin sensitivity was calculated using the mathematical models QUICKI and HOMA. MS was diagnosed when three or more of the following criteria were met: a waist circumference over percentile 90, a blood pressure over percentile 90, serum triglycerides over 110 mg/dl, HDL cholesterol of less than 40 mg/dl or a fasting blood glucose level over 100 mg/dl. MS was present in 4% of children with overweight and 30% of obese children. No differences in prevalence were observed for sex or puberal development. The most prevalent cardiovascular risk factors were abdominal obesity, present in 76% of the sample and high triclycerides levels in 39%. The less prevalent risk factor was a fasting blood glucose over 100 mg/dl in 3.7%. The risk for MS increased ten fold in children with severe obesity, compared with those with overweight. Those with abdominal obesity had a 17 times higher risk of MS. Basal insulin sensitivity was significantly associated with the number of cardiovascular risk factors and the presence of MS. In this sample of children, fat distribution and the severity of obesity were strong determinants of MS. Waist circumference had a higher impact on MS than body mass index.


Effect of an opt-out point-of-care HIV-1 nucleic acid testing intervention to detect acute and prevalent HIV infection in symptomatic adult outpatients and reduce HIV transmission in Kenya: a randomized controlled trial.
In sub-Saharan Africa, adult outpatients with symptoms of acute infectious illness are not routinely tested for prevalent or acute HIV infection (AHI) when seeking healthcare. Adult symptomatic outpatients aged 18-39 years were evaluated by a consensus AHI risk score. Patients with a risk score ≥ 2 and no previous HIV diagnosis were enrolled in a stepped-wedge trial of opt-out delivery of point-of-care (POC) HIV-1 nucleic acid testing (NAAT), compared with standard provider-initiated HIV testing using rapid tests in the observation period. The primary outcome was the number of new diagnoses in each study period. Generalized estimating equations with a log-binomial link and robust variance estimates were used to account for clustering by health facility. The trial is registered with ClinicalTrials.gov NCT03508908. Between 2017 and 2020, 13 (0.9%) out of 1374 participants in the observation period and 37 (2.5%) out of 1500 participants in the intervention period were diagnosed with HIV infection. Of the 37 newly diagnosed cases in the intervention period, two (5.4%) had AHI. Participants in the opt-out intervention had a two-fold greater odds of being diagnosed with HIV (odds ratio = 2.2, 95% confidence interval: 1.39-3.51) after adjustment for factors imbalanced across study periods. Among symptomatic adults aged 18-39 years targeted by our POC NAAT intervention, we identified one chronic HIV infection for every 40 patients and one AHI patient for every 750 patients tested. Although AHI yield was low in this population, routinely offered opt-out testing could diagnose twice as many patients as an approach relying on provider discretion.


Past changes in Arctic terrestrial ecosystems, climate and UV radiation.
At the last glacial maximum, vast ice sheets covered many continental areas. The beds of some shallow seas were exposed thereby connecting previously separated landmasses. Although some areas were ice-free and supported a flora and fauna, mean annual temperatures were 10-13 degrees C colder than during the Holocene. Within a few millennia of the glacial maximum, deglaciation started, characterized by a series of climatic fluctuations between about 18,000 and 11,400 years ago. Following the general thermal maximum in the Holocene, there has been a modest overall cooling trend, superimposed upon which have been a series of millennial and centennial fluctuations in climate such as the "Little Ice Age spanning approximately the late 13th to early 19th centuries. Throughout the climatic fluctuations of the last 150,000 years, Arctic ecosystems and biota have been close to their minimum extent within the most recent 10,000 years. They suffered loss of diversity as a result of extinctions during the most recent large-magnitude rapid global warming at the end of the last glacial stage. Consequently, Arctic ecosystems and biota such as large vertebrates are already under pressure and are particularly vulnerable to current and projected future global warming. Evidence from the past indicates that the treeline will very probably advance, perhaps rapidly, into tundra areas, as it did during the early Holocene, reducing the extent of tundra and increasing the risk of species extinction. Species will very probably extend their ranges northwards, displacing Arctic species as in the past. However, unlike the early Holocene, when lower relative sea level allowed a belt of tundra to persist around at least some parts of the Arctic basin when treelines advanced to the present coast, sea level is very likely to rise in future, further restricting the area of tundra and other treeless Arctic ecosystems. The negative response of current Arctic ecosystems to global climatic conditions that are apparently without precedent during the Pleistocene is likely to be considerable, particularly as their exposure to co-occurring environmental changes (such as enhanced levels of UV-B, deposition of nitrogen compounds from the atmosphere, heavy metal and acidic pollution, radioactive contamination, increased habitat fragmentation) is also without precedent.


The evolution of a neglected disease: tuberculosis discoveries in the centuries.
Tuberculosis (TB) and humans have coexisted for more than 40,000 years. The word "tuberculosis" derives from "tubercle", the histological lesion which appears in the organs, described by Pott in the late Eighteenth century and found, by molecular biology, in human skeletons dating back to 5000 BC. Early description of TB can be found in the writings of ancient India and China and in the Bible. In ancient Greece tuberculosis was not considered contagious, but Aristotle recognized the contagious nature of the pig's and ox's scrofula. The suspicion that phthisis is a contagious disease and that isolation can reduce the risk of transmission was expressed for the first time by the Arabian Avicenna, in his work "The canon of medicine". In 1699, the Health Council of the Republic of Lucca founded the "sanatorium" concept as place of care and isolation. In 1865 Villemain inoculated tubercular material from a human lymph node into a rabbit, obtaining for the first time the typical tubercular lesions. Some years later, on March 24, 1882, Robert Koch announced to the Berlin Society of Physiology the discovery of Mycobacterium tuberculosis. In the same period Virchow improved awareness of risk factors and correct behaviours among the general population. In 1952 Waksman won the Nobel Prize for the discovery of the first active drug against TB: streptomycin. Nevertheless, drug resistance appeared rapidly some years later and it is still a great challenge in TB fight nowadays.


Field-scale remediation of a metolachlor-contaminated spill site using zerovalent iron.
Pesticide spills are common occurrences at agricultural cooperatives and farmsteads. When inadvertent spills occur, chemicals normally beneficial can become point sources of ground and surface water contamination. We report results from a field trial where approximately 765 m3 of soil from a metolachlor [2-chloro-N-(2-ethyl-6-methylphenyl)-N-(2-methoxy-1-methylethyl) acetamide] spill site was treated with zerovalent iron (Fe0). Preliminary laboratory experiments confirmed metolachlor dechlorination by Fe0 in aqueous solution and that this process could be accelerated by adding appropriate proportions of Al2(SO4)3 or acetic acid (CH3COOH). The field project was initiated by moving the stockpiled, contaminated soil into windrows using common earth-moving equipment. The soil was then mixed with water (0.35-0.40 kg H2O kg(-1)) and various combinations of 5% Fe0 (w/w),2% Al2(SO4)3 (w/w), and 0.5% acetic acid (v/w). Windrows were covered with clear plastic and incubated without additional mixing for 90 d. Approximately every 14 d, the plastic sheeting was removed for soil sampling and the surface of the windrows rewetted. Metolachlor concentrations were significantly reduced and varied among treatments. The addition of Fe0 alone decreased metolachlor concentration from 1789 to 504 mg kg(-1) within 90 d, whereas adding Fe0 with Al2(SO4)3 and CH3COOH decreased the concentration from 1402 to 13 mg kg(-1). These results provide evidence that zerovalent iron can be used for on-site, field-scale treatment of pesticide-contaminated soil.


Knowledge and use of antimicrobial stewardship resources by spinal cord injury providers.
To assess the knowledge and the use of antimicrobial stewardship resources, such as hospital antibiograms and infectious disease consultants, by spinal cord injury or disorder (SCI/D) providers. Anonymous Internet-based, cross-sectional survey. A total of 314 SCI/D physicians, nurse practitioners, and physician assistants who prescribe antibiotics were invited to complete a survey. Knowledge of and behaviors related to antibiograms and infectious disease (ID) consults. A total of 118 providers (80 physicians, 20 nurse practitioners, 18 physician assistants) completed the survey (37.6% response rate). Approximately one-third of respondents indicated that they did not have access to (11.0%) or were unsure of (28.0%) the existence of facility antibiograms. Half of the providers indicated that they never used antibiograms to determine treatment for their SCI/D patients. Respondent factors associated with viewing facility antibiograms were older age, employment at SCI/D specialty centers, a longer duration since completion of training, and years of SCI/D patient care. Nearly all respondents (95%) indicated that they believed that improving access to antibiotic prescribing data or antibiograms would reduce antibiotic resistance. More than one-third reported that they never or seldom used ID consults. A significant portion of SCI/D providers who prescribe antibiotics do not have access to facility antibiograms or are unaware of their existence and thus could not use them for determining antibiotic treatment. Interventions could include formal education of providers on how to access antibiograms and the use of ID physicians as a resource, as well as providing technologic support, such as electronic facility-level antibiograms as part of the medical record system, which can be easily identified if a provider is making a decision on an antibiotic.


Inflammatory arthritis increases mouse osteoclast precursors with myeloid suppressor function.
Increased osteoclastic bone resorption leads to periarticular erosions and systemic osteoporosis in RA patients. Although a great deal is known about how osteoclasts differentiate from precursors and resorb bone, the identity of an osteoclast precursor (OCP) population in vivo and its regulatory role in RA remains elusive. Here, we report the identification of a CD11b(-/lo)Ly6C(hi) BM population with OCP activity in vitro and in vivo. These cells, which can be distinguished from previously characterized precursors in the myeloid lineage, display features of both M1 and M2 monocytes and expand in inflammatory arthritis models. Surprisingly, in one mouse model of RA (adoptive transfer of SKG arthritis), cotransfer of OCP with SKG CD4+ T cells diminished inflammatory arthritis. Similar to monocytic myeloid-derived suppressor cells (M-MDSCs), OCPs suppressed CD4+ and CD8+ T cell proliferation in vitro through the production of NO. This study identifies a BM myeloid precursor population with osteoclastic and T cell-suppressive activity that is expanded in inflammatory arthritis. Therapeutic strategies that prevent the development of OCPs into mature bone-resorbing cells could simultaneously prevent bone resorption and generate an antiinflammatory milieu in the RA joint.


Temporal Gene Expression Analysis and RNA Silencing of Single and Multiple Members of Gene Family in the Lone Star Tick Amblyomma americanum.
Saliva is an integral factor in the feeding success of veterinary and medically important ticks. Therefore, the characterization of the proteins present in tick saliva is an important area of tick research. Here, we confirmed previously generated sialotranscriptome data using quantitative real-time PCR. The information obtained in this in-depth study of gene expression was used to measure the effects of metalloprotease gene silencing on tick feeding. We analyzed the temporal expression of seven housekeeping genes and 44 differentially expressed salivary molecules selected from a previously published Amblyomma americanum sialotranscriptome. Separate reference genes were selected for the salivary glands and midgut from among the seven housekeeping genes, to normalize the transcriptional expression of differentially expressed genes. The salivary gland reference gene, ubiquitin, was used to normalize the expression of 44 salivary genes. Unsurprisingly, each gene family was expressed throughout the blood meal, but the expression of specific genes differed at each time point. To further clarify the complex nature of the many proteins found in the saliva, we disrupted the translation of several members of the metalloprotease family. Intriguingly, the nucleotide sequence similarity of the reprolysin metalloprotease gene family is so homologous that a single synthesized dsRNA sequence knocked down multiple members of the family. The use of multigene knockdown yielded a more significant picture of the role of metalloproteases in tick feeding success, and changes were observed in the female engorgement weight and larval hatching success. Interestingly, the depletion of metalloprotease transcripts also reduced the total number of bacteria present in the salivary glands. These data provide insight into the expression and functions of tick salivary proteins expressed while feeding on its host.


A review of US anthropometric reference data (1971-2000) with comparisons to both stylized and tomographic anatomic models.
Two classes of anatomic models currently exist for use in both radiation protection and radiation dose reconstruction: stylized mathematical models and tomographic voxel models. The former utilize 3D surface equations to represent internal organ structure and external body shape, while the latter are based on segmented CT or MR images of a single individual. While tomographic models are clearly more anthropomorphic than stylized models, a given model's characterization as being anthropometric is dependent upon the reference human to which the model is compared. In the present study, data on total body mass, standing/sitting heights and body mass index are collected and reviewed for the US population covering the time interval from 1971 to 2000. These same anthropometric parameters are then assembled for the ORNL series of stylized models, the GSF series of tomographic models (Golem, Helga, Donna, etc), the adult male Zubal tomographic model and the UF newborn tomographic model. The stylized ORNL models of the adult male and female are found to be fairly representative of present-day average US males and females, respectively, in terms of both standing and sitting heights for ages between 20 and 60-80 years. While the ORNL adult male model provides a reasonably close match to the total body mass of the average US 21-year-old male (within approximately 5%), present-day 40-year-old males have an average total body mass that is approximately 16% higher. For radiation protection purposes, the use of the larger 73.7 kg adult ORNL stylized hermaphrodite model provides a much closer representation of average present-day US females at ages ranging from 20 to 70 years. In terms of the adult tomographic models from the GSF series, only Donna (40-year-old F) closely matches her age-matched US counterpart in terms of average body mass. Regarding standing heights, the better matches to US age-correlated averages belong to Irene (32-year-old F) for the females and Golem (38-year-old M) for the males. Both Helga (27-year-old F) and Donna, however, provide good matches to average US sitting heights for adult females, while Golem and Otoko (male of unknown age) yield sitting heights that are slightly below US adult male averages. Finally, Helga is seen as the only GSF tomographic female model that yields a body mass index in line with her average US female counterpart at age 26. In terms of dose reconstruction activities, however, all current tomographic voxel models are valuable assets in attempting to cover the broad distribution of individual anthropometric parameters representative of the current US population. It is highly recommended that similar attempts to create a broad library of tomographic models be initiated in the United States and elsewhere to complement and extend the limited number of tomographic models presently available for these efforts.


Nonlytic cellular release of hepatitis A virus requires dual capsid recruitment of the ESCRT-associated Bro1 domain proteins HD-PTP and ALIX.
Although picornaviruses are conventionally considered 'nonenveloped', members of multiple picornaviral genera are released nonlytically from infected cells in extracellular vesicles. The mechanisms underlying this process are poorly understood. Here, we describe interactions of the hepatitis A virus (HAV) capsid with components of host endosomal sorting complexes required for transport (ESCRT) that play an essential role in release. We show release of quasi-enveloped virus (eHAV) in exosome-like vesicles requires a conserved export signal located within the 8 kDa C-terminal VP1 pX extension that functions in a manner analogous to late domains of canonical enveloped viruses. Fusing pX to a self-assembling engineered protein nanocage (EPN-pX) resulted in its ESCRT-dependent release in extracellular vesicles. Mutational analysis identified a 24 amino acid peptide sequence located within the center of pX that was both necessary and sufficient for nanocage release. Deleting a YxxL motif within this sequence ablated eHAV release, resulting in virus accumulating intracellularly. The pX export signal is conserved in non-human hepatoviruses from a wide range of mammalian species, and functional in pX sequences from bat hepatoviruses when fused to the nanocage protein, suggesting these viruses are released as quasi-enveloped virions. Quantitative proteomics identified multiple ESCRT-related proteins associating with EPN-pX, including ALG2-interacting protein X (ALIX), and its paralog, tyrosine-protein phosphatase non-receptor type 23 (HD-PTP), a second Bro1 domain protein linked to sorting of ubiquitylated cargo into multivesicular endosomes. RNAi-mediated depletion of either Bro1 domain protein impeded eHAV release. Super-resolution fluorescence microscopy demonstrated colocalization of viral capsids with endogenous ALIX and HD-PTP. Co-immunoprecipitation assays using biotin-tagged peptides and recombinant proteins revealed pX interacts directly through the export signal with N-terminal Bro1 domains of both HD-PTP and ALIX. Our study identifies an exceptionally potent viral export signal mediating extracellular release of virus-sized protein assemblies and shows release requires non-redundant activities of both HD-PTP and ALIX.


An integrative analysis of gene expression and molecular interaction data to identify dys-regulated sub-networks in inflammatory bowel disease.
Inflammatory bowel disease (IBD) consists of two main disease-subtypes, Crohn's disease (CD) and ulcerative colitis (UC); these subtypes share overlapping genetic and clinical features. Genome-wide microarray data enable unbiased documentation of alterations in gene expression that may be disease-specific. As genetic diseases are believed to be caused by genetic alterations affecting the function of signalling pathways, module-centric optimisation algorithms, whose aim is to identify sub-networks that are dys-regulated in disease, are emerging as promising approaches. In order to account for the topological structure of molecular interaction networks, we developed an optimisation algorithm that integrates databases of known molecular interactions with gene expression data; such integration enables identification of differentially regulated network modules. We verified the performance of our algorithm by testing it on simulated networks; we then applied the same method to study experimental data derived from microarray analysis of CD and UC biopsies and human interactome databases. This analysis allowed the extraction of dys-regulated subnetworks under different experimental conditions (inflamed and uninflamed tissues in CD and UC). Optimisation was performed to highlight differentially expressed network modules that may be common or specific to the disease subtype. We show that the selected subnetworks include genes and pathways of known relevance for IBD; in particular, the solutions found highlight cross-talk among enriched pathways, mainly the JAK/STAT signalling pathway and the EGF receptor signalling pathway. In addition, integration of gene expression with molecular interaction data highlights nodes that, although not being differentially expressed, interact with differentially expressed nodes and are part of pathways that are relevant to IBD. The method proposed here may help identifying dys-regulated sub-networks that are common in different diseases and sub-networks whose dys-regulation is specific to a particular disease.


Significance of pre-epiglottic space invasion in supracricoid partial laryngectomy with cricohyoidopexy.
Cancerous involvement of the pre-epiglottic space has been known for many years to be an important prognostic factor. The aim of this study was to investigate the prognostic value of pre-epiglottic space invasion, according to the degree of invasion (i.e. absence, minimal or gross), and to assess the oncological suitability for supracricoid partial laryngectomy in patients with supraglottic laryngeal carcinomas. This study included 52 patients with squamous cell carcinomas of the supraglottic and glotto-supraglottic larynx, treated with supracricoid partial laryngectomy-cricohyoidopexy, between 1992 and 2001. Clinical and histopathological parameters were evaluated. Pre-epiglottic space invasion was seen in 35 patients (67.3 per cent); there was gross invasion in seven patients and minimal invasion in 28. Neoplastic invasion of the anterior commissure was seen in 18 patients (34.6 per cent) and thyroid cartilage involvement in eight (15.4 per cent). Neoplastic spread through the extralaryngeal tissues was not seen in any patient. The five-year overall survival was 71.5 per cent for patients with gross pre-epiglottic space invasion, 82.2 per cent for those with minimal pre-epiglottic space invasion, and 76.4 per cent for those without pre-epiglottic space invasion. It was observed that gross or minimal pre-epiglottic space invasion did not have a statistically significant effect on survival. Univariate analysis showed that nodal positivity was associated with a poor prognosis. None of the other parameters analysed showed a statistically significant relationship with survival. Four (7.6 per cent) patients had local laryngeal recurrence. Distant metastasis and a second primary tumour were detected in three (5.8 per cent) and four (7.6 per cent) patients, respectively. The five-year overall survival and cause-specific survival were 78.8 and 82 per cent, respectively. Supracricoid partial laryngectomy with cricohyoidopexy can safely be performed in supraglottic and glotto-supraglottic carcinomas with minimal or gross invasion of the pre-epiglottic space which have no extralaryngeal spread. Nodal status is an important predictor affecting survival.


Phenological asynchrony between herbivorous insects and their hosts: signal of climate change or pre-existing adaptive strategy?
Climate change alters phenological relations between interacting species. We might expect the historical baseline, or starting-point, for such effects to be precise synchrony between the season at which a consumer most requires food and the time when its resources are most available. We synthesize evidence that synchrony was not the historical condition in two insect-plant interactions involving Edith's checkerspot butterfly (Euphydryas editha), the winter moth (Operophtera brumata) and their host plants. Initial observations of phenological mismatch in both systems were made prior to the onset of anthropogenically driven climate change. Neither species can detect the phenology of its host plants with precision. In both species, evolution of life history has involved compromise between maximizing fecundity and minimizing mortality, with the outcome being superficially maladaptive strategies in which many, or even most, individuals die of starvation through poor synchrony with their host plants. Where phenological asynchrony or mismatch with resources forms the starting point for effects of anthropogenic global warming, consumers are particularly vulnerable to impacts that exacerbate the mismatch. This vulnerability likely contributed to extinction of a well-studied metapopulation of Edith's checkerspot, and to the skewed geographical pattern of population extinctions underlying a northward and upward range shift in this species.


How physicians' organizations compete: protectionism and efficiency.
This article develops a framework that distinguishes four types of competitive strategies that physicians' organizations can adopt in their interactions with health plans. Two types of strategies protect physicians' incomes and autonomy from incursion and control by insurers; the other two enhance the efficiency of health care markets by controlling costs and embedding physicians' caregiving in a community of professionals. The mix of strategies that each organization adopts at any given time depends on the market conditions and regulatory policies it faces, as well as its organizational capacity. The article reviews recent developments in the field that indicate that today's markets and regulations create neither the pressures nor the capacity for physicians' organizations to adopt strategies that enhance efficiency. The managed care backlash has led to a relaxation of pressures to control costs, and the lack of a business case for quality has discouraged embedded caregiving. These developments instead have encouraged and enabled physicians' organizations to adopt strategies that protect their members from the bargaining power and micromanagement of health plans. The article therefore proposes changes in purchasing and regulatory policies to alter the pressures and improve the capacity of physicians' organizations to pursue efficiency and eschew protectionism.


WALK 2.0: examining the effectiveness of Web 2.0 features to increase physical activity in a 'real world' setting: an ecological trial.
Low levels of health-enhancing physical activity require novel approaches that have the potential to reach broad populations. Web-based interventions are a popular approach for behaviour change given their wide reach and accessibility. However, challenges with participant engagement and retention reduce the long-term maintenance of behaviour change. Web 2.0 features present a new and innovative online environment supporting greater interactivity, with the potential to increase engagement and retention. In order to understand the applicability of these innovative interventions for the broader population, 'real-world' interventions implemented under 'everyday conditions' are required. The aim of this study is to investigate the difference in physical activity behaviour between individuals using a traditional Web 1.0 website with those using a novel Web 2.0 website. In this study we will aim to recruit 2894 participants. Participants will be recruited from individuals who register with a pre-existing health promotion website that currently provides Web 1.0 features (http://www.10000steps.org.au). Eligible participants who provide informed consent will be randomly assigned to one of the two trial conditions: the pre-existing 10 000 Steps website (with Web 1.0 features) or the newly developed WALK 2.0 website (with Web 2.0 features). Primary and secondary outcome measures will be assessed by self-report at baseline, 3 months and 12 months, and include: physical activity behaviour, height and weight, Internet self-efficacy, website usability, website usage and quality of life. This study has received ethics approval from the University of Western Sydney Human Research Ethics Committee (Reference Number H8767) and has been funded by the National Health and Medical Research Council (Reference Number 589903). Study findings will be disseminated widely through peer-reviewed publications, academic conferences and local community-based presentations. Australian New Zealand Clinical Trials Registry Number: ACTRN12611000253909, WHO Universal Trial Number: U111-1119-1755.


Porocytosis: a new approach to synaptic function.
We propose a new approach to address the question of how a single quantum of neurotransmitter is secreted from a presynaptic terminal whose clustered secretory vesicles are locally bathed in high levels of calcium ions [Proceedings of the Symposium on Bioelectrogenesis (1961) 297-309; The Physiology of Synapses (1964) Chapters 1, 4, 5, 6; How the Self Controls its Brain (1994) Chapters 1, 4, 5, 6; Science 256 (1992) 677-679]. This hypothesis, which we term 'porocytosis', posits that the post-synaptic quantal response results from transmitter secreted through an array of docked vesicle/secretory pore complexes. The transient increase in calcium ions, which results from the voltage activated calcium channels, stimulates the array of secretory pores to simultaneously flicker open to pulse transmitter. Porocytosis is consistent with the quantal nature of presynaptic secretion and transmission, and with available biochemical, morphological and physiological evidence. It explains the frequency dependency of quantal size as a function of the secretion process. It permits a signature amount of transmitter release for different frequencies allowing a given synapse to be employed in different behavioral responses. The porocytosis hypothesis permits fidelity of secretion and the seemingly apposed characteristic of synaptic plasticity. The dynamics inherent in an array insure a constant quantal size as a function of the number of units within the array. In this hypothesis, plasticity is a consequence of concurrent pre- and post-synaptic changes due to a change in array size. Changes in the number of docked vesicle-secretory pore complexes composing the array can explain facilitation, depletion, graded excitation-secretion and long term plasticity.


Wrinkling of two-dimensional materials: methods, properties and applications.
Recently, two-dimensional (2D) materials, including graphene, its derivatives, metal films, MXenes and transition metal dichalcogenides (TMDs), have been widely studied because of their tunable electronic structures and special electrical and optical properties. However, during the fabrication of these 2D materials with atomic thickness, formation of wrinkles or folds is unavoidable to enable their stable existence. Meaningfully, it is found that wrinkled structures simultaneously impose positive changes on the 2D materials. Specifically, the architecture of wrinkled structures in 2D materials additionally induces excellent properties, which are of great importance for their practical applications. In this review, we provide an overview of categories of 2D materials, which contains formation and fabrication methods of wrinkled patterns and relevant mechanisms, as well as the induced mechanical, electrical, thermal and optical properties. Furthermore, these properties are modifiable by controlling the surface topography or even by dynamically stretching the 2D materials. Wrinkling offers a platform for 2D materials to be applied in some promising fields such as field emitters, energy containers and suppliers, field effect transistors, hydrophobic surfaces, sensors for flexible electronics and artificial intelligence. Finally, the opportunities and challenges of wrinkled 2D materials in the near future are discussed.


Endoscopic valvuloplasty for GERD.
The transoral, endoscopic route has been suggested as a possible approach for the correction of severe gastroesophageal reflux. Such a procedure would involve no mobilization of the cardia or other structures. The optimal placement, number, and configuration of sutures remains undefined. With the use of a previously developed endoscopic sewing machine, this study was undertaken in baboons with two suture arrangements immediately below the lower esophageal sphincter. A linear arrangement (group I) and a circular arrangement (group II) were compared. During the 6 months after the procedure, the animals were evaluated using manometry, fluoroscopic barium swallow, upper gastrointestinal endoscopy, and a pressure volume test. A significant increase in lower esophageal sphincter length was demonstrated only in group II (p = 0. 010). A significant increase in lower esophageal sphincter pressure was demonstrated only in group I animals (p = 0.008). The abdominal length increased in group I (p = 0.004) and group II (p = 0.004). The yield pressure and yield volume did not differ significantly from those measured previously in control animals. No evidence of reflux, stricture formation, esophagitis, or other pathology was noted. Some manometric parameters associated with gastroesophageal reflux are altered by the endoscopic placement of sutures below the gastroesophageal junction, with no associated serious complications.


Cells move when ions and water flow.
Cell migration is a process that plays an important role throughout the entire life span. It starts early on during embryogenesis and contributes to shaping our body. Migrating cells are involved in maintaining the integrity of our body, for instance, by defending it against invading pathogens. On the other side, migration of tumor cells may have lethal consequences when tumors spread metastatically. Thus, there is a strong interest in unraveling the cellular mechanisms underlying cell migration. The purpose of this review is to illustrate the functional importance of ion and water channels as part of the cellular migration machinery. Ion and water flow is required for optimal migration, and the inhibition or genetic ablation of channels leads to a marked impairment of migration. We briefly touch cytoskeletal mechanisms of migration as well as cell-matrix interactions. We then present some general principles by which channels can affect cell migration before we discuss each channel group separately.


The use of HeRo catheter in catheter-dependent dialysis patients with superior vena cava occlusion.
Hemodialysis (HD) patients with superior vena cava (SVC) occlusion have limited access options. Femoral access is commonly employed but is associated with high complication rates. Hemodialysis Reliable Outflow (HeRO) catheters can be used in tunneled catheter-dependent (TCD) patients who have exhausted other access options. The HeRO graft bypasses occlusion and traverses stenosis with outflow directly into the central venous circulation. At our institution we have used the inside-out central venous access technique (IOCVA) to traverse an occluded vena cava for HeRO graft placement. We review our experience with this technique. A retrospective chart review was conducted of patients with HeRO graft placement at our institution. All were dependent on a tunneled femoral dialysis catheter due to central venous occlusion (CVO). The IOCVA technique was used in each case. This technique was used as last resort for patients who had no other dialysis access option. Demographics, patency rates, complications, and mortality were recorded. A total of 11 HeRO grafts were placed in 11 patients from January 2012 to June 2013, with 100% technical success rate. Three grafts were ligated due to steal syndrome. Two grafts were lost due to thrombosis. Five of 11 patients experienced a 30-day complication. Three patients died within the follow-up period; however, none were directly related to the graft placement. Follow up range was 65-573 days; 5 of 11 grafts were used for dialysis at the end of the follow-up period. The 12-month patency rate was 30%. HeRO grafts are one option for dialysis patients with CVO. There is, however, a high incidence of steal syndrome and other complications. These grafts should be offered as a final potential alternative to catheter dependence.


Immune response to flour and dust mites in a United Kingdom bakery.
In a study of 279 United Kingdom bakery workers a high prevalence of immunological response to storage mites was found. To determine whether this was the consequence of exposure to storage mites in bakery work, a population of salt packing workers was examined as a comparison group not at occupational risk of exposure to storage mites. Forty two per cent of both groups were atopic (had a positive skin prick response greater than negative controls to D pteronyssinus, grass pollen, or cat fur by 2 mm or more) and 33% had an immediate skin prick test response to at least one of four storage mites (L destructor, G domesticus, T putrescentiae, A Siro). A higher percentage of the salt packing workers than the bakery workers had a positive radioallergosorbent test (RAST) (greater than or equal to 0.35 PRU) to D pteronyssinus and to the four storage mites. Logistic regression analysis identified atopy as the most significant variable for a positive skin test and RAST response to storage mites in both groups of workers. RAST inhibition was used to analyse extracted area and personal air samples. Analysis of static area samples for aeroallergen showed immunological identity with flour but L destructor was found in only one of seven exposed filters. The concentration of airborne flour was related to exposure rank of perceived dustiness and gravimetric measurement of total dust. Nineteen out of 32 filters from workers in jobs with higher dust exposure (rank >/=6) had a level of > 10 microgram/m(3) flour whereas this concentrations was exceeded in only one of 23 filters from workers in low dust exposure (< rank 6). It is concluded that storage mites are not of special significance in allergic responses in bakery workers. The development of immunological (and airway) responsiveness to inhaled flour dust is increased in those exposed to higher concentrations of airborne allergen, which appears to be predominantly flour and not storage mites.


Rapid Acting Insulin Use and Persistence among Elderly Type 2 Diabetes Patients Adding RAI to Oral Antidiabetes Drug Regimens.
We examined the real-world utilization and persistence of rapid acting insulin (RAI) in elderly patients with type 2 diabetes who added RAI to their drug (OAD) regimen. Insulin-naïve patients aged ≥65 years, with ≥1 OAD prescription during the baseline period, who were continuously enrolled in the US Humana Medicare Advantage insurance plan for 18 months and initiated RAI were included. Among patients with ≥2 RAI prescriptions (RAIp), persistence during the 12-month follow-up was assessed. Multivariate logistic regression analyses identified factors affecting RAI use and persistence. Of 3734 patients adding RAI to their OAD regimen, 2334 (62.5%) had a RAIp during follow-up. Factors associated with RAIp included using ≤2 OADs; cognitive impairment, basal insulin use during follow-up; and higher RAI out-of-pocket costs ($36 to <$56 versus $0 to $6.30). Patients were less likely to persist with RAI when on ≤2 OADs versus ≥3 OADs and when having higher RAI out-of-pocket costs ($36 to <$56 versus $0 to $6.30) and more likely to persist when they had cognitive impairment and basal insulin use during follow-up. Real-world persistence of RAI in insulin-naïve elderly patients with type 2 diabetes was very poor when RAI was added to an OAD regimen.


Dietary Carotenoids and Non-Alcoholic Fatty Liver Disease among US Adults, NHANES 2003⁻2014.
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. Oxidative stress is thought to be a major mechanism, and previous epidemiological studies found higher serum levels of antioxidant carotenoids were associated with reduced risk for development and progression of NAFLD. The objective of this analysis is to examine cross-sectional associations between dietary and serum levels of carotenoids in relation to NAFLD among a nationally representative sample of US adults. We used data from the 2003-2014 National Health and Nutrition Examination Survey (NHANES). Dietary carotenoid intake was estimated from a 24-hour recall, while serum carotenoids were measured from 2003 to 2006. The NAFLD status was determined based upon US Fatty Liver Index (FLI) value ≥30. Regression models were used to estimate associations between carotenoids and NAFLD by controlling for covariates and adjusting for survey design variables. Overall, 33% of participants were classified as having NAFLD. Intake of all carotenoids, with the exception of lycopene, was lower among those with NAFLD. This association was significant for the highest quartiles of intake of α-carotene, β-carotene, β-cryptoxanthin, and lutein/zeaxanthin. For serum measures, the highest level of all carotenoids was associated with significantly reduced odds of NAFLD. In conclusion, higher intake and serum levels of most carotenoids were associated with lower odds of having NAFLD. Identification of such modifiable lifestyle factors provide an opportunity to limit or prevent the disease and its progression.


Prognostic Significance of New AJCC Tumor Stage in Patients With Pancreatic Ductal Adenocarcinoma Treated With Neoadjuvant Therapy.
The American Joint Committee for Cancer has adopted a size-based T stage system (eighth edition) for pancreatic ductal adenocarcinoma (PDAC), defined as follows: pT1≤2 cm (pT1a≤0.5 cm, pT1b>0.5 and<1 cm, and pT1c 1-2 cm); pT2>2 and ≤4 cm; and pT3> 4 cm. However, the prognostic value of this new T staging system has not been validated in patients who underwent pancreaticoduodenectomy (PD) after neoadjuvant therapy. In this study, we analyzed 398 PDAC patients who underwent neoadjuvant therapy and PD at our institution from 1999 to 2012. The results were correlated with clinicopathologic parameters and survival. The new T stage correlated with lymph nodes metastasis (P<0.001), tumor response grade (P<0.001), disease-free survival (DFS, P<0.001) and overall survival (OS, P<0.001). None of the patients with ypT0 had recurrence or died of disease. Among the patients with ypT1 disease, patients with ypT1a and ypT1b had better DFS (P=0.046) and OS (P=0.03) than those with ypT1c. However, there was no significant difference in either DFS or OS between ypT1c and ypT2 or between ypT2 and ypT3 groups (P>0.05). In multivariate analysis, new ypT3 stage was associated with shorter OS (P=0.04), but not DFS (P=0.16). Our results show that the new ypT stage better stratify survival than the ypT stage in American Joint Committee for Cancer seventh edition for PDAC patients who received PD after neoadjuvant therapy, and that tumor size cutoff of 1.0 cm work better for ypT2 than the proposed tumor size cutoff of 2.0 cm in this group of patients.


Interruption of cytokine networks by poxviruses: lessons from myxoma virus.
Myxoma virus is an infectious poxvirus pathogen that induces a virulent systemic disease called myxomatosis in European rabbits. The disease is rapidly and uniformly fatal to susceptible rabbits and is characterized by generalized dysfunction of cellular immunity and multiple interruptions of the host cytokine network. A number of virus genes are classified as virulence factors because virus constructs bearing targeted gene disruptions induce attenuated disease symptoms. Many of these genes encode proteins that interact directly with effector elements of the host immune system. Included among these immunosubversive viral proteins are secreted mimics of host ligands or regulators (virokines) and homologues of cellular cytokine receptors (viroceptors). Five examples of these immune modulator proteins encoded by myxoma virus are reviewed: (1) myxoma growth factor, a member of the epidermal growth factor ligand superfamily; (2) SERP-1, a secreted serine proteinase inhibitor; (3) M11L, a receptor-like surface protein; (4) T2, a tumor necrosis factor receptor homologue; and (5) T7, an interferon-gamma receptor homologue. The origin of viral strategies designed to subvert immune regulation by host cytokines is considered in the context of the biology of myxoma virus within immunocompetent hosts.