Breast masses in young women.
To better define the risk of breast cancer in young patients, a retrospective review of all breast biopsies in women under age 40 years at Grady Memorial Hospital, Atlanta, from Dec 1, 1981, to Aug 15, 1987, was performed. During this time, 751 biopsies were performed on patients aged 9 to 40 years. None of the 128 patients aged 20 years or less had carcinoma. Of 150 patients aged 21 to 25 years, two had carcinoma. At age 26, there began a steady rise in the incidence of carcinoma, such that in the 36- to 40-year age group, carcinoma was present in 24.4% of the specimens. This retrospective review confirms previous reports that suggest that carcinoma of the breast is distinctly unusual in patients under age 20 and that breast masses in these young patients should be managed conservatively. As the incidence of carcinoma increases with the age of the patient, one's threshold for excisional biopsy should decrease.


Nonequilibrium atomistic molecular dynamics simulation of tubular nanomotor propelled by bubble propulsion.
We develop a molecular nanoscaled model for tubular motors propelled by bubble propulsion. The motor is modeled by a carbon nanotube, and the bubble is represented by a particle interacting with water by a time-dependent potential. Effects of liquid viscosity, fuel concentration, geometry, and size of the tube on the performance of the motor are effectively encoded into two parameters: time scales of the bubble expansion and bubble formation. Our results are qualitatively consistent with experimental data of much larger motors. Simulations suggest that (i) the displacement of the tube is optimized if two time scales are as short as possible, (ii) the compromise between the performance and fuel consumption is achieved if the bubble formation time is shorter than the velocity correlation time of the tube, (iii) the motor efficiency is higher with slow expansion, short formation of the bubble than fast growth but long formation time, and (iv) the tube is propelled by strong forces on the order of mN, reaching high speeds up to ∼60 m/s. Our simulation may be useful for refining and encouraging future experimental work on nanomotors having the size of a few nanometers. The tiny size and high speed motors could have great potential applications in real life.


Effects of extrusion, infrared and microwave processing on Maillard reaction products and phenolic compounds in soybean.
The Maillard reaction indicators furosine, hydroxymethylfurfural (HMF), acrylamide and color were determined to evaluate heat effects induced during extrusion, infrared and microwave heating of soybean. In addition, the present paper aimed to study changes in the phenolic compounds, as well as in the overall antioxidant properties of different soybean products in relation to heating at 45-140 °C during the processes. Soybean proteins were highly sensible to Maillard reaction and furosine was rapidly formed under slight heating conditions during extrusion and infrared heating. Microwave heating at lower temperatures for a longer time yielded lower acrylamide levels in the final soybean products, as a result of its partial degradation. However, during infrared heating, acrylamide formation greatly increased with decreasing moisture content. After a short time of extrusion and infrared heating at 140 °C and microwave heating at 135 °C for 5 min, concentrations of HMF increased to 11.34, 26.21 and 34.97 µg g(-1), respectively. The heating conditions caused formation of acrylamide, HMF and furosine in high concentration. The results indicate that the complex structure of soybeans provides protection of phenolic compounds from thermal degradation, and that Maillard reaction products improved the antioxidant properties of heat-treated soybean.


Characterization of the major catalase from Streptomyces coelicolor ATCC 10147.
Streptomyces coelicolor ATCC 10147 produced catalases whose electrophoretic mobility varied depending on the growth phase in liquid culture. Polyacrylamide gel electrophoresis of cell extracts resulted in six catalase activity bands, which were designated Cat1 to Ca6. Of these, Cat4 appeared during all growth phases, whereas Cat1 appeared only during the stationary phase. Catalase-deficient mutants were screened by the H2O2 bubbling test following NTG mutagenesis. In all the non-bubbling mutants tested, the Cat4 activity band significantly decreased or disappeared, suggesting that Cat4 is the major catalase. Cat4 was purified to electrophoretic homogeneity and some of its properties analysed. The enzyme has a native molecular mass of 225 kDa, as determined by gel permeation column chromatography, and consists of four identical subunits of 57 kDa, as determined by SDS-PAGE. The enzyme contains 2.6 molecules of protohaem IX per tetramer, as indicated by the absorption spectrum. It was not reducible by sodium dithionite and exhibited no peroxidase activity with o-dianisidine as the substrate. All these characteristics, as well as inhibitor studies, indicate that the major vegetative catalase in S. coelicolor, unlike E. coli vegetative catalase, is a member of the typical monofunctional catalases found in eukaryotes and some bacteria.


Evaluation of radioactive and heavy metal pollution in agricultural soil surrounding the lignite-fired thermal power plant using pollution indices.
Soil pollution caused by heavy metals negatively affects the environment and human health. However, the assessment of the environmental and ecological risks caused by heavy metals in agricultural soils in developing countries is limited. This study was carried out to determine heavy metal pollution and its possible sources in the agricultural lands surrounding the lignite-fired Afşin-Elbistan thermal power plant (TPP). A total of 52 soil samples were collected from the agricultural soils surrounding the TPP, and seven different heavy metal (U, Th, Ni, Fe, Cu, Cr and Zn) analyzes were performed on these samples. Soil samples were taken according to the prevailing wind direction. Nickel had a higher geoaccumulation index (1.40) and enrichment factor (5.09) values than the other metals. In addition, U posed a "moderate potential ecological risk" in the study area. Pearson correlation and principal component analyses showed that U, Ni, and Cr were controlled by anthropogenic sources.


Molecular electrodes at the exposed edge of metal/insulator/metal trilayer structures.
Producing reliable electrical contacts of molecular dimensions has been a critical challenge in the field of molecule-based electronics. Conventional thin film deposition and photolithography techniques have been utilized to construct novel nanometer-sized electrodes on the exposed vertical plane on the edge of a thin film multilayer structure (metal/insulator/metal). Via thiol surface attachment to metal leads, an array of paramagnetic, cyanide-bridged octametal complexes, [(pzTp)FeIII(CN)3]4[NiII(L)]4[O3SCF3]4 (1) [(pzTp) = tetra(pyrazol-1-yl)borate; L = 1-S(acetyl)tris(pyrazolyl)decane], were covalently linked onto the electrodes forming a dominant conduction pathway. A series of molecule-based devices were fabricated using Ni, NiFe, Ta, and Au as metal electrodes separated by insulating Al2O3 spacers, followed by treatment with 1. A series of control experiments were also performed to demonstrate that the conduction path was through tethered metal clusters. The molecular current was analyzed via the Simmons tunnel model, and calculations are consistent with electron tunneling through the alkane ethers to the central metal core. With a Ni/Al2O3/Au molecular electrode, the tether binding was found to be reversible to the top Au layer, allowing for a new class of chemical detection based on the steric bulk of coordinating analytes to disconnect the molecular current path. Simple and economical photolithography/liftoff/self-assembly fabrication techniques afford robust molecular junctions with high reproducibility (>90%) and long operational lifetimes (>1 year).


Renal transport of neutral amino acids. Tubular localization of Na+-dependent phenylalanine- and glucose-transport systems.
The transport properties for phenylalanine and glucose in luminal-membrane vesicles from outer cortex (pars convoluta) and outer medulla (pars recta) of rabbit kidney were studied by a spectrophotometric method. Uptake of phenylalanine as well as of glucose by the two types of membrane vesicles was found to be Na+-dependent, electrogenic and stereospecific. Na+-dependent transport of L-phenylalanine by outer-cortical membrane vesicles could be accounted for by one transport system (KA congruent to 1.5 mM). By contrast, in the outer-medullary preparation, L-phenylalanine transport occurred via two transport systems, namely a high-affinity system with K1A congruent to 0.33 mM and a low-affinity system with K2A congruent to 7 mM respectively. Na+-dependent uptake of D-glucose by pars convoluta and pars recta membrane vesicles could be described by single, but different, transport systems, namely a low-affinity system with KA congruent to 3.5 mM and a high-affinity system with KA congruent to 0.30 mM respectively. Attempts to calculate the stoichiometry of the different Na+/D-glucose transport systems by using Hill-type plots revealed that the ratio of the Na+/hexose co-transport probably is 1:1 in the case of pars convoluta and 2:1 in membrane vesicles from pars recta. The Na+/L-phenylalanine stoichiometry of the pars convoluta transporter probably is 1:1. Both the high-affinity and the low-affinity Na+-dependent L-phenylalanine transport system of pars recta membrane vesicles seem to operate with a 1:1 stoichiometry. The physiological importance of the arrangement of low-affinity and high-affinity transport systems along the kidney proximal tubule is discussed.


MRI detection of early bone metastases in b16 mouse melanoma models.
Bone metastasis causes significant morbidity in cancer patients, including bone pain, pathologic fractures, nerve compression syndrome, and hypercalcemia. Animal models are utilized to study the pathogenesis of skeletal metastases and to evaluate potential therapeutic agents. Previously published methods for imaging bone metastasis in rodent models have focused on identifying advanced stage metastasis using simple X-rays. Here we report MRI as a method for detecting early bone metastases in mouse models in vivo. B16 mouse melanoma cells were injected into the left cardiac ventricle of C57BL/6 mice and magnetic resonance (MR) images were obtained of the left leg following the development of metastatic disease, when tumor associated bone destruction was histologically present but not visible by X-ray. T1 and T2 relaxation times of bone marrow were measured in healthy control mice and B16 melanoma tumor-bearing mice. Mean T2 values for normal marrow were 28 ms (SD 5) and for diseased bone marrow were 41 ms (SD 3). T2 relaxation time of diseased bone marrow is significantly longer than that of normal bone marrow (P < 0.0001) and can be used as a marker of early bone metastases. These studies demonstrate that MR imaging can detect bone marrow metastases in small animals prior to development of cortical bone loss identified by X-ray.


[Mechanisms that limit pollinator range in Ericaceae].
Studies were conducted in 2001-2003 at Valdai National Park (Novgorod region) and at the Zvenigorod biological station of Moscow State University. The morphology of flowers, flowering dynamics and composition of insect visiting flowers of Ericaceae species: Andromeda polifolia, Chamaedaphne calyculata, Ledum palustre, Oxycoccus palustris, Vaccinium myrtillus, V. uliginosum, and V. vitis-idaea L. were studied. Some species of insects visiting flowers were excluded from the list of pollinators on the basis of observation on their behavior. L. palustre was visited mainly by flies where as other investigated species were visited mainly by bumblebees. In some cases bumblebees were the only visitors of the investigated plants. Mechanisms that protect flowers from flies and short-tongued solitary bees visits and ensure a best pollination by bumblebees are various among different species of Ericaceae. Efficiency of nectary protection also differs among different plant species and is defined by particularities of their habitats and flowering phenology. As far as all species of this family during the flowering are dominants in typical habitats, a competition for the pollination with species of other families in most cases is megligible. Flowering periods of V. vitis-idaea and V. myrtillus in forest ecosystems overlapped weakly. Moreover, V. myrtillus is pollinated mainly by bumblebee queens where as pollinators of V. vitis-idaea are bumblebee workers, solitary bees and horse flies. The other investigated plant species inhabit only oligotrophic peat bogs. Thery are pollinated by bumblebees but periods of flowering are not overlapped and consequently follow one after another. L. palustre and V. uliginosum flower simultaneosly but they are pollinated by different pollinators.


Reinforcing the role of the conventional C-arm--a novel method for simplified distal interlocking.
The common practice for insertion of distal locking screws of intramedullary nails is a freehand technique under fluoroscopic control. The process is technically demanding, time-consuming and afflicted to considerable radiation exposure of the patient and the surgical personnel. A new concept is introduced utilizing information from within conventional radiographic images to help accurately guide the surgeon to place the interlocking bolt into the interlocking hole. The newly developed technique was compared to conventional freehand in an operating room (OR) like setting on human cadaveric lower legs in terms of operating time and radiation exposure. The proposed concept (guided freehand), generally based on the freehand gold standard, additionally guides the surgeon by means of visible landmarks projected into the C-arm image. A computer program plans the correct drilling trajectory by processing the lens-shaped hole projections of the interlocking holes from a single image. Holes can be drilled by visually aligning the drill to the planned trajectory. Besides a conventional C-arm, no additional tracking or navigation equipment is required.Ten fresh frozen human below-knee specimens were instrumented with an Expert Tibial Nail (Synthes GmbH, Switzerland). The implants were distally locked by performing the newly proposed technique as well as the conventional freehand technique on each specimen. An orthopedic resident surgeon inserted four distal screws per procedure. Operating time, number of images and radiation time were recorded and statistically compared between interlocking techniques using non-parametric tests. A 58% reduction in number of taken images per screw was found for the guided freehand technique (7.4 ± 3.4) (mean ± SD) compared to the freehand technique (17.6 ± 10.3) (p < 0.001). Total radiation time (all 4 screws) was 55% lower for the guided freehand technique compared to conventional freehand (p = 0.001). Operating time per screw (from first shot to screw tightened) was on average 22% reduced by guided freehand (p = 0.018). In an experimental setting, the newly developed guided freehand technique for distal interlocking has proven to markedly reduce radiation exposure when compared to the conventional freehand technique. The method utilizes established clinical workflows and does not require cost intensive add-on devices or extensive training. The underlying principle carries potential to assist implant positioning in numerous other applications within orthopedics and trauma from screw insertions to placement of plates, nails or prostheses.


Association of Low Fecal Elastase-1 and Non-Ulcer Dyspepsia.
Non-ulcer dyspepsia (NUD) is a term used to define a set of symptoms that are believed to originate from the gastroduodenal region, and no underlying organic, systemic, or metabolic reason can be found. The majority of patients suffer from chronic symptoms although half of the patients report improvement in symptoms with time. The potential role exocrine pancreatic insufficiency in NUD patients has not been clarified yet. We aimed to identify exocrine pancreas function with pancreatic fecal elastase-1 in patients diagnosed with non-ulcer dyspepsia and no typical exocrine pancreatic insufficiency (EPI) symptoms. Thirty-five patients referred to gastroenterology clinics with NUD and 35 people with no dyspeptic symptoms as a control group were included in this prospective study. Non-ulcer dyspepsia patients were classified as group 1 and control subjects classified as group 2. Upper gastrointestinal endoscopies were performed in both groups. Assessment of exocrine pancreatic function was performed by measuring fecal elastase-1 concentration with a commercial ELISA kit using polyclonal antibodies (BioServ Diagnostics) in NUD patients compared to control subjects. Mean fecal elastase-1 levels were significantly lower in group 1 patients compared with group 2 (367.47 ± 43.27; 502.48 ± 50.94 respectively; p = 0.04). The percentage of the patients with EPI was significantly higher in group 1 (p = 0.02). Patients with NUD should be re-evaluated if they do not show satisfactory improvement with treatment. Exocrine pancreatic insufficiency was significantly higher in patients with NUD in our study. Evaluation for the presence of EPI can be a cost effective approach in management of refractory patients during the process of ruling out organic reasons.


What is Ebola?
On 23 March 2014, the World Health Organization first announced a new Ebola virus outbreak that started in December 2013 in the eastern part of the Republic of Guinea. Human infections shortly emerged in Liberia, Sierra Leone, and Nigeria. On 30 September 2014, the Centers for Disease Control and Prevention confirmed through laboratory testing the first Ebola virus infection diagnosed in the USA, in a patient who travelled from West Africa to Texas. On 6 October 2014, the first human infection occurring outside of Africa was reported, in a Spanish nurse who treated two priests, both of whom died, and on 23 October 2014, the first human infection was reported in New York City. To date, the 2014 Ebola virus outbreak is the longest, largest, and most persistent one since 1976, when the virus was first identified in humans, and the number of human cases exceeded, as of mid-September 2014, the cumulative number of infections from all the previous outbreaks. The early clinical presentation overlaps with other infectious diseases, opening differential diagnosis difficulties. Understanding the transmission routes and identifying the natural reservoir of the virus are additional challenges in studying Ebola hemorrhagic fever outbreaks. Ebola virus is as much a public health challenge for developing countries as it is for the developed world, and previous outbreaks underscored that the relative contribution of the risk factors may differ among outbreaks. The implementation of effective preparedness plans is contingent on integrating teachings from previous Ebola virus outbreaks with those from the current outbreak and with lessons provided by other infectious diseases, along with developing a multifaceted inter-disciplinary and cross-disciplinary framework that should be established and shaped by biomedical as well as sociopolitical sciences.


Effects of Live Music Therapy on Autonomic Stability in Preterm Infants: A Cluster-Randomized Controlled Trial.
Unbuffered stress levels may negatively influence preterm-infants' autonomic nervous system (ANS) maturation, thus affecting neurobehavior and psycho-emotional development. Music therapy (MT) is an evidence-based treatment modality in neonatal care. When coupled with skin-to-skin care (SSC), it may reduce stress responses in both preterm infants and their parents and enhance family-centered care. Accordingly, we aimed to compare the effects of combined MT and SSC and SSC alone on ANS stabilization in preterm infants. In a single-center, cluster-randomized trial design, ten two-month time-clusters were randomized to either combined MT and SSC or SSC alone. Families of preterm infants were offered two sessions of the allocated condition in the NICU, and a three-month follow up session at home. The primary outcome variable was stabilization of the ANS, defined by change in the high frequency (HF) power of heart rate variability (HRV) during the second session. Secondary outcomes included other HRV measures, parent-infant attachment, and parental anxiety at each session. Sixty-eight families were included. MT combined with SSC improved infants' ANS stability, as indicated by a greater increase in HF power during MT compared to SSC alone (mean difference 5.19 m2/Hz, SE = 1.27, p < 0.001) (95% confidence interval 0.87 to 2.05). Most secondary outcomes were not significantly different between the study groups. MT contributes to preterm-infants' autonomic stability, thus laying an important foundation for neuro-behavioral and psycho-emotional development. Studies evaluating longer-term effects of MT on preterm infants' development are warranted.


Dexamethasone treatment impairs calcium regulation and reduces bone mineralization in infant pigs.
Calcium and vitamin D metabolism, bone mineralization, and growth were studied in piglets randomly assigned to 15 d of dexamethasone (0.5 mg.kg-1.d-1, orally) or placebo. Growth velocity was significantly reduced by dexamethasone treatment (P < 0.001). Pigs in the dexamethasone group demonstrated lower 45Ca absorption by in situ intestinal perfusion (P < 0.01). Plasma 25-hydroxycholecalciferol (calcidiol) and 1,25-dihydroxycholecalciferol (calcitriol) were lower (P < 0.05) and the urinary ratio of calcium to creatinine was higher (P < 0.05) after 15 d of dexamethasone compared with placebo. Differences between pre- and postosteocalcin (P < 0.01) and pyridinoline (P < 0.01) were higher and wholebody, lumbar, and femur bone mineral density were lower (P < 0.05) in dexamethasone-treated piglets. Dexamethasone-induced reductions in bone mineral mass likely result from reduced vitamin D status, reduced intestinal calcium absorption, elevated urinary calcium loss and direct effects of the steroid on bone. When dexamethasone is used in premature infants to improve lung function, negative effects on growth and bone metabolism could occur.


Psychomotor development index in children younger than 6 years from Argentine provinces.
To obtain a psychomotor development index (PDI) for each Argentine province. Using a national, probabilistic, and stratified sample of 13 323 male and female children younger than 6 years selected for the National Survey on Nutrition and Health (Encuesta Nacional de Nutrición y Salud, ENNyS 2004), we estimated the PDI per province based on compliance with 10 developmental milestones. The median age at attainment (median age) of each milestone was estimated adjusting a logistic regression. The PDI was estimated as 100* (1 + b), where "b" is the regression coefficient of y= a + b x, where "y" is the median age as per the national reference (x) minus the median age at attainment of a milestone. The theoretical value expected for the PDI was 100. The PDI per province ranged between 72.1 and 106.4. Most provinces showed a negative regression coefficient, which indicated a progressive increase of the delay in the age at attainment of milestones. The correlation coefficient between the PDI per province and infant mortality in 2005was extremely high: -0.85, suggesting that both indicators share similar biological and social determinants. The PDI was negative because the higher the mortality, the lower the PDI. We have now a positive health indicator available in Argentina: the psychomotor development index, which is a low-cost, easy to collect, and reliable tool that may be used in national health statistics.


First-Principles Algorithm for Air Quality Electrochemical Gas Sensors.
We report here a simple approach that allows for rapid mapping of raw voltage readings to concentrations for parts-per-billion level air quality electrochemical sensors. The key step is the introduction of an auxiliary sensor and then covering it with a thin Nafion membrane, one that is well-known for its both highly efficient and selective permeation of water vapor. This sensor captures any signal that is induced by changes of relative humidity, and such a signal can then be used to rapidly correct for drifts of the main sensor which sees both the target gas and the ambient water vapor. The whole process is entirely based on first principles, preserves physical clarity, is very amenable for implementation by routine sensor users, and delivers data that compare favorably with those from reference instruments. We also suggest that this double-sensor setup can be further condensed into one sensor in which one of the electrodes is coated by Nafion and exposed to ambient air in the same way as the normal sensing electrode.


Clinical trials in gynecological cancer.
The Gynecologic Cancer Intergroup is comprised representatives from international gynecological cancer trials organizations, which collaborate in multicenter studies to answer the clinical challenges in gynecological cancer. This review article highlights the key clinical questions facing clinical trialists over the next decade, the information and infrastructure resources available for trials, and the methods of trial development. We cover human papillomavirus (HPV)-associated neoplasia, including cervical cancer, together with endometrial cancer, ovarian cancer, and vulvar cancer. Infrastructure for clinical trials includes a database for trials, templates for protocol development, patient educational material, and financial support for clinical trials. Other critical issues include support from government and charities and government regulations.


Neural Wiskott-Aldrich syndrome protein modulates Wnt signaling and is required for hair follicle cycling in mice.
The Rho family GTPases Cdc42 and Rac1 are critical regulators of the actin cytoskeleton and are essential for skin and hair function. Wiskott-Aldrich syndrome family proteins act downstream of these GTPases, controlling actin assembly and cytoskeletal reorganization, but their role in epithelial cells has not been characterized in vivo. Here, we used a conditional knockout approach to assess the role of neural Wiskott-Aldrich syndrome protein (N-WASP), the ubiquitously expressed Wiskott-Aldrich syndrome-like (WASL) protein, in mouse skin. We found that N-WASP deficiency in mouse skin led to severe alopecia, epidermal hyperproliferation, and ulceration, without obvious effects on epidermal differentiation and wound healing. Further analysis revealed that the observed alopecia was likely the result of a progressive and ultimately nearly complete block in hair follicle (HF) cycling by 5 months of age. N-WASP deficiency also led to abnormal proliferation of skin progenitor cells, resulting in their depletion over time. Furthermore, N-WASP deficiency in vitro and in vivo correlated with decreased GSK-3beta phosphorylation, decreased nuclear localization of beta-catenin in follicular keratinocytes, and decreased Wnt-dependent transcription. Our results indicate a critical role for N-WASP in skin function and HF cycling and identify a link between N-WASP and Wnt signaling. We therefore propose that N-WASP acts as a positive regulator of beta-catenin-dependent transcription, modulating differentiation of HF progenitor cells.


Scoring Targets of Transcription in Bacteria Rather than Focusing on Individual Binding Sites.
Reliable identification of targets of bacterial regulators is necessary to understand bacterial gene expression regulation. These targets are commonly predicted by searching for high-scoring binding sites in the upstream genomic regions, which typically leads to a large number of false positives. In contrast to the common approach, here we propose a novel concept, where overrepresentation of the scoring distribution that corresponds to the entire searched region is assessed, as opposed to predicting individual binding sites. We explore two implementations of this concept, based on Kolmogorov-Smirnov (KS) and Anderson-Darling (AD) tests, which both provide straightforward P-value estimates for predicted targets. This approach is implemented for pleiotropic bacterial regulators, including σ70 (bacterial housekeeping σ factor) target predictions, which is a classical bioinformatics problem characterized by low specificity. We show that KS based approach is both faster and more accurate, departing from the current paradigm of AD being slower, but more accurate. Moreover, KS approach leads to a significant increase in the search accuracy compared to the standard approach, while at the same time straightforwardly assigning well established P-values to each potential target. Consequently, the new KS based method proposed here, which assigns P-values to fixed length upstream regions, provides a fast and accurate approach for predicting bacterial transcription targets.


Dendromonocotyle lasti n. sp. from the skin and Monocotyle caseyae n. sp. (Monogenea: Monocotylidae) from the gills of Himantura sp. (Dasyatidae) in Moreton Bay, Queensland, Australia.
Seven specimens of rays of the genus Himantura which could not be identified to species were collected from waters near Dunwich, Stradbroke Island, Moreton Bay, Queensland, Australia. The five smallest specimens of Himanturasp. (disc width 218-302 mm; four female, one male) had a banded tail and the dorsal surface was uniformly grey/brown. The two largest individuals of Himantura sp. (disc widths 460, 533 mm; female and male, respectively) also had a banded tail but the grey/brown dorsal surface had white spots. Two new monogenean species (Monocotylidae: Monocotylinae) are described from both the 'plain' and 'white-spotted' specimens of Himantura. Dendromonocotyle lastin. sp. is distinguished from other species in the genus by the number of papillae on the haptor, by the morphology of the male copulatory organ and by the morphology of the proximal portion of the vagina. The muscular sheath which surrounds the male copulatory organ is also unique having sclerotised spines at the distal end. Dendromonocotyle species are skin parasites, but a total of five juvenile specimens of D. lasti were found on the gills of four rays. Monocotyle caseyae n. sp. from the gills is characterised by the morphology of the male copulatory organ and its accessory piece. One specimen of M. spiremae Measures, Beverley-Burton & Williams, 1990, originally described from the gills of Himantura fai Jordan & Seale off Heron Island, Great Barrier Reef, Queensland, Australia, was also found on the gills of one Himantura specimen. The site and host-specificity of the parasites and the identity of the hosts are discussed.


Interview with Guillermo Arrévalo, a Shipibo urban shaman, by Roger Rumrrill. Interview by Roger Rumrrill.
Roger Rumrrill, a journalist headquartered in Lima, Peru who is a noted expert on the Peruvian Amazon, interviewed Guillermo Arrévalo, a Shipibo urban shaman in Pucallpa, who utilizes ayahuasca in curing rituals. Sr. Arrévalo comments on the phenomenon known as drug tourism, where urban men and women provide tours for foreigners, for a price, to experience drug-induced mystical experiences in urban settings like Iquitos and Pucallpa, Peru, as well as in Brazil, Bolivia and Ecuador. Arrévalo distinguishes between folkloric shamanism and touristic practices which are currently in vogue and, in his opinion, are the result of people trying to resolve personal problems. Arrévalo sees a spiritual and psychological crisis in Europe and North American society. The Shipibo shaman laments the misuse of toxic plants as additives to the ayahuasca potion and the damage that these plants cause to the unsuspecting tourist who doesn't really get his money's worth from shamans without experience, people who are liars and cheats and who don't have the capacity, the preparation or the boldness to do the work.


Phylogenetic classification of Cordyceps and the clavicipitaceous fungi.
Cordyceps, comprising over 400 species, was historically classified in the Clavicipitaceae, based on cylindrical asci, thickened ascus apices and filiform ascospores, which often disarticulate into part-spores. Cordyceps was characterized by the production of well-developed often stipitate stromata and an ecology as a pathogen of arthropods and Elaphomyces with infrageneric classifications emphasizing arrangement of perithecia, ascospore morphology and host affiliation. To refine the classification of Cordyceps and the Clavicipitaceae, the phylogenetic relationships of 162 taxa were estimated based on analyses consisting of five to seven loci, including the nuclear ribosomal small and large subunits (nrSSU and nrLSU), the elongation factor 1alpha (tef1), the largest and the second largest subunits of RNA polymerase II (rpb1 and rpb2), beta-tubulin (tub), and mitochondrial ATP6 (atp6). Our results strongly support the existence of three clavicipitaceous clades and reject the monophyly of both Cordyceps and Clavicipitaceae. Most diagnostic characters used in current classifications of Cordyceps (e.g., arrangement of perithecia, ascospore fragmentation, etc.) were not supported as being phylogenetically informative; the characters that were most consistent with the phylogeny were texture, pigmentation and morphology of stromata. Therefore, we revise the taxonomy of Cordyceps and the Clavicipitaceae to be consistent with the multi-gene phylogeny. The family Cordycipitaceae is validated based on the type of Cordyceps, C. militaris, and includes most Cordyceps species that possess brightly coloured, fleshy stromata. The new family Ophiocordycipitaceae is proposed based on Ophiocordyceps Petch, which we emend. The majority of species in this family produce darkly pigmented, tough to pliant stromata that often possess aperithecial apices. The new genus Elaphocordyceps is proposed for a subclade of the Ophiocordycipitaceae, which includes all species of Cordyceps that parasitize the fungal genus Elaphomyces and some closely related species that parasitize arthropods. The family Clavicipitaceaes. s. is emended and includes the core clade of grass symbionts (e.g., Balansia, Claviceps, Epichloë, etc.), and the entomopathogenic genus Hypocrella and relatives. In addition, the new genus Metacordyceps is proposed for Cordyceps species that are closely related to the grass symbionts in the Clavicipitaceaes. s.Metacordyceps includes teleomorphs linked to Metarhizium and other closely related anamorphs. Two new species are described, and lists of accepted names for species in Cordyceps, Elaphocordyceps, Metacordyceps and Ophiocordyceps are provided.


The phosphorylation of myosin II at the Ser1 and Ser2 is critical for normal platelet-derived growth factor induced reorganization of myosin filaments.
Phosphorylation of the regulatory light chain of myosin II (MLC(20)) at the activation sites promotes both the motor activity and the filament formation of myosin II, thus playing an important role in various cell motile processes. In contrast, the physiological function of phosphorylation of MLC(20) at the inhibitory sites is unknown. Here we report for the first time the function of the inhibitory site phosphorylation in the cells. We successfully produced the antibodies specifically recognizing the phosphorylation sites of MLC(20) at Ser1, and the platelet-derived growth factor (PDGF)-induced change in the phosphorylation at the Ser1 was monitored. The phosphorylation of MLC(20) at the Ser1 significantly increased during the PDGF-induced actin cytoskeletal reorganization. PDGF disassembled the stress fibers, and this was attenuated with the expression of unphosphorylatable MLC(20) at the Ser1/Ser2 phosphorylation sites. The present results suggest that the down-regulation of myosin II activity achieved by the phosphorylation at the Ser1/Ser2 sites plays an important role in the normal reorganization of actomyosin filaments triggered by PDGF receptor stimulation.


Healing of peptic ulcers on conventional antacid therapy with or without butriptyline.
A group of ulcer patients taking conventional doses of antacids were subjected to a double-blind randomized trial to examine the possible effect of butriptyline on ulcer healing. The study failed to show any advantage of butriptyline over placebo, but this may well have been due to the very success of antacid therapy. The healing rates of gastric and duodenal ulcers in patients on conventional antacid therapy were found to be comparable to those reported with many of the newer ulcer preparations. This study also showed that larger ulcers tend to take longer to heal than small ones.


Nanoscale extracellular vesicle-derived DNA is superior to circulating cell-free DNA for mutation detection in early-stage non-small-cell lung cancer.
The comparison between relatively intact nanoscale extracellular vesicle-derived DNA (nEV-DNA) and fragmented circulating cell-free DNA (cfDNA) in mutation detection among patients with non-small-cell lung cancer (NSCLC) has not been carried out yet, and thus deserves investigation. Both nEV-DNA and cfDNA was obtained from 377 NSCLC patients with known EGFR mutation status and 69 controls. The respective EGFRE19del/T790M/L858R mutation status was interrogated with amplification-refractory-mutation-system-based PCR assays (ARMS-PCR). Neither nEV-DNA nor cfDNA levels show a strong correlation with tumor volumes. There is no correlation between cfDNA and nEV-DNA levels either. The detection sensitivity of nEV-DNA and cfDNA using ARMS-PCR in early-stage NSCLC was 25.7% and 14.2%, respectively, with 96.6% and 91.7% specificity, respectively. In late-stage NSCLC, both nEV-DNA and cfDNA show ∼80% sensitivity and over 95% specificity. nEV-DNA is superior to cfDNA for mutation detection in early-stage NSCLC using ARMS-PCR. However, the advantages vanish in late-stage NSCLC.


Vaginal films for drug delivery.
Vaginal dosage forms have been studied in relation to many drugs as the vagina presents several advantages as a site for drug delivery, such as large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to several drugs, and self-insertion. Traditional vaginal dosage forms have been associated with disadvantages such as low residence time and discomfort and have been surpassed by newly designed drug delivery systems, particularly those based on bioadhesive polymers. Vaginal films are solid dosage forms that rapidly dissolve in contact with vaginal fluids and are unlikely to be associated with leakage and messiness. They have been studied for some female genital problems, aiming either contraceptive, antimicrobial, or microbicide effects. Precise and complex processes of manufacturing and characterization are required to achieve successful film formulation. Although scarce, the available user's acceptability studies show promising results. Vaginal films gather a lack of opportunities for both therapeutic and prophylactic actions, and therefore should be considered when designing and developing new vaginal drug delivery systems.


Embedded ensemble encoding hypothesis: The role of the "Prepared" cell.
We here reconsider current theories of neural ensembles in the context of recent discoveries about neuronal dendritic physiology. The key physiological observation is that the dendritic plateau potential produces sustained depolarization of the cell body (amplitude 10-20 mV, duration 200-500 ms). Our central hypothesis is that synaptically-evoked dendritic plateau potentials lead to a prepared state of a neuron that favors spike generation. The plateau both depolarizes the cell toward spike threshold, and provides faster response to inputs through a shortened membrane time constant. As a result, the speed of synaptic-to-action potential (AP) transfer is faster during the plateau phase. Our hypothesis relates the changes from "resting" to "depolarized" neuronal state to changes in ensemble dynamics and in network information flow. The plateau provides the Prepared state (sustained depolarization of the cell body) with a time window of 200-500 ms. During this time, a neuron can tune into ongoing network activity and synchronize spiking with other neurons to provide a coordinated Active state (robust firing of somatic APs), which would permit "binding" of signals through coordination of neural activity across a population. The transient Active ensemble of neurons is embedded in the longer-lasting Prepared ensemble of neurons. We hypothesize that "embedded ensemble encoding" may be an important organizing principle in networks of neurons.


Crooks Fluctuation Theorem for Single Polymer Dynamics in Time-Dependent Flows: Understanding Viscoelastic Hysteresis.
Nonequilibrium work relations have fundamentally advanced our understanding of molecular processes. In recent years, fluctuation theorems have been extensively applied to understand transitions between equilibrium steady-states, commonly described by simple control parameters such as molecular extension of a protein or polymer chain stretched by an external force in a quiescent fluid. Despite recent progress, far less is understood regarding the application of fluctuation theorems to processes involving nonequilibrium steady-states such as those described by polymer stretching dynamics in nonequilibrium fluid flows. In this work, we apply the Crooks fluctuation theorem to understand the nonequilibrium thermodynamics of dilute polymer solutions in flow. We directly determine the nonequilibrium free energy for single polymer molecules in flow using a combination of single molecule experiments and Brownian dynamics simulations. We further develop a time-dependent extensional flow protocol that allows for probing viscoelastic hysteresis over a wide range of flow strengths. Using this framework, we define quantities that uniquely characterize the coil-stretch transition for polymer chains in flow. Overall, generalized fluctuation theorems provide a powerful framework to understand polymer dynamics under far-from-equilibrium conditions.


Susceptibility of avian ovarian granulosa cells to apoptosis is dependent upon stage of follicle development and is related to endogenous levels of bcl-xlong gene expression.
Studies were conducted to evaluate the susceptibility of avian ovarian granulosa cells to apoptosis when incubated in vitro and to relate this relative susceptibility to both the stage of follicle development from which granulosa cells were collected (atresia-prone vs. -resistant) and to the expression of a gene previously linked to the regulation of cell viability, bcl-xlong. Granulosa cells from slow growing, prehierarchal (4- to 8-mm diameter; atresia-prone) follicles were found to undergo rapid and progressively extensive apoptosis after incubation in defined medium for 6-24 h (P < 0.05 vs. unincubated controls). By contrast, cells from the largest preovulatory (F1) follicle, as well as from follicles most recently recruited into the follicle hierarchy (9- to 12-mm diameter), showed significantly less low molecular wt labeling at 6 h of incubation (P < 0.05 vs. 4- to 8-mm follicles). Furthermore, the amount of low molecular wt labeling did not significantly increase in cells from either stage of follicle development at 12 or 24 h of incubation (P < 0.05 vs. 6 h incubation). This biochemical indication of ongoing apoptosis in prehierarchal follicle granulosa cells was confirmed by an increased incidence of pyknotic nuclei detected by morphological analysis. Thus, increased susceptibility to apoptosis in incubated prehierarchal follicle granulosa cells is correlated with the high rate of follicle atresia that is known to occur at this stage of development in vivo. Recombinant human FSH (100 mIU) and transforming growth factor-alpha (3.3 nM) partially suppressed apoptosis in prehierarchal follicle granulosa cells after 6 h of incubation (by 46-57%; P < 0.05 vs. control), as did the cAMP analog, 8-Br-cAMP (1 mM; by 59%; P < 0.05). A single form of the bcl-2-related gene, bcl-x, was detected in hen ovarian tissues; this transcript corresponded to bcl-xlong, the death-suppressing form of bcl-x. The highest levels of bcl-xlong messenger RNA were found in granulosa tissue from preovulatory follicles, with significantly lower levels detected in prehierarchal follicle granulosa tissue (P < 0.05). Elevated expression of bcl-xlong in preovulatory follicles was correlated to increased resistance to the process of apoptosis, in vitro, and the virtual absence of follicle atresia at this stage of development, in vivo. We conclude that there is a direct relationship between the inherent susceptibility of avian granulosa cells to apoptosis and the high rate of follicle atresia in follicles not yet selected into the preovulatory hierarchy. Moreover, our results are consistent with the proposal that the expression of death-suppressing genes, including bcl-xlong, is capable of rendering cells resistant to the process of apoptosis. The findings reported herein provide the foundation for a novel model with which to further elucidate molecular mechanisms related not only to the initiation of follicle atresia, but also events associated with the process of follicle selection.


Role of remote scaffolding residues in the inhibitory loop pre-organization, flexibility, rigidification and enzyme inhibition of serine protease inhibitors.
Canonical serine protease inhibitors interact with cognate enzymes through the P3-P2' region of the inhibitory loop while its scaffold hardly makes any contact. Neighboring scaffolding residues like Arginines or Asparagine shape-up the inhibitory loop and favor the resynthesis of cleaved scissile bond. However, role of remote scaffolding residues, which are not involved in religation, was not properly explored. Crystal structures of two engineered winged bean chymotrypsin inhibitor (WCI) complexed with Bovine trypsin (BPT) namely L65R-WCI:BPT and F64Y/L65R-WCI:BPT show that the inhibitory loop of these engineered inhibitors are recognized and rigidified properly at the enzyme active site like other strong trypsin inhibitors. Chimeric protein ETI(L)-WCI(S), having a loop of Erythrina caffra Trypsin Inhibitor, ETI on the scaffold of WCI, was previously shown to behave like substrate. Non-canonical structure of the inhibitory loop and its flexibility are attributed to the presence of smaller scaffolding residues which cannot act as barrier to the inhibitory loop like in ETI. Double mutant A76R/L115Y-(ETI(L)-WCI(S)), where the barrier is reintroduced on ETI(L)-WCI(S), shows regaining of inhibitory activity. The structure of A76R/L115Y-(ETI(L)-WCI(S)) along with L65R-WCI:BPT and F64Y/L65R-WCI:BPT demonstrate here that the lost canonical conformation of the inhibitory loop is fully restored and loop flexibility is dramatically reduced. Therefore, residues at the inhibitory loop interact with the enzyme playing the primary role in recognition and binding but scaffolding residues having no direct interaction with the enzyme are crucial for rigidification event and the inhibitory potency. B-factor analysis indicates that the amount of inhibitory loop rigidification varies between different inhibitor families.


Biotin-avidin as a protease-responsive cap system for controlled guest release from colloidal mesoporous silica.
Tell your guests when it's time to go: When avidin caps are attached to biotinylated colloidal mesoporous silica, the four subunits of the protein avidin can each bind to a biotin moiety attached to the surface (see picture). The resulting material is a promising candidate for the design of smart detergents or drug-delivery systems. The caps can be opened to release guest molecules by controlled enzymatic hydrolysis of the protein.


Evaluation of Cutaneous Drug Reactions in Patients Visiting Out Patient Departments of Indira Gandhi Government Medical College and Hospital (IGGMC and H), Nagpur.
To detect cutaneous drug reactions through spontaneous reporting system in IGGMCand H, Nagpur and analyze them using standard assessment scales. An observational, prospective study was performed in patients attending dermatology OPD of IGGMC and H, Nagpur from 1(st) June 05 to 31(st) May 09. Patients were examined for cutaneous drug reactions (CDRs) by spontaneous Adverse Drug Reaction reporting system. Among 2693 total ADRs reported, 872 (33.04%) were CDRs. Antimicrobials (55.5%) were the main drugs involved followed by NSAIDs (18.56%) and steroids (12.61%). Maculopapular rash (37.73%) followed by fixed drug eruption (17.2%) and urticaria (14.56%) were the most frequently observed CDRs. The common drugs causing CDRs were cotrimoxazole (20.41%), topical steroids (betamethasone), ibuprofen (7.91%), ampicillin (6.54%), diclofenac (4.7%) and iron dextran (3.44%). It was observed that commonly used drugs like antibiotics and NSAIDs lead to maximum number of CDRs. Hence strict vigilance is required while using them. This study provides a database of ADRs due to common drugs, which will help clinicians in safe use of these drugs.


Defect in insulin binding to receptors in obese man. Amelioration with calorie restriction.
With insulin at 0.1 ng/ml, the binding of (125I)insulin in vitro to circulating lymphocytes from 11 obese patients was less than that observed with cells from 10 thin volunteers. Furthermore, with obese cells, unlabeled insulin was less effective in competing with labeled hormone for binding, both at low and high concentrations of unlabeled insulin. These differences were not accounted for by the high concentrations of insulin in the circulation of the obese patients at the time fthe blood was drawn, or by differences in degradation of hormone, or in the characteristics of the cell population. The decrease in binding appears to be due to a lowering of the receptor concentration, but some loss of affinity has not been excluded. Institution of a calorie restricted diet (nine patients) which ameliorated the hyperinsulinemia, produced an improvement in hormone binding. Since the insulin receptors of lymphocytes in metabolic disorders seem to reflect the state of insulin receptors or target cells such as liver and fat, the lymphocytes or other leukocytes appear to be ideal for studies of impaired cell responsiveness to hormones in man.


Mouse models for atherosclerosis and pharmaceutical modifiers.
Atherosclerosis is a multifactorial highly-complex disease with numerous etiologies that work synergistically to promote lesion development. The ability to develop preventive and ameliorative treatments will depend on animal models that mimic the human subject metabolically and pathophysiologically and will develop lesions comparable to those in humans. The mouse is the most useful, economic, and valid model for studying atherosclerosis and exploring effective therapeutic approaches. Among the most widely used mouse models for atherosclerosis are apolipoprotein E-deficient (ApoE-/-) and LDL receptor-deficient (LDLr-/-) mice. An up-and-coming model is the ApoE*3Leiden (E3L) transgenic mouse. Here, we review studies that have explored how and to what extent these mice respond to compounds directed at treatment of the risk factors hypercholesterolemia, hypertriglyceridemia, hypertension, and inflammation. An important outcome of this survey is that the different models used may differ markedly from one another in their response to a specific experimental manipulation. The choice of a model is therefore of critical importance and should take into account the risk factor to be studied and the working spectrum of the compounds tested.


Air gap technique is recommended in axiolateral hip radiographs.
To investigate the replacement of conventional grid by air gap in axiolateral hip radiographs. The optimal air gap distance was studied with respect to radiation dose and image quality using phantom images, as well as 26 patient axiolateral hip radiographs. The CDRAD phantom, along with polymethylmethacrylate slabs with thicknesses of 10.0, 14.6, and 20.0 cm was employed. The inverse image quality index and dose area product (DAP), as well as their combination, so called figure-of-merit (FOM) parameter, were evaluated for these images, with air gaps from 20 to 50 cm in increments of 10 cm. Images were compared to those acquired using a conventional grid utilized in hip radiography. Radiation dose was measured and kept constant at the surface of the detector by using a reference dosimeter. Verbal consent was asked from 26 patients to participate to the study. Air gap distances from 20 to 50 cm and tube current-time products from 8 to 50 mAs were employed. Exposure index, DAP, as well as patient height and weight were recorded. Two radiologists evaluated the image quality of 26 hip axiolateral projection images on a 3-point nondiagnostic - good/sufficiently good - too good scale. Source-to-image distance of 200 cm and peak tube voltage of 90 kVp were used in both studies. Based on the phantom study, it is possible to reduce radiation dose by replacing conventional grid with air gap without compromising image quality. The optimal air gap distance appears to be 30 cm, based on the FOM analysis. Patient study corroborates this observation, as sufficiently good image quality was found in 24 of 26 patient radiographs, with 7 of 26 images obtained with 30 cm air gap. Thus, air gap method, with an air gap distance of 30 cm, is recommended in axiolateral hip radiography.


Auditory-evoked potential to pattern-reversal stimulation.
The late auditory-evoked potential (AEP) was studied in response to a frequency-modulated complex synthesized from discrete tones, somewhat analogous to visual stimulation using reversals of alternating light and dark stripes. The "pattern-reversal' AEP was found to be a heartier response than the familiar transient-evoked AEP (e.g. tone-burst-elicited potential), but the latencies of the component potentials were longer. The apparent enhancement of the AEP is postulated to be due to response summation across critical bands, akin perhaps to loudness growth as stimulus bandwidth increases.


Determination of appropriate sampling time for job stress assessment: the salivary chromogranin A and cortisol in adult females.
This study was conducted to determine the appropriate sampling time of the salivary stress markers, chromogranin A (CgA) and cortisol as objective indices of job stress assessment in adult females. The subjects were 20 approximately 39-year-old women (13 office workers, 11 sales-service workers, and 11 college students) who were eligible for the study and free of acute and chronic medical conditions. Salivary CgA and cortisol levels were determined by enzyme-linked immunosorbent assay (ELISA). Saliva samples were collected (2 ml each) at 7:00, 8:00, 10:30, 12:00, 17:30, and 22:30 on a typical day. Salivary CgA and cortisol levels, according to sampling time, were compared among the three groups using general linear model. The full version of the Korean Occupational Stress Scale (KOSS), which includes socioeconomic characteristics, health behavior, work-related characteristics, and BMI, was used to access the subjects' job stress. Multiple regression analysis of the job stressors identified by the KOSS was performed on salivary CgA and cortisol levels. The salivary CgA level peaked at 7:00 (time of awakening), then decreased and were maintained at a low level throughout the day, and increased slightly at 17:30. The salivary cortisol level increased steeply within the 1st hour after awakening, followed by a gradual decrease by 12:00, and was then maintained at a low level throughout the day. The salivary cortisol levels of subjects who worked < or = 5 days per week and graduated from the university were significantly lower at 8:00 (p=0.006). The salivary cortisol levels of non-smokers were significantly lower at 7:00 (p=0.040) and 8:00 (p=0.003) compared to smokers. There were no significant differences in salivary CgA and cortisol levels at 10:30 and 12:00 in general characteristics. The regression coefficients on salivary CgA level were significant with interpersonal conflict at 17:30 and job insecurity at 22:30. Regression coefficients on salivary cortisol level were significant with organizational system and total job stressors at 17:30. We suggest that the appropriate sampling times for the salivary stress markers, CgA and cortisol, are at 7:00 (time of awakening), 8:00 (1 hour after awakening), 17:30 (early evening), and 22:30 (before sleep).


Vascular remodeling in pulmonary hypertension.
Pulmonary hypertension is a complex, progressive condition arising from a variety of genetic and pathogenic causes. Patients present with a spectrum of histologic and pathophysiological features, likely reflecting the diversity in underlying pathogenesis. It is widely recognized that structural alterations in the vascular wall contribute to all forms of pulmonary hypertension. Features characteristic of the remodeled vasculature in patients with pulmonary hypertension include increased stiffening of the elastic proximal pulmonary arteries, thickening of the intimal and/or medial layer of muscular arteries, development of vaso-occlusive lesions, and the appearance of cells expressing smooth muscle-specific markers in normally non-muscular small diameter vessels, resulting from proliferation and migration of pulmonary arterial smooth muscle cells and cellular transdifferentiation. The development of several animal models of pulmonary hypertension has provided the means to explore the mechanistic underpinnings of pulmonary vascular remodeling, although none of the experimental models currently used entirely replicates the pulmonary arterial hypertension observed in patients. Herein, we provide an overview of the histological abnormalities observed in humans with pulmonary hypertension and in preclinical models and discuss insights gained regarding several key signaling pathways contributing to the remodeling process. In particular, we will focus on the roles of ion homeostasis, endothelin-1, serotonin, bone morphogenetic proteins, Rho kinase, and hypoxia-inducible factor 1 in pulmonary arterial smooth muscle and endothelial cells, highlighting areas of cross-talk between these pathways and potentials for therapeutic targeting.


Identification of X chromosome regions in Caenorhabditis elegans that contain sex-determination signal elements.
The primary sex-determination signal of Caenorhabditis elegans is the ratio of X chromosomes to sets of autosomes (X/A ratio). This signal coordinately controls both sex determination and X chromosome dosage compensation. To delineate regions of X that contain counted signal elements, we examined the effect on the X/A ratio of changing the dose of specific regions of X, using duplications in XO animals and deficiencies in XX animals. Based on the mutant phenotypes of genes that are controlled by the signal, we expected that increases (in males) or decreases (in hermaphrodites) in the dose of X chromosome elements could cause sex-specific lethality. We isolated duplications and deficiencies of specific X chromosome regions, using strategies that would permit their recovery regardless of whether they affect the signal. We identified a dose-sensitive region at the left end of X that contains X chromosome signal elements. XX hermaphrodites with only one dose of this region have sex determination and dosage compensation defects, and XO males with two doses are more severely affected and die. The hermaphrodite defects are suppressed by a downstream mutation that forces all animals into the XX mode of sex determination and dosage compensation. The male lethality is suppressed by mutations that force all animals into the XO mode of both processes. We were able to subdivide this region into three smaller regions, each of which contains at least one signal element. We propose that the X chromosome component of the sex-determination signal is the dose of a relatively small number of genes.


Significance of scaling and root planing with and without adjunctive use of a water-cooled pulsed Nd:YAG laser for the treatment of periodontal inflammation.
The aim was to assess the significance of scaling and root planing (SRP) with adjunctive use of a water-cooled pulsed neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for the treatment of periodontal inflammation. Thirty-nine patients were equally divided into three groups. In group 1, the upper jaw was treated with Nd:YAG laser application; whereas in groups 2 and 3, the upper jaw was treated with SRP alone and Nd:YAG laser application immediately after SRP, respectively. In each group, probing pocket depth (PPD), plaque index (PI), and gingival index (GI) were measured and gingival crevicular fluid (GCF) volume was determined after using at 1 week and after 3 months. Three-month follow-up results showed that PPD, PI, GI, and GCF volume were significantly reduced in group 3 compared to groups 1 and 2. In short term, SRP with a single application of a water-cooled pulsed Nd:YAG laser reduced PI, GI, PPD, and GCF volume more significantly compared to when Nd:YAG laser and SRP are used alone to treat periodontal inflammation.


Summary of skeletal identification in Tennessee: 1971-1981.
Records of 111 forensic anthropology cases from Tennessee received from September 1971 through September 1981 are analyzed. Thirty percent of the cases in which no identification existed when the skeleton arrived were positively identified and an additional "probable" identification was made in 11%. The skull or skull bones were the most common element recovered followed by femora, mandibles, and innominates, in that order. The sternum was the single major postcranial bone least likely to be recovered. January has been the single busiest month for the discovery of skeletal remains in Tennessee, and there are almost twice as many fire-related discoveries between September and February. In the first half of the decade, from 1971 through 1978, there were 39 cases with 72 cases occurring from 1977 through 1981. This increase is probably because of efforts to educate students at the University of Tennessee as well as lectures to law enforcement and citizens' groups.


The anti-tumor effect of a small polypeptide from Coriolus versicolor (SPCV).
A new small polypeptide was isolated from the crude extraction of polysaccharide peptide of Coriolus versicolor (Cov-1) by HPLC and CIEF. It has a smaller molecular weight (10K) compared with that of PSP (100K) and was named small peptide of Coriolus versicolor, SPCV. It was found that SPCV possesses potent cytotoxic effect on human tumor cell lines of HL-60, LS174-T, SMMU-7721, and SCG-7901. The IC50 of SPCV on HL-60 was 30 micrograms/ml. The inhibition rates of leukemia cells and SCG-7901 were significantly higher in SPCV treated group than that in PSP and PSK groups. SPCV also has immunopotentiating effect as it increased WBC and IgG levels. Pretreatment of SPCV for two weeks decreased the incidence of tumor mass in nude mice inoculated with tumor cells.


Crucial impact of exchange between layers on temperature programmed desorption.
Desorption of molecules from surfaces constitutes an elementary process that is fundamental in both natural and application-oriented fields, including dewetting, weathering and catalysis. A powerful method to investigate desorption processes is temperature-programmed desorption (TPD), which offers the potential to provide mechanistic insights into the desorption kinetics. Using TPD, the desorption order, the energy barrier as well as the entropy change upon desorption can be accessed. In the past, several analysis methods have been developed for TPD data. These methods have in common that they rely on the Polanyi-Wigner equation, which requires proposing a desorption mechanism with a single (or at least dominating) desorption path. For real systems, however, several coupled desorption paths can be easily envisioned, which cannot be disentangled. Here, we analyse the influence of exchange between the first and the second adsorbate layer on the desorption process. We present a kinetic model, in which molecules can desorb directly from the first layer or change into the second layer and desorb from there. Interestingly, considering this additional desorption pathway alters the desorption spectrum considerably, even if the transient second-layer occupation remains as small as 4 × 10-6 monolayers. We show that the impact of this layer exchange can be described by a modified Polanyi-Wigner equation. Our study demonstrates that layer exchange can crucially impact the TPD data.


Renal NOXA1/NOX1 Signaling Regulates Epithelial Sodium Channel and Sodium Retention in Angiotensin II-induced Hypertension.
Aims: NADPH oxidase (NOX)-derived reactive oxygen species (ROS) are implicated in the pathophysiology of hypertension in chronic kidney disease patients. Genetic deletion of NOX activator 1 (Noxa1) subunit of NOX1 decreases ROS under pathophysiological conditions. Here, we investigated the role of NOXA1-dependent NOX1 activity in the pathogenesis of angiotensin II (Ang II)-induced hypertension (AIH) and possible involvement of abnormal renal function. Results: NOXA1 is present in epithelial cells of Henle's thick ascending limb and distal nephron. Telemetry showed lower basal systolic blood pressure (BP) in Noxa1-/-versus wild-type mice. Ang II infusion for 1 and 14 days increased NOXA1/NOX1 expression and ROS in kidney of male but not female wild-type mice. Mean BP increased 30 mmHg in wild-type males, with smaller increases in Noxa1-deficient males and wild-type or Noxa1-/- females. In response to an acute salt load, Na+ excretion was similar in wild-type and Noxa1-/- mice before and 14 days after Ang II infusion. However, Na+ excretion was delayed after 1-2 days of Ang II in male wild-type versus Noxa1-/- mice. Ang II increased epithelial Na+ channel (ENaC) levels and activation in the collecting duct principal epithelial cells of wild-type but not Noxa1-/- mice. Aldosterone induced ROS levels and Noxa1 and Scnn1a expression and ENaC activity in a mouse renal epithelial cell line, responses abolished by Noxa1 small-interfering RNA. Innovation and Conclusion: Ang II activation of renal NOXA1/NOX1-dependent ROS enhances tubular ENaC expression and Na+ reabsorption, leading to increased BP. Attenuation of AIH in females is attributed to weaker NOXA1/NOX1-dependent ROS signaling and efficient natriuresis. Antioxid. Redox Signal. 36, 550-566.


[The meaning of being a mother of a child with a heart disease: a phenomenological study].
The objective of this study is to understand what it means to a mother to have a child with a heart disease. In order to do so, a phenomenological approach was used. The study was carried out with mothers of children with congenital cyanotic cardiopathy at the Infant Cardiology Center of a public hospital in Campo Grande, State of Mato Grosso do Sul. Ten open interviews were made based on the following guiding question: What does it mean to you to have a child with a heart disease? The comprehensive analysis of the reported speeches made possible the construction of three categories: "Discovering the disease: being up against the unknown"; "Living together with cardiopathy: being with the child in the disease", and "Believing in a stronger force: the necessary support". The impact of the disease on the mother begins the moment the child is born. Desperation, guilt and insecurity are mentioned as present feelings. It is in God, however, that such mothers look for the necessary support to follow this new path--a path of pain and faith.


Recommendations for the use of Serious Games in people with Alzheimer's Disease, related disorders and frailty.
Alzheimer's disease and other related disorders (ADRD) represent a major challenge for health care systems within the aging population. It is therefore important to develop better instruments to assess the disease severity and progression, as well as to improve its treatment, stimulation, and rehabilitation. This is the underlying idea for the development of Serious Games (SG). These are digital applications specially adapted for purposes other than entertaining; such as rehabilitation, training and education. Recently, there has been an increase of interest in the use of SG targeting patients with ADRD. However, this field is completely uncharted, and the clinical, ethical, economic and research impact of the employment of SG in these target populations has never been systematically addressed. The aim of this paper is to systematically analyze the Strengths, Weaknesses, Opportunities, and Threats (SWOT) of employing SG with patients with ADRD in order to provide practical recommendations for the development and use of SG in these populations. These analyses and recommendations were gathered, commented on and validated during a 2-round workshop in the context of the 2013 Clinical Trial of Alzheimer's Disease (CTAD) conference, and endorsed by stakeholders in the field. The results revealed that SG may offer very useful tools for professionals involved in the care of patients suffering from ADRD. However, more interdisciplinary work should be done in order to create SG specifically targeting these populations. Furthermore, in order to acquire more academic and professional credibility and acceptance, it will be necessary to invest more in research targeting efficacy and feasibility. Finally, the emerging ethical challenges should be considered a priority.


Properties of a new calcium ion antagonist on cellular uptake and mitochondrial efflux of calcium ions.
Compound YS 035 [NN-bis-(3,4-dimethoxyphenethyl)-N-methylamine] is a new synthetic compound capable of inhibiting Ca2+ uptake by different cells. The inhibition of Ca2+ uptake by muscle cells isolated from chicken embryo is dose-dependent in the compound YS 035 concentration range 10-30 microM. The new compound also inhibits Ca2+ entry into rat brain synaptosomes and less effectively into baby-hamster kidney cells. Compound YS 035 partially inhibits the slow Ca2+ release induced by Ruthenium Red and the rapid Na+-dependent efflux from heart mitochondria. The inhibition of the Na+/Ca2+ exchange appears to be of a non-competitive type with an apparent Ki of 28 microM. The new Ca2+ antagonist totally inhibits the Ca2+ efflux from liver mitochondria induced by Ruthenium Red, but it does not affect the release induced by uncoupler, respiratory inhibitor or chelator, nor the mitochondrial ATP synthesis and membrane potential. The properties shown by the new compound indicate it to be a Ca2+ antagonist and a useful tool for studies on the mitochondrial Ca2+ transport.


[Seroepidemiological survey of influenza and infectious anemia in Equidae in northeastern Tunisia].
Using the haemagglutination inhibition and immunodiffusion tests, a national serological survey was carried out to detect antibodies to equine influenza (EI) (A/equi/1/Prague 56 and A/equi/2/Miami 63) and equine infectious anaemia (EIA) in horse sera collected in northeastern Tunisia. 533 samples were analysed for EIA antibodies. All were negative. 13.6% of 433 equine sera tested for EI antibodies were positive. These results are discussed and compared with others obtained in Tunisia and bordering countries.


Insulin resistance in myotonic dystrophy.
The aim of the present study was to obtain a comprehensive picture of the rate of insulin secretion and of tissue sensitivity to the endogenous hormone in myotonic dystrophy patients (MyD). The minimal model approach was utilized for the analysis of frequently sampled intravenous glucose tolerance test data (FSIGT). This method provided the characteristic parameters: SI, insulin sensitivity index; SG fractional glucose disappearance independent of dynamic insulin; n, fractional insulin clearance; phi 1 and phi 2 first and second phase insulin delivery sensitivities to glucose stimulation. In MyD patients SI was reduced (p less than 0.01) by 71% to 1.4 +/- 0.3 x 10(-4) min-1/(microU/ml), whereas in controls it was 4.85 +/- 0.77; SG was within the normal range: 0.044 +/- 0.012 min-1 in MyD patients and 0.036 +/- 0.017 min-1 in controls; phi 1 increased in MyD patients (7.4 +/- 1.3 min (microU/ml)/(mg/dl) versus 4.1 +/- 1.2 in controls); phi 2 increased in MyD patients (126 +/- 47 x 10(4) min-2/(microU/ml)/(mg/dl) versus 17 +/- 6 in controls; p less than 0.05). MyD patients showed a normal tolerance with the glucose disappearance constant, KG within the normal range: 2.75 versus 2.62% min-1 in controls. In MyD patients insulin resistance was associated with a higher than normal insulin delivery for both secretory phases, although the second phase was responsible for releasing a greater amount of hormone. In conclusion MyD patients try to compensate for overall insulin resistance by a more marked pancreatic response.


Small melanomas: a clinical study on 270 consecutive cases of cutaneous melanoma.
The ABCD (asymmetry, border, colour, dimension) criteria represent a commonly used clinical guide for the diagnosis of early cutaneous melanoma (CM). This guide stipulates that CMs usually are more than 6 mm in diameter. The purpose of this retrospective study was to establish the frequency of occurrence of small (< or =6 mm) melanomas in a clinical context. Our series consisted of 270 consecutive CMs (39 in situ and 231 invasive) in 267 patients. Of these 270 lesions, 47 (17%) were small lesions, ranging from 2 to 6 mm in maximum linear extent, with a median value of 5 mm. Of these small lesions, 14 were in situ and 33 Invasive CMs. The median thickness of the 33 small invasive lesions was 0.31 mm. The clinical features of CMs were sufficiently distinctive to suggest a diagnosis of CM in half of the cases, irrespective of the invasiveness or not of the lesions. Dermatoscopy was performed on 36 of the small lesions and achieved a correct diagnosis in 72% of the cases. The combination of simple visual examination with dermatoscopy allowed a higher rate of recognition (86%) than when the two methods were considered separately. Results of our study show that small CMs represent a considerable clinical subset of all CMs. Clinicians must be aware of this fact in their diagnostic activity.


Enantioselective reductive coupling of 1,3-enynes to heterocyclic aromatic aldehydes and ketones via rhodium-catalyzed asymmetric hydrogenation: mechanistic insight into the role of Brønsted acid additives.
Hydrogenation of 1,3-enynes 1a-e in the presence of heterocyclic aromatic aldehydes and ketones using chirally modified cationic rhodium precatalysts results in reductive coupling to afford dienylated alpha-hydroxy heteroarenes 2-23 with exceptional levels of regio- and enantiocontrol. Coupling of enyne 1a to 2-pyridinecarboxaldehyde using an achiral rhodium catalyst in the presence of a chiral Akiyama-Terada-type phosphoric acid derived from BINOL as the Brønsted acid co-catalyst provides the coupling product 2 with substantial levels of optical enrichment (82% ee). This result suggests that substrate protonation and/or formation of a strong hydrogen bond occurs in advance of the stereogenic C-C bond forming event. Further, the high levels of asymmetric induction demonstrate that interaction of the aldehyde with the Brønsted acid activates the system toward C-C coupling. Reductive coupling of enyne 1a and 2-pyridinecarboxaldehyde under an atmosphere of elemental deuterium provides the monodeuterated product deuterio-2, consistent with a catalytic mechanism involving alkyne-carbonyl oxidative coupling followed by hydrogenolytic cleavage of the resulting oxametallacycle. The diene side chain of the coupling products is subject to diverse selective transformations, as demonstrated by the conversion of coupling products 2 and 8 to compounds 24-26 and 27-29, respectively.


The Incidence of Amyotrophic Lateral Sclerosis in Ohio 2016-2018: The Ohio Population-Based ALS Registry.
Amyotrophic lateral sclerosis (ALS) is a fatal, neuromuscular disease with no cure. ALS incidence rates have not been assessed specifically in Ohio, yet the state contains both metropolitan and rural areas with a variety of environmental factors that could contribute to disease etiology. We report the incidence of ALS in Ohio residents diagnosed from October 2016 through September 2018. We engaged practitioners from 9 Ohio sites to identify newly diagnosed ALS patients and to complete case report forms with demographic and clinical information. ALS was diagnosed according to the Awaji criteria and classified as either definite, probable, or possible. We developed a method to estimate missing cases using a Poisson regression model to impute cases in counties with evidence of undercounting. We identified 333 newly diagnosed ALS patients residing in Ohio during the 2-year index period and found incidence rates varied in the 88 state counties. After incorporating the estimated 27% of missing cases, the corrected crude annual incidence was 1.96/100,000 person-years, and the age- and gender-standardized incidence was 1.71/100,000 person-years (standardized to the 2010 US census). The estimated Ohio incidence of ALS is overall similar to that reported in other states in the USA. This study reveals a geospatial variation in incidence within the state, and areas with higher rates warrant future investigation.


Immunization with a live, attenuated simian immunodeficiency virus (SIV) prevents early disease but not infection in rhesus macaques challenged with pathogenic SIV.
An infectious, virulence-attenuated molecular clone of simian immunodeficiency virus (SIV), SIVMAC-1A11, was derived from an SIV isolate that causes fatal immunodeficiency in rhesus macaques. When inoculated intravenously in rhesus macaques, SIVMAC-1A11 induced transient viremia (1 to 6 weeks) without clinical disease and a persistent humoral antibody response. The antibodies were directed mainly against the viral envelope glycoproteins, as determined by immunoblots and virus neutralization. The potential of this virulence-attenuated virus to protect against intravenous challenge with a pathogenic SIVMAC strain was assessed. Five rhesus macaques were each given two intravenous inoculations with SIVMAC-1A11 7 months apart. Three of the five immunized monkeys and four naive control animals were then challenged with 100 to 1,000 100% animal infectious doses of pathogenic SIVMAC. All seven animals became persistently viremic following the challenge. Four of four unimmunized animals developed severe clinical signs of simian acquired immunodeficiency syndrome by 38 to 227 days after challenge and were euthanatized 91 to 260 days postchallenge. However, no signs of illness were seen in immunized monkeys until 267 to 304 days postchallenge, when two of three immunized animals developed mild thrombocytopenia and lymphopenia; one of these animals died with clinical signs of simian immunodeficiency disease at 445 days after challenge. The two SIVMAC-1A11-immunized monkeys that were not challenged were healthy and antibody positive 22 months after the initial immunization. Thus, although live SIVMAC-1A11 was immunogenic and did not induce any disease, it failed to protect rhesus macaques against infection with a moderately high dose of pathogenic virus. However, immunization prevented severe, early disease and prolonged the lives of monkeys subsequently infected with pathogenic SIV.


An unbiased genome-wide analysis of zinc-finger nuclease specificity.
Zinc-finger nucleases (ZFNs) allow gene editing in live cells by inducing a targeted DNA double-strand break (DSB) at a specific genomic locus. However, strategies for characterizing the genome-wide specificity of ZFNs remain limited. We show that nonhomologous end-joining captures integrase-defective lentiviral vectors at DSBs, tagging these transient events. Genome-wide integration site analysis mapped the actual in vivo cleavage activity of four ZFN pairs targeting CCR5 or IL2RG. Ranking loci with repeatedly detectable nuclease activity by deep-sequencing allowed us to monitor the degree of ZFN specificity in vivo at these positions. Cleavage required binding of ZFNs in specific spatial arrangements on DNA bearing high homology to the intended target site and only tolerated mismatches at individual positions of the ZFN binding sites. Whereas the consensus binding sequence derived in vivo closely matched that obtained in biochemical experiments, the ranking of in vivo cleavage sites could not be predicted in silico. Comprehensive mapping of ZFN activity in vivo will facilitate the broad application of these reagents in translational research.


Modelling climate change impacts on tourism demand: A comparative study from Sardinia (Italy) and Cap Bon (Tunisia).
Tourism represents an important source of income and employment in many Mediterranean regions, including the island of Sardinia (Italy) and the Cap Bon peninsula (Tunisia). Climate change may however impact tourism in both regions, for example, by altering the regions' climatic suitability for common tourism types or affecting water availability. This paper assesses the potential impacts of climate change on tourism in the case study regions of Sardinia and Cap Bon. Direct impacts are studied in a quantitative way by applying a range of climate scenario data on the empirically estimated relationship between climatic conditions and tourism demand, using two different approaches. Results indicate a potential for climate-induced tourism revenue gains especially in the shoulder seasons during spring and autumn, but also a threat of climate-induced revenue losses in the summer months due to increased heat stress. Annual direct net impacts are nevertheless suggested to be (slightly) positive in both case study regions. Significant climate-induced reductions in total available water may however somewhat counteract the positive direct impacts of climate change by putting additional water costs on the tourism industry.


Chronic polioencephalitis with cerebral atrophy in infantile X-linked hypogammaglobulineaemia.
The development of a chronic polioencephalitis is reported in a patient with infantile X-linked hypogammaglobulinaemia (IXH Bruton type agammaglobulinaemia). In early childhood, the patient had multiple episodes of purulent inflammation involving the meninges and respiratory tract. He was given continuous administration of gammaglobulin and intermittent treatment with antibiotics, and survived for 21 years. The neuropathological lesion, which revealed severe cerebral atrophy, is described.


Taming of a poison: biosynthesis of the NiFe-hydrogenase cyanide ligands.
NiFe-hydrogenases have an Ni-Fe site in which the iron has one CO and two CN groups as ligands. Synthesis of the CN ligands requires the activity of two hydrogenase maturation proteins: HypF and HypE. HypF is a carbamoyltransferase that transfers the carbamoyl moiety of carbamoyladenylate to the COOH-terminal cysteine of HypE and thus forms an enzyme-thiocarbamate. HypE dehydrates the S-carbamoyl moiety in an adenosine triphosphate-dependent process to yield the enzyme thiocyanate. Chemical model reactions corroborate the feasibility of this unprecedented biosynthetic route and show that thiocyanates can donate CN to iron. This finding underscores a striking parallel between biochemistry and organometallic chemistry in the formation of an iron-cyano complex.


IL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease.
It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic gastrointestinal inflammation in Crohn's disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to 500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF, or anti-α4β7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controlled α4β7 integrin expression and imprinted gut-homing specificity on T cells. IL-7R blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.


Comparative analysis of adaptive immune responses following experimental infections of cattle with bovine viral diarrhoea virus-1 and an Asiatic atypical ruminant pestivirus.
Atypical ruminant pestiviruses are closely related to the two bovine viral diarrhoea virus (BVDV) species, BVDV-1 and BVDV-2. While there is evidence of cross-protective immune responses between BVDV-1 and BVDV-2, despite antigenic differences, there is little information on the antigenic cross-reactivity with atypical ruminant pestiviruses. The aim of this study was therefore to assess the specificity of antibody and T cell responses induced by experimental infection of calves with BVDV-1 strain Ho916, Th/04_KhonKaen (TKK), an Asiatic atypical ruminant pestivirus, or co-infection with both viruses. Homologous virus neutralization was observed in sera from both single virus infected and co-infected groups, while cross-neutralization was only observed in the TKK infected group. T cell IFN-γ responses to both viruses were observed in the TKK infected animals, whereas Ho916 infected calves responded better to homologous virus. Specifically, IFN-γ responses to viral non-structural protein, NS3, were observed in all infected groups while responses to viral glycoprotein, E2, were virus-specific. Broader antigen-specific cytokine responses were observed with similar trends between inoculation groups and virus species. The limited T cell and antibody immune reactivity of Ho916 inoculated animals to TKK suggests that animals vaccinated with current BVDV-1-based vaccines may not be protected against atypical ruminant pestiviruses.


Evolution of a conspicuous melanin-based ornament in gulls Laridae.
Melanin- and carotenoid-based ornaments often signal different aspects of individual quality or similar components of quality under different environmental conditions and, thus, they may become evolutionarily integrated into a composite sexual trait. On the other hand, functionally and developmentally different characters (e.g. coloration characters of different developmental origin) are more likely to evolve independently from each other than more similar traits. Here, we examined evolutionary correlations between the occurrence of a conspicuous melanin-based ornament (hood) and carotenoid-based bare-part ornaments within gull family. We also aimed to identify major ecological, life-history and biogeographical predictors of hood occurrence and reconstruct evolutionary history of this ornament. We found that hood occurrence was associated with red or dark coloration of unfeathered traits (bill and legs), whereas combinations of hood with yellow carotenoid-based coloration of integument were evolutionarily avoided. Also, hood occurrence correlated negatively with the occurrence of other melanin-based plumage character (mantle). Breeding latitude and habitat were identified as major predictors of hood occurrence in gulls, as hoods were recorded more frequently in low-latitude and inland (rather than marine) species. Finally, our analysis provided support for evolutionary lability in hood occurrence, with a dominance of transitions towards hood loss in the evolutionary history of gulls. The results of our study provide one of the first evidence for a correlated evolution of melanin- and carotenoid-based ornaments in an avian lineage, which supports evolutionary modularity of developmentally and functionally different coloration traits.


Impact of prenatal exposure characterization on early risk detection: Methodologic insights for the HEALthy Brain and Child Development (HBCD) study.
A major challenge in prenatal drug exposure research concerns the balance of measurement quality with sample sizes necessary to address confounders. To inform the selection of optimal exposure measures for the HEALthy Brain and Child Development (HBCD) Study, we employed integrated analysis to determine how different methods used to characterize prenatal tobacco exposure influence the detection of exposure-related risk, as reflected in normal variations in birth weight. Participants were N = 2323 mother-infant dyads derived from 7 independent developmental cohorts harmonized on measures of exposure, outcome (birthweight), and covariates. We compared estimates of PTE-related effects on birthweight derived from linear regression models when PTE was categorized dichotomously based on any fetal exposure (30% exposed; 69% not exposed); versus categorically, based on common patterns of maternal smoking during pregnancy (never smoked 69%; quit smoking 16%; smoked intermittently 2%; smoked persistently 13%). We secondarily explored sex differences in PTE-birthweight associations across these categorization methods. When PTE was categorized dichotomously, exposure was associated with a - 125-g difference in birthweight (95% C.I. -173.7 - -76.6, p < .0001). When PTE was characterized categorically based on maternal smoking patterns, however, exposure was associated with either no difference in birthweight if mothers quit smoking by the end of the first trimester (B = -30.6, 95% C.I. -88.7-27.4, p = .30); or a - 221.8 g difference in birthweight if mothers did not [95% C.I. (-161.7 to -282.0); p < .001]. Qualitative sex differences were also detected though PTE x sex interactions did not reach statistical significance. Maternal smoking cessation during pregnancy was associated with a 239.3 g increase in birthweight for male infants, and a 114.0 g increase in birthweight for females infants (p = .07). Categorization of PTE based on patterns of maternal smoking rather than the presence or absence of exposure alone revealed striking nuances in estimates of exposure-related risk. The described method that captures both between-individual and within-individual variability in prenatal drug exposure is optimal and recommended for future developmental investigations such as the HBCD Study.


[Steady-state kinetics of reactions catalyzed by serine sulfhydrases of Saccharomyces serevisiae].
The steady-state kinetics of the two substrate reaction of L-cysteine desulfation in the presence of 2-mercaptoethanol catalyzed by serine sulfhydrase from bakers yeast -- a pyridoxal phosphate-containing enzyme of the beta -- substituting lyase type -- were studied. Highly purified enzyme preparations (approximately 90% purity) of Saccharomyces cerevisiae with specific activity of 25 mumoles of H2S per 1 hr per mg of protein were used. The values of V, KS1, KS2 and alpha were calculated from the initial rates of the reaction under constant concentration of L-cysteine (S1) and variable concentration of 2-mercaptoethanol (S2) and vice versa. The data obtained suggest that under conditions of a two-substrate reaction catalyzed by serine sulfhydrase and in case of beta-cyanoalanine synthase of blue lupin the substrate binding to the enzyme is interdependent and obeys a unordered mechanism with o formation of a ternary aminosubstrate-pyridoxal phosphateenzyme-cosubstrate complex (alpha = 2.6).


Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells.
The aim of this study was to elucidate some of the possible mechanisms of action of the vitamin D analogue calcipotriol in vivo. Calcipotriol is finding increasing use in the treatment of psoriasis, but the primary target cell in vivo has not yet been identified. We treated psoriatic patients and healthy volunteers with calcipotriol and placebo ointment for 4 and 7 days, and obtained epidermal cell suspensions from treated areas. Epidermal cells were cocultured with autologous T cells, isolated from peripheral blood, in the absence or the presence of a classical antigen or a superantigen. In both psoriatic and normal skin, calcipotriol treatment did not alter the capacity of epidermal antigen-presenting cells to stimulate the proliferation of autologous T cells, either in the absence or in the presence of exogenous antigen. Epidermal cell suspensions were analysed further by staining for infiltrating leucocytes (CD45+) and Langerhans cells (CD1a+). Flow cytometric analysis showed that calcipotriol did not alter the number of CD45+ cells or Langerhans cells in psoriatic skin. These results indicate that calcipotriol does not alter either the number of the function of epidermal antigen-presenting cells in psoriatic epidermis. In contrast, we found that calcipotriol significantly inhibited the proliferation of epidermal cells isolated from psoriatic skin after in vivo treatment, as determined by propidium iodide staining and flow cytometry. More specifically, we stained for CD29+ keratinocytes and found an even more significant reduction in proliferative capacity. This cell type contains the population of hyperproliferative keratinocytes in psoriatic epidermis. In conclusion, calcipotriol seems to act via an inhibitory effect on hyperproliferative basal keratinocytes of psoriatic epidermis, rather than via an effect on infiltrating leucocytes, including antigen-presenting cells.


Risk factors for osteoporotic fracture.
Fracture prevention requires the identification of individuals at risk prior to fracture. Bone density, a history of previous fractures, biochemical markers, and the frequency and types of falls are important risk factors for fractures. There are also many other risk factors for bone loss, falls, and fractures. When considered alone or in combination, risk factors can identify a wide range of fracture risk among individuals. Persons with multiple risk factors are at greater risk than are those with either a single risk factor or none. It is not possible to modify some risk factors such as age and gender. Although it is possible in theory to modify other risk factors such as calcium or vitamin D deficiency, the resulting benefits are often small. In contrast, the determination of BMD provides a precise, noninvasive measure of fracture risk, and effective treatments are available to prevent bone loss and increase BMD. Current BMD represents the cumulative, combined influence of all past and current risk factors for bone loss, and prospective changes in biochemical markers and BMD can be used to monitor treatment efficacy. Persons with low BMD and those with multiple risk factors may benefit the most from treatments to preserve or increase BMD. Bone density should always be measured directly, because it is not possible to predict this parameter and fracture risk from other risk factors for bone loss.


Plants and mushrooms of abuse.
The plants described earlier are only a few of those that can be misused. Most have effects similar to those of more popular synthetic drugs but can cause unpleasant side effects and unpredictable results. Identification of the offending botanic agent can be problematic. These plants are still used because most are legal to possess, and they do produce desired hallucinogenic and stimulant effects. Because the active ingredients are similar pharmacologically to agents such as LSD and amphetamine, required treatment is often similar. The challenge for the Emergency Department physician is to recognize the potential for abuse of these botanic agents, their probable side effects, and the need for appropriate, usually supportive, treatment. There are many more plants with abuse potential than can be discussed in detail in an article of this size. Table 1 lists a number of other agents that might be misused. Phenylamine hallucinogens occur in several species and include N,N-dimethyltryptamine (DMT), N-monomethyltryptamine (MMT), 5-methoxy-N-N-dimethyltryptamine (5-MeO-DMT), 5-methoxy-N-monomethyltryptamine (5-MeO-DMT), 5-methoxy-N-monomethyltryptamine (5-MeO-MMT), 5-hydroxy-N-N-dimethyltryptamine (bufotenine or 5-H-DMT), and N,N-dimethyltryptamine-N-oxide (DMT-N-oxide).