Education and training of occupational therapists for neonatal intensive care units.
The neonatal intensive care unit (NICU) is an area in which occupational therapists require specialized advanced training and skills. The purpose of this study was to evaluate the nature of current practice among occupational therapists in NICU settings, their training, and their opinions regarding educational experiences necessary for NICU work. One hundred seventy-four NICU occupational therapists completed a survey questionnaire designed to elicit information about these issues. The majority of respondents were engaged in similar practice duties in NICUs, most of which had been using therapy services for less than 10 years. Most of the respondents (83%) reported that their primary source of training was on the job rather than through formal course work or training programs. Many of the respondents (40%) lacked training in the use of any infant assessments, and 50% had 2 years or less of pediatric work experience before entering practice in the NICU. The respondents indicated that mentored experience, on-the-job training, pediatric work experience, extended continuing education courses, and formal internships could prove helpful to future occupational therapists who wish to acquire the knowledge and skills to become competent in the NICU. Results of the survey indicate that current training and education to work in an NICU is inadequate and needs to be addressed. Occupational therapists working in NICUs desire and express the need for specialized training to work in this practice area. A more aggressive effort toward standard NICU education and training is necessary to ensure that occupational therapists are competent members of the NICU team.


Human sleep under the influence of pulsed radiofrequency electromagnetic fields: a polysomnographic study using standardized conditions.
To investigate the influence of radiofrequency electromagnetic fields (EMFs) of cellular phone GSM signals on human sleep electroencephalographic (EEG) pattern, all-night polysomnographies of 24 healthy male subjects were recorded, both with and without exposure to a circular polarized EMF (900 MHz, pulsed with a frequency of 217 Hz, pulse width 577 micros, power flux density 0.2 W/m2. Suppression of rapid eye movement (REM) sleep as well as a sleep-inducing effect under field exposure did not reach statistical significance, so that previous results indicating alterations of these sleep parameters could not be replicated. Spectral power analysis also did not reveal any alterations of the EEG rhythms during EMF exposure. The failure to confirm our previous results might be due to dose-dependent effects of the EMF on the human sleep profile.


A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned.
Increasingly, reports of frequent and occasionally catastrophic complications associated with use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal fusion surgeries are being published. In the original peer review, industry-sponsored publications describing the use of rhBMP-2 in spinal fusion, adverse events of these types and frequency were either not reported at all or not reported to be associated with rhBMP-2 use. Some authors and investigators have suggested that these discrepancies were related to inadequate peer review and editorial oversight. To compare the conclusions regarding the safety and related efficacy published in the original rhBMP-2 industry-sponsored trials with subsequently available Food and Drug Administration (FDA) data summaries, follow-up publications, and administrative and organizational databases. Systematic review. Results and conclusions from original industry-sponsored rhBMP-2 publications regarding safety and related efficacy were compared with available FDA data summaries, follow-up publications, and administrative and organizational database analyses. There were 13 original industry-sponsored rhBMP-2 publications regarding safety and efficacy, including reports and analyses of 780 patients receiving rhBMP-2 within prospective controlled study protocols. No rhBMP-2-associated adverse events (0%) were reported in any of these studies (99% confidence interval of adverse event rate <0.5%). The study designs of the industry-sponsored rhBMP-2 trials for use in posterolateral fusions and posterior lateral interbody fusion were found to have potential methodological bias against the control group. The reported morbidity of iliac crest donor site pain was also found to have serious potential design bias. Comparative review of FDA documents and subsequent publications revealed originally unpublished adverse events and internal inconsistencies. From this review, we suggest an estimate of adverse events associated with rhBMP-2 use in spine fusion ranging from 10% to 50% depending on approach. Anterior cervical fusion with rhBMP-2 has an estimated 40% greater risk of adverse events with rhBMP-2 in the early postoperative period, including life-threatening events. After anterior interbody lumbar fusion rates of implant displacement, subsidence, infection, urogenital events, and retrograde ejaculation were higher after using rhBMP-2 than controls. Posterior lumbar interbody fusion use was associated with radiculitis, ectopic bone formation, osteolysis, and poorer global outcomes. In posterolateral fusions, the risk of adverse effects associated with rhBMP-2 use was equivalent to or greater than that of iliac crest bone graft harvesting, and 15% to 20% of subjects reported early back pain and leg pain adverse events; higher doses of rhBMP-2 were also associated with a greater apparent risk of new malignancy. Level I and Level II evidence from original FDA summaries, original published data, and subsequent studies suggest possible study design bias in the original trials, as well as a clear increased risk of complications and adverse events to patients receiving rhBMP-2 in spinal fusion. This risk of adverse events associated with rhBMP-2 is 10 to 50 times the original estimates reported in the industry-sponsored peer-reviewed publications.


Use of bacterial spores in monitoring water quality and treatment.
Because Clostridium perfringens spores are both specific to sewage contamination and environmentally stable, they are considered as possible conservative indicators of human fecal contamination and possible surrogates for environmentally stable pathogens. This review discusses the reasons and summarizes methods for monitoring spores in water. Cultural methods are still preferred over qPCR for routine water quality monitoring because of their low costs. Membrane filter (MF) methods are preferred over the more laborious and less accurate most probable number methods. The most commonly used MF media are TSC medium and mCP medium. TSC normally allows higher recoveries than mCP. TSC produces fewer false-positive results than mCP; however, it does produce more false-negatives. Two newer methods have substantial potential, CP Chromo Select agar, which allows better recoveries and greater specificity than mCP, and the Fung double tube method, which creates anaerobic conditions and allows enumeration of colonies in tubes in 5-6 hours. Aerobic spores are not associated with fecal contamination but they can be surrogates for environmentally stable pathogens in monitoring water for treatment efficacy; Bacillus cereus spores are normally measured on nutrient agar by the MF method.


Reproductive Biology and Ecology of the Green Mussel Perna viridis: A Multidisciplinary Approach.
A multidisciplinary approach was applied to explore deeper knowledge about the reproductive biology and ecology of the green mussel (Perna viridis) by interlinking among ecological factors, ingested gut plankton, gonad fatty acid profile, and reproductive traits. Mussels were collected throughout the year from the coastal region of the Bay of Bengal of Bangladesh, and the histological analysis of 242 mussels revealed five stages of gametogenesis with an annual spawning season from January to April. The gonadosomatic index showed a strong correlation with the water quality parameters, ingested gut plankton groups, and gonadal fatty acids, and also displayed prominent effects of seasonality. In all datasets, we performed principal component analysis in which the first two principal components showed that seasonality explained >65% of the variability, and the multivariate spaces of seasonality corresponded to the gonad development. High salinity, nutrients, chlorophyll a, and plankton abundance in the water column were positively correlated with gonad development and the spawning of mussels. During the development stage, mussel ingested more plankton, particularly Bacillariophyceae and Pyrrophyceae, which were an important source of increased n-3 polyunsaturated fatty acids content in gonads. Furthermore, gonads accumulated more lipids and saturated fatty acids during the mature and spawning stages, which were probably utilized during embryogenesis and early larval development as energy sources and constituents of the cell membrane. This research provides a model toward a better understanding of reproductive biological traits and how these traits are interrelated with the surrounding environmental variables of the green mussel, which would be helpful in marine aquaculture and the sustainable exploitation of the fishery resources.


Retinal ischemia and reperfusion causes capillary degeneration: similarities to diabetes.
Retinal neurons and vasculature interact with each other under normal conditions, and occlusion of the retinal vasculature can result in damage to retinal neurons. Whether damage to the neural retina will damage the vasculature, however, is less clear. This study was conducted to explore the relationship between vascular and nonvascular cells of the retina. The response of the retinal vasculature to an injury (ischemia and reperfusion; I/R) that is known to cause neuronal degeneration was studied. I/R injury to the retinas was induced in Lewis rats and C57BL/6J mice by elevating intraocular pressure (IOP), and reperfusion was established immediately afterward. Some rats were pretreated with aminoguanidine (AMG, 50 mg/Kg BW in drinking water) before the procedure. Poly(ADP-ribose) polymerase (PARP) activity and expression of inducible nitric oxide synthase (iNOS), and cycloxygenase-2 (COX-2) were measured by Western blot analysis, and levels of TNF-alpha and intercellular adhesion molecule (ICAM)-1 mRNA were measured by qPCR at 2 and 7 days after the procedure. Also at 2 and 7 days after the I/R injury, apoptosis of retinal neural cells (demonstrated by TUNEL assay), density of cells in the ganglion cell layer, and thickness of retinas were quantitated, and the number of TUNEL-positive capillary cells and degenerated capillaries were assessed. Retinal neurodegeneration and capillary degeneration were also examined in C57BL/6J mice 2, 5, 8, and 14 days after I/R injury. As expected, loss of cells in the retinal ganglion cell layer was apparent 2 days after I/R injury in the rat and mouse models. In contrast, the retinal vasculature had essentially no pathology at this time in either model. Surprisingly, the number of degenerated capillaries increased greatly by 7 to 8 days after the injury. Administration of aminoguanidine significantly inhibited the I/R-induced capillary degeneration as well as neurodegeneration in the rat model. Retinal I/R caused increased PARP activity (detected by poly(ADP-ribosy)lated proteins), as well as upregulation of iNOS, COX-2, TNF-alpha, and ICAM-1 levels in rats, consistent with an inflammatory process. Capillary degeneration is an unrecognized component of acutely elevated IOP and develops only after neurodegeneration is severe. Thus, this finding raises the possibility that damage to the neural retina contributes to capillary degeneration. Aminoguanidine, a nonspecific inhibitor of iNOS, inhibited I/R-induced degeneration of both neuronal and vascular cells of the retina. The model of retinal ischemia and reperfusion will be a useful tool for investigating the relationship between neuronal damage and vascular damage in glaucoma and other diseases such as diabetic retinopathy.


A solution to release twisted DNA during chromosome replication by coupled DNA polymerases.
Chromosomal replication machines contain coupled DNA polymerases that simultaneously replicate the leading and lagging strands. However, coupled replication presents a largely unrecognized topological problem. Because DNA polymerase must travel a helical path during synthesis, the physical connection between leading- and lagging-strand polymerases causes the daughter strands to entwine, or produces extensive build-up of negative supercoils in the newly synthesized DNA. How DNA polymerases maintain their connection during coupled replication despite these topological challenges is unknown. Here we examine the dynamics of the Escherichia coli replisome, using ensemble and single-molecule methods, and show that the replisome may solve the topological problem independent of topoisomerases. We find that the lagging-strand polymerase frequently releases from an Okazaki fragment before completion, leaving single-strand gaps behind. Dissociation of the polymerase does not result in loss from the replisome because of its contact with the leading-strand polymerase. This behaviour, referred to as 'signal release', had been thought to require a protein, possibly primase, to pry polymerase from incompletely extended DNA fragments. However, we observe that signal release is independent of primase and does not seem to require a protein trigger at all. Instead, the lagging-strand polymerase is simply less processive in the context of a replisome. Interestingly, when the lagging-strand polymerase is supplied with primed DNA in trans, uncoupling it from the fork, high processivity is restored. Hence, we propose that coupled polymerases introduce topological changes, possibly by accumulation of superhelical tension in the newly synthesized DNA, that cause lower processivity and transient lagging-strand polymerase dissociation from DNA.


Hypervalent organoiodine(v) metal-organic frameworks: syntheses, thermal studies and stoichiometric oxidants.
Iodinated analogues of the highly porous IRMOF-9 and UiO-67 frameworks were prepared and post-synthetically oxidised with dimethyldioxirane (DMDO). Analysis by X-ray photoelectron spectroscopy (XPS) confirmed promotion to the iodine(v) state and detailed differential scanning calorimetry-thermal gravimetric analysis (DSC-TGA) showed the hypervalent metal-organic frameworks (MOFs) undergo exothermic elimination at ∼200 °C with XPS showing hypervalency is maintained. The hypervalent MOFs are active heterogeneous reagents in sulfoxidation and alcohol oxidation reactions. The crystallinity and porosity of the MOFs were maintained following post-synthetic oxidation, thermolysis and after the heterogeneous reactions, as shown by powder X-ray diffraction (PXRD) and gas adsorption analyses. This work showcases the unique ability MOFs hold for studying chemical reactions and the potential for hypervalent organoiodine MOFs as reuseable oxidants.


The gut microbiota influences skeletal muscle mass and function in mice.
The functional interactions between the gut microbiota and the host are important for host physiology, homeostasis, and sustained health. We compared the skeletal muscle of germ-free mice that lacked a gut microbiota to the skeletal muscle of pathogen-free mice that had a gut microbiota. Compared to pathogen-free mouse skeletal muscle, germ-free mouse skeletal muscle showed atrophy, decreased expression of insulin-like growth factor 1, and reduced transcription of genes associated with skeletal muscle growth and mitochondrial function. Nuclear magnetic resonance spectrometry analysis of skeletal muscle, liver, and serum from germ-free mice revealed multiple changes in the amounts of amino acids, including glycine and alanine, compared to pathogen-free mice. Germ-free mice also showed reduced serum choline, the precursor of acetylcholine, the key neurotransmitter that signals between muscle and nerve at neuromuscular junctions. Reduced expression of genes encoding Rapsyn and Lrp4, two proteins important for neuromuscular junction assembly and function, was also observed in skeletal muscle from germ-free mice compared to pathogen-free mice. Transplanting the gut microbiota from pathogen-free mice into germ-free mice resulted in an increase in skeletal muscle mass, a reduction in muscle atrophy markers, improved oxidative metabolic capacity of the muscle, and elevated expression of the neuromuscular junction assembly genes Rapsyn and Lrp4 Treating germ-free mice with short-chain fatty acids (microbial metabolites) partly reversed skeletal muscle impairments. Our results suggest a role for the gut microbiota in regulating skeletal muscle mass and function in mice.


Introduced Pheidole of the world: taxonomy, biology and distribution.
The objective of this study is to provide a detailed taxonomic resource for identifying and studying ants in the genus Pheidole that have established beyond their native ranges. There is an increasing need for systematists to study taxa of specific concern to 21(st) century environmental, food security and public health challenges. Systematics has an important role to play in both the theoretical and applied disciplines of invasion biology. Few invaders impact terrestrial ecosystems more than ants. Among the world's 100 worst invasive species is the cosmopolitan and highly destructive Pheidole megacephala (Fabricius). Accurate identification of Pheidole megacephala is imperative for the success of screening, management and eradication programs designed to protect native ecosystems from the impacts of this destructive species. However, accurate identification of Pheidole species is difficult because of their taxonomic diversity, dimorphic worker caste and lack of taxonomic resources. Illustrated keys are included, along with the taxonomic history, taxonomic diagnoses, biological notes and risk statements for the 14 most invasive members of the genus. Global distribution maps based on over 14,000 specimen and literature records are presented for each species. These results of this work will facilitate identification of pest species, determination of climatic and habitat requirements, discovery of pest origins, horizon scanning and assessment of invasion pathways. The following new synonym is proposed, with the senior synonym listed first and the junior synonyms in parentheses: Pheidole indica Mayr (= Pheidole teneriffana Forel, and its synonyms Pheidole taina Aguayo and Pheidole voeltzkowii Forel). Pheidole navigans Forel, stat. rev., stat. n. is removed from synonymy and elevated to species rank. It is proposed that records of Pheidole moerens Forel outside of the Mesoamerica and the Caribbean refer instead to Pheidole navigans or other heterospecific taxa in the Pheidole flavens species complex. We propose that the names Pheidole anastasii Emery and Pheidole floridana Emery have been widely misapplied to North American outdoor records of Pheidole bilimeki Mayr. It is suggested that the synonymy of Pheidole lauta Wheeler be transferred from Pheidole floridana Emery to Pheidole bilimeki Mayr.


Cwp19 Is a Novel Lytic Transglycosylase Involved in Stationary-Phase Autolysis Resulting in Toxin Release in Clostridium difficile.
Clostridium difficile is the major etiologic agent of antibiotic-associated intestinal disease. Pathogenesis of C. difficile is mainly attributed to the production and secretion of toxins A and B. Unlike most clostridial toxins, toxins A and B have no signal peptide, and they are therefore secreted by unusual mechanisms involving the holin-like TcdE protein and/or autolysis. In this study, we characterized the cell surface protein Cwp19, a newly identified peptidoglycan-degrading enzyme containing a novel catalytic domain. We purified a recombinant His6-tagged Cwp19 protein and showed that it has lytic transglycosylase activity. Moreover, we observed that Cwp19 is involved in cell autolysis and that a C. difficilecwp19 mutant exhibited delayed autolysis in stationary phase compared to the wild type when bacteria were grown in brain heart infusion (BHI) medium. Wild-type cell autolysis is correlated to strong alterations of cell wall thickness and integrity and to release of cytoplasmic material. Furthermore, we demonstrated that toxins were released into the extracellular medium as a result of Cwp19-induced autolysis when cells were grown in BHI medium. In contrast, Cwp19 did not induce autolysis or toxin release when cells were grown in tryptone-yeast extract (TY) medium. These data provide evidence for the first time that TcdE and bacteriolysis are coexisting mechanisms for toxin release, with their relative contributions in vitro depending on growth conditions. Thus, Cwp19 is an important surface protein involved in autolysis of vegetative cells of C. difficile that mediates the release of the toxins from the cell cytosol in response to specific environment conditions.IMPORTANCEClostridium difficile-associated disease is mainly known as a health care-associated infection. It represents the most problematic hospital-acquired infection in North America and Europe and exerts significant economic pressure on health care systems. Virulent strains of C. difficile generally produce two toxins that have been identified as the major virulence factors. The mechanism for release of these toxins from bacterial cells is not yet fully understood but is thought to be partly mediated by bacteriolysis. Here we identify a novel peptidoglycan hydrolase in C. difficile, Cwp19, exhibiting lytic transglycosylase activity. We show that Cwp19 contributes to C. difficile cell autolysis in the stationary phase and, consequently, to toxin release, most probably as a response to environmental conditions such as nutritional signals. These data highlight that Cwp19 constitutes a promising target for the development of new preventive and curative strategies.


Dietary iron intake and risk of coronary disease among men.
We prospectively studied iron intake in relation to the incidence of coronary disease in a 4-year follow-up of 44,933 men (with no previous history of cardiovascular disease) aged 40 to 75 years in 1986 who completed a food frequency questionnaire at baseline. We documented 844 incident cases of coronary disease (249 nonfatal myocardial infarctions, 137 coronary disease fatalities, and 458 bypass operations or angioplasties). After adjustment for established risk factors, there was no significant association between total iron intake and risk of coronary heart disease. Men in the highest quintile of total intake (median, 37 mg/d) had a relative risk (RR) of fatal coronary disease or nonfatal myocardial infarction of 0.73 (95% confidence intervals [CI], 0.51, 1.06) compared with men in the lowest quintile of intake (median, 11 mg/d). Dietary intake of heme iron--mainly from red meat--also was not significantly associated with risk of coronary heart disease. However, incidence of fatal coronary disease or nonfatal myocardial infarction was higher among men in the top quintile of heme iron intake compared with men in the lowest quintile (RR, 1.42; 95% CI, 1.02, 1.98). This association remained after adjustment for dietary cholesterol and fats. Heme iron but not total iron intake was positively correlated with serum ferritin among 123 members of the cohort who participated in a validation study. These results do not support the hypothesis that dietary iron in general increases coronary risk in men; they are consistent, however, with an increased risk of myocardial infarction among men with higher intake of heme iron, which is itself positively associated with iron stores.


Synthesis and physicochemical characterization of a series of hemoglobin-based oxygen carriers: objective comparison between cellular and acellular types.
A series of hemoglobin (Hb)-based O(2) carriers, acellular and cellular types, were synthesized and their physicochemical characteristics were compared. The acellular type includes intramolecularly cross-linked Hb (XLHb), polyoxyethylene (POE)-conjugated pyridoxalated Hb (POE-PLP-Hb), hydroxyethylstarch-conjugated Hb (HES-XLHb), and glutaraldehyde-polymerized XLHb (Poly-XLHb). The cellular type is Hb-vesicles (HbV) of which the surface is modified with POE (POE-HbV). Their particle diameters are 7 +/- 2, 22 +/- 2, 47 +/- 17, 68 +/- 24, and 224 +/- 76 nm, respectively, thus all the materials penetrate across membrane filters with 0.4 microm pore size, though only the POE-HbV cannot penetrate across the filter with 0.2 microm pore size. These characteristics of permeability are important to consider an optimal particle size in microcirculation in vivo. POE-PLP-Hb ([Hb] = 5 g/dL) showed viscosity of 6.1 cP at 332 s(-1) and colloid osmotic pressure (COP) of 70.2 Torr, which are beyond the physiological conditions (human blood, viscosity = 3-4 cP, COP = ca. 25 Torr). XLHb and Poly-XLHb showed viscosities of 1.0 and 1.5 cp, respectively, which are significantly lower than that of blood. COP of POE-HbV is regulated to 20 Torr in 5% human serum albumin (HSA). HES-XLHb and POE-HbV/HSA showed comparable viscosity with human blood. Microscopic observation of human red blood cells (RBC) after mixing blood with POE-PLP-Hb or HES-XLHb disclosed aggregates of RBC, a kind of sludge, indicating a strong interaction with RBC, which is anticipated to modify peripheral blood flow in vivo. On the other hand, XLHb and POE-HbV showed no rouleaux or aggregates of RBC. The acellular Hbs (P(50) = 14-32 Torr) have their specific O(2) affinities determined by their structures, while that of the cellular POE-HbV is regulated by coencapsulating an appropriate amount of an allosteric effector (e.g., P(50) = 18, 32 Torr). These differences in physicochemical characteristics between the acellular and cellular types indicate the advantages of the cellular type from the physiological points of view.


The science of contemporary street protest: New efforts in the United States.
Since the inauguration of Donald Trump, there has been substantial and ongoing protest against the Administration. Street demonstrations are some of the most visible forms of opposition to the Administration and its policies. This article reviews the two most central methods for studying street protest on a large scale: building comprehensive event databases and conducting field surveys of participants at demonstrations. After discussing the broader development of these methods, this article provides a detailed assessment of recent and ongoing projects studying the current wave of contention. Recommendations are offered to meet major challenges, including making data publicly available in near real time, increasing the validity and reliability of event data, expanding the scope of crowd surveys, and integrating ongoing projects in a meaningful way by building new research infrastructure.


Effect of pharmacological doses of 3-0-methyl-D-glucose and 2-deoxy-D-glucose on rat brain glucose and lactate.
The present investigation examined the effects of two glucose analogues, 3-0-methyl-D-glucose (30MG) and 2-deoxy-D-glucose (2DOG) on basal levels of rat brain glucose and lactate. The results showed that pretreatment (iv) with 30MG up to 2 g/kg caused a transient drop in brain glucose levels to 42% of control value within 2.5 min and a drop in lactate levels to 75% of control value by 5 min. 2DOG administration (2 g/kg) affected glucose in a biphasic response with an initial drop to 46% of control value seen by 2.5 min, followed by a progressive increase to 290% of the control value by 40 min. This elevated level of glucose was sustained for approximately 40 min. Lactate levels responded to 2DOG administration by a decrease to 37% of control value within 10 min post-injection and returned to near basal levels by 160 min. A dose response was also examined for both compounds. Behaviorally 30MG had no apparent effects. However, the response to 2DOG was a reduction in voluntary movements, piloerection, irregular clonic jerks, splayed limbs and fits of wild running. These experiments were designed to evaluate the potential of 30MG or 2DOG for attenuating the well documented rise in brain lactate levels following an ischemic insult. Our results suggest that under certain experimental conditions either 30MG or 2DOG could prevent brain lactate rise and might have beneficial effects in minimizing the neuropathological consequences of ischemic damage that could be related to increases in brain lactate.


Gelatin-fibrinogen cryogel dermal matrices for wound repair: preparation, optimisation and in vitro study.
Macroporous sponge-like gelatin-fibrinogen (Gl-Fg) scaffolds cross-linked with different concentrations (0.05-0.5%) of glutaraldehyde (GA) were produced using cryogelation technology, which allows for the preparation of highly porous scaffolds without compromising their mechanical properties, and is a more cost-efficient process than freeze-drying. The produced Gl-Fg-GA(X) scaffolds had a uniform interconnected open porous structure with a porosity of up to 90-92% and a pore size distribution of 10-120 microm. All of the obtained cryogels were elastic and mechanically stable, except for the Gl-Fg-GA(0.05) scaffolds. Swelling kinetics and degradation rate, but not the porous structure of the cryogels, were strongly dependent on the degree of cross-linking. A ten-fold increase in the degree of cross-linking resulted in an almost 80-fold decrease in the rate of degradation in a solution of protease. Cryogels were seeded with primary dermal fibroblasts and the densities observed on the surface, plus the expression levels of collagen types I and III observed 5 days post-seeding, were similar to those observed on a control dermal substitute material, Integra. Fibroblast proliferation and migration within the scaffolds were relative to the GA content. Glucose consumption rate was 3-fold higher on Gl-Fg-GA(0.1) than on Gl-Fg-GA(0.5) cryogels 10 days post-seeding. An enhanced cell motility on cryogels with reducing GA crosslinking was obtained after long time culture. Particularly marked cell infiltration was seen in gels using 0.1% GA as a crosslinker. The scaffold started to disintegrate after 42 days of in vitro culturing. The described in vitro studies demonstrated good potential of Gl-Fg-GA(0.1) scaffolds as matrices for wound healing.


Thorax closure in Drosophila: involvement of Fos and the JNK pathway.
Dorsal closure, a morphogenetic movement during Drosophila embryogenesis, is controlled by the Drosophila JNK pathway, D-Fos and the phosphatase Puckered (Puc). To identify principles of epithelial closure processes, we studied another cell sheet movement that we term thorax closure, the joining of the parts of the wing imaginal discs which give rise to the adult thorax during metamorphosis. In thorax closure a special row of margin cells express puc and accumulate prominent actin fibres during midline attachment. Genetic data indicate a requirement of D-Fos and the JNK pathway for thorax closure, and a negative regulatory role of Puc. Furthermore, puc expression co-localises with elevated levels of D-Fos, is reduced in a JNK or D-Fos loss-of-function background and is ectopically induced after JNK activation. This suggests that Puc acts downstream of the JNK pathway and D-Fos to mediate a negative feed-back loop. Therefore, the molecular circuitry required for thorax closure is very similar to the one directing dorsal closure in the embryo, even though the tissues are not related. This finding supports the hypothesis that the mechanism controlling dorsal closure has been co-opted for thorax closure in the evolution of insect metamorphosis and may represent a more widely used functional module for tissue closure in other species as well.


SB-334867-A antagonises orexin mediated excitation in the locus coeruleus.
Electrophysiological recordings from identified noradrenergic locus coeruleus (LC) neurones in rat brain slices have revealed that the orexins can cause direct and reversible depolarisation of the postsynaptic membrane. Whilst it is known that the membrane depolarisation produced by orexin-A can triple the firing rate of spontaneously active LC neurones, quantitative pharmacological analysis that determines the receptor subtype(s) mediating the orexinergic response has not yet been performed. Here we demonstrate that the effects of orexin-A are five-fold more potent than orexin-B on LC neuronal excitability. We show further that the orexin receptor antagonist SB-334867-A inhibits the effects of both agonists with pK(B) values similar to those calculated for human OX1 receptors expressed in CHO cells. Finally, we found no evidence for tonic activation of OX1 receptors in LC noradrenergic neurones despite electron microscopic evidence that orexin terminals directly contact these neurones. These data demonstrate that SB-334867-A is a useful tool compound with which to study the physiology of OX1 receptors.


Organometallic rhodium(III) and iridium(III) cyclopentadienyl complexes with curcumin and bisdemethoxycurcumin co-ligands.
A series of half-sandwich cyclopentadienyl rhodium(III) and iridium(III) complexes of the type [Cp*M(curc/bdcurc)Cl] and [Cp*M(curc/bdcurc)(PTA)][SO3CF3], in which Cp* = pentamethylcyclopentadienyl, curcH = curcumin and bdcurcH = bisdemethoxycurcumin as O^O-chelating ligands, and PTA = 1,3,5-triaza-7-phosphaadamantane, is described. The X-ray crystal structures of three of the complexes, i.e. [Cp*Rh(curc)(PTA)][SO3CF3] (5), [Cp*Rh(bdcurc)(PTA)][SO3CF3] (6) and [Cp*Ir(bdcurc)(PTA)][SO3CF3] (8), confirm the expected "piano-stool" geometry. With the exception of 5, the complexes are stable under pseudo-physiological conditions and are moderately cytotoxic to human ovarian carcinoma (A2780 and A2780cisR) cells and also to non-tumorigenic human embryonic kidney (HEK293) cells, but lack the cancer cell selectivity observed for related arene ruthenium(II) complexes.


Conformational heterogeneity within the Michaelis complex of lactate dehydrogenase.
A series of isotope edited IR measurements, both static as well as temperature jump relaxation spectroscopy, are performed on lactate dehydrogenase (LDH) to determine the ensemble of structures available to its Michaelis complex. There clearly has been a substantial reduction in the number of states available to the pyruvate substrate (as modeled by the substrate mimic, oxamate) and NADH when bound to protein compared to dissolved in solution, as determined by the bandwidths and positions of the critical C(2)═O band of the bound substrate mimic and the C(4)-H stretch of the NADH reduced nicotinamide group. Moreover, it is found that a strong ionic bond (characterized by a signature IR band discovered in this study) is formed between the carboxyl group of bound pyruvate with (presumably) Arg171, forming a strong "anchor" within the protein matrix. However, conformational heterogeneity within the Michaelis complex is found that has an impact on both catalytic efficiency and thermodynamics of the enzyme.


Progressive ratio performance following challenge with antipsychotics, amphetamine, or NMDA antagonists in adult rats treated perinatally with phencyclidine.
Previous research has shown that rats exposed perinatally to phencyclidine (PCP) exhibited neuroanatomical abnormalities and altered cognition. In addition to cognitive deficits, schizophrenic patients may also exhibit negative symptoms such as lack of motivation. In this study, we used a progressive ratio (PR) schedule of food reinforcement to assess motivation following early exposure to PCP. Male rat pups were injected SC with 10 mg/kg PCP on postnatal days (PN) 7, 9, and 11. On PN 120, they began training in a PR 5 schedule of food reinforcement. Significant PCP effects on acquisition and baseline performance were not noted. After acquisition of the task, challenges with PCP, dizocilpine, amphetamine, haloperidol, and clozapine resulted in dose-dependent decreases in response rates of similar magnitudes in both groups. In rats that continued to respond at higher doses, PCP, dizocilpine, and clozapine failed to alter breakpoints. In contrast, a 5.6 mg/kg dose of amphetamine selectively increased breakpoints in PCP-treated rats, although very few rats responded at this dose. Haloperidol decreased breakpoints in most rats at non-sedating doses. These results suggest that a regimen of perinatal PCP administration sufficient to disrupt cognition did not alter motivation for food reinforcement, regardless of whether rats also received challenges with NMDA antagonists or antipsychotics. Interpretation of amphetamine's high dose effects on breakpoints was complicated by the failure of many rats to respond at this dose. Further research is needed to determine whether negative symptoms such as social withdrawal may be modeled within this neurodevelopmental approach to schizophrenia.


Textual Analysis and Data Mining: An Interpreting Research on Nursing.
Every day there is a data explosion on the web. In 2013, 5 exabytes of content were created each day. Every hour internet networks carries a quantity of texts equivalent to twenty billion books. For idea Iit is a huge mass of information on the linguistic behavior of people and society that was unthinkable until a few years ago. It is an opportunity for valuable analysis for understanding social phenomena, also in nursing and health care sector.This poster shows the the steps of an idealy strategy for textual statistical analysis and the process of extracting useful information about health care, referring expecially nursing care from journal and web information. We show the potential of web tools of Text Mining applications (DTM, Wordle, Voyant Tools, Taltac 2.10, Treecloud and other web 2.0 app) analyzing text data and information extraction about sentiment, perception, scientific activites and visibility of nursing. This specific analysis is conduct analyzing "Repubblica", first newspaper in Italy (years of analisys: 2012-14) and one italian scientific nursing journal (years: 2012-14).


Factors influencing speech production in elementary and high school-aged cochlear implant users.
The objectives of this study were to (a) evaluate changes in speech intelligibility in a group of 110 adolescent users of cochlear implants who were first assessed in elementary school (CI-E) and later in high school (CI-HS) and (b) examine factors influencing speech intelligibility performance at the CI-E and CI-HS sessions. Participants were 110 adolescents who participated in an earlier study examining 181 young elementary school-aged children. Primary outcome measures included speech intelligibility under quiet and multispeaker background conditions and consonants correct produced in the sentences. Multiple linear regressions were used to evaluate how participant, family, and performance measures influenced their speech production during adolescence. Performance measures included estimates of speech perception, working memory, sign enhancement, and duration of seven-syllable sentences. Participant and family measures included duration of deafness, performance intelligence quotients, gender, family size, and socioeconomic status. Principal component analyses were used to construct common variables across highly intercorrelated measures. Three sets of multiple linear regressions evaluated the contributions of the variables to the variance associated with adolescent speech intelligibility. Speech intelligibility and consonants correct significantly increased nearly 22% between the two test sessions. Speech intelligibility significantly decreased by approximately 20% in the multispeaker babble condition relative to the quiet condition. Duration of seven-syllable sentences significantly decreased during the two test sessions. Data revealed that 65.8% of the variance in adolescent speech intelligibility was predicted from participant, family, and performance measures observed in elementary school. Forty-nine percent of the variance at adolescence was accounted for by the participant, family, and performance measures observed during the high school test session. Evaluation of variance including participant and family measures at both time periods, in conjunction with the adolescent performance measures, accounted for 49% of the variance in adolescence performance. After contributions from participant and family variables at the elementary and adolescent test sessions were removed, 21% of the variance in adolescent speech intelligibility was due to the performance measures at adolescence. Independent predictors of performance at adolescence included negative effects of sign enhancement and duration of seven-syllable sentences. Substantial improvements were made in consonant accuracy, sentence duration, and speech intelligibility between elementary and high school test sessions. Reductions in speech intelligibility performance suggest that allophonic variations, distortions, or use of speech sounds in a nonambient language may contribute to the reductions observed in multispeaker background conditions. Although a significant amount of variance in adolescent performance is accounted for by participant and family characteristics, elementary school speech production and an early reliance on speaking and listening independently account for variance in adolescence speech intelligibility. Over and beyond all the contributions made by participant, family and performance measures, greater reliance on oral communication, and shorter sentence durations independently account for variance at adolescence.


Valuing avoided morbidity using meta-regression analysis: what can health status measures and QALYs tell us about WTP?
Many economists argue that willingness-to-pay (WTP) measures are most appropriate for assessing the welfare effects of health changes. Nevertheless, the health evaluation literature is still dominated by studies estimating nonmonetary health status measures (HSMs), which are often used to assess changes in quality-adjusted life years (QALYs). Using meta-regression analysis, this paper combines results from both WTP and HSM studies applied to acute morbidity, and it tests whether a systematic relationship exists between HSM and WTP estimates. We analyze over 230 WTP estimates from 17 different studies and find evidence that QALY-based estimates of illness severity--as measured by the Quality of Well-Being (QWB) Scale--are significant factors in explaining variation in WTP, as are changes in the duration of illness and the average income and age of the study populations. In addition, we test and reject the assumption of a constant WTP per QALY gain. We also demonstrate how the estimated meta-regression equations can serve as benefit transfer functions for policy analysis. By specifying the change in duration and severity of the acute illness and the characteristics of the affected population, we apply the regression functions to predict average WTP per case avoided.


Improved Endurance Running Performance Following Haskap Berry (Lonicera caerulea L.) Ingestion.
Food high in (poly)phenolic compounds, such as anthocyanins, have the potential to improve exercise recovery and exercise performance. Haskap berries are rich in anthocyanins, but no research has examined the potential to improve human performance. The aim of this study was to determine the influence of Haskap berry on parameters of endurance running performance. Using a double-blind, placebo controlled, independent groups design, 30 male recreational runners (mean ± SD age, 33 ± 7 years; stature, 178.2 ± 7.2 cm; mass, 77.7 ± 10.6 kg; V˙O2peak, 52.2 ± 6.6 mL/kg/min) volunteered to participate. Following familiarisation, volunteers visited the laboratory twice (separated by seven days) to assess submaximal, maximal and 5 km time trial running performance. After the first visit, volunteers were randomly assigned to consume either the Haskap berry intervention or an isocaloric placebo control. There were modest changes in heart rate and V˙O2 at submaximal intensities (p < 0.05). Time to exhaustion during the V˙O2peak test was longer in the Haskap group by 20 s (p = 0.031). Additionally, 5 km time trial performance was improved in the Haskap group by ~21 s (p = 0.016), which equated to a 0.25 km/h increase in mean running speed compared to the placebo control; this represented a >2% improvement in running performance. The application of this newly identified functional food to athletes has the capacity to improve endurance running performance.


ProteoLens: a visual analytic tool for multi-scale database-driven biological network data mining.
New systems biology studies require researchers to understand how interplay among myriads of biomolecular entities is orchestrated in order to achieve high-level cellular and physiological functions. Many software tools have been developed in the past decade to help researchers visually navigate large networks of biomolecular interactions with built-in template-based query capabilities. To further advance researchers' ability to interrogate global physiological states of cells through multi-scale visual network explorations, new visualization software tools still need to be developed to empower the analysis. A robust visual data analysis platform driven by database management systems to perform bi-directional data processing-to-visualizations with declarative querying capabilities is needed. We developed ProteoLens as a JAVA-based visual analytic software tool for creating, annotating and exploring multi-scale biological networks. It supports direct database connectivity to either Oracle or PostgreSQL database tables/views, on which SQL statements using both Data Definition Languages (DDL) and Data Manipulation languages (DML) may be specified. The robust query languages embedded directly within the visualization software help users to bring their network data into a visualization context for annotation and exploration. ProteoLens supports graph/network represented data in standard Graph Modeling Language (GML) formats, and this enables interoperation with a wide range of other visual layout tools. The architectural design of ProteoLens enables the de-coupling of complex network data visualization tasks into two distinct phases: 1) creating network data association rules, which are mapping rules between network node IDs or edge IDs and data attributes such as functional annotations, expression levels, scores, synonyms, descriptions etc; 2) applying network data association rules to build the network and perform the visual annotation of graph nodes and edges according to associated data values. We demonstrated the advantages of these new capabilities through three biological network visualization case studies: human disease association network, drug-target interaction network and protein-peptide mapping network. The architectural design of ProteoLens makes it suitable for bioinformatics expert data analysts who are experienced with relational database management to perform large-scale integrated network visual explorations. ProteoLens is a promising visual analytic platform that will facilitate knowledge discoveries in future network and systems biology studies.


Family-focused treatment for adolescents with bipolar disorder.
Research has begun to elucidate the optimal pharmacological treatments for pediatric-onset bipolar patients, but few studies have examined the role of psychosocial interventions as adjuncts to pharmacotherapy in maintenance treatment. This article describes an adjunctive family-focused psychoeducational treatment for bipolar adolescents (FFT-A). The adult version of FFT has been shown to be effective in forestalling relapses in two randomized clinical trials involving bipolar adults. FFT-A is administered to adolescents who have had an exacerbation of manic, depressed, or mixed symptoms within the last 3 months. It is given in 21 outpatient sessions of psychoeducation, communication enhancement training, and problem solving skills training. We describe modifications to the adult FFT model to address the developmental issues and unique clinical presentations of pediatric-onset patients. An open treatment trial involving 20 bipolar adolescents (11 boys, 9 girls; mean age 14.8+/-1.6) found that the combination of FFT-A and mood stabilizing medications was associated with improvements in depression symptoms, mania symptoms, and behavior problems over 1 year. These early results are based on a small-scale open trial. Results from an ongoing randomized controlled trial will clarify whether combining FFT-A with pharmacotherapy improves the 2-year course of adolescent bipolar disorder. If the results are positive, then a structured manual-based psychosocial approach will be available for clinicians who treat adolescent bipolar patients in the community.


Multi-subject Stochastic Blockmodels for adaptive analysis of individual differences in human brain network cluster structure.
There is considerable interest in elucidating the cluster structure of brain networks in terms of modules, blocks or clusters of similar nodes. However, it is currently challenging to handle data on multiple subjects since most of the existing methods are applicable only on a subject-by-subject basis or for analysis of an average group network. The main limitation of per-subject models is that there is no obvious way to combine the results for group comparisons, and of group-averaged models that they do not reflect the variability between subjects. Here, we propose two new extensions of the classical Stochastic Blockmodel (SBM) that use a mixture model to estimate blocks or clusters of connected nodes, combined with a regression model to capture the effects of subject-level covariates on individual differences in cluster structure. The proposed Multi-Subject Stochastic Blockmodels (MS-SBMs) can flexibly account for between-subject variability in terms of homogeneous or heterogeneous covariate effects on connectivity using subject demographics such as age or diagnostic status. Using synthetic data, representing a range of block sizes and cluster structures, we investigate the accuracy of the estimated MS-SBM parameters as well as the validity of inference procedures based on the Wald, likelihood ratio and permutation tests. We show that the proposed multi-subject SBMs recover the true cluster structure of synthetic networks more accurately and adaptively than standard methods for modular decomposition (i.e. the Fast Louvain and Newman Spectral algorithms). Permutation tests of MS-SBM parameters were more robustly valid for statistical inference and Type I error control than tests based on standard asymptotic assumptions. Applied to analysis of multi-subject resting-state fMRI networks (13 healthy volunteers; 12 people with schizophrenia; n=268 brain regions), we show that Heterogeneous Stochastic Blockmodel (Het-SBM) identifies a range of network topologies simultaneously, including modular and core structures.


The effectiveness of management interventions used to control ragwort species.
Ragwort (Senecio jacobaea and S. aquaticus) causes major losses to agricultural revenue and induces livestock morbidity throughout parts of Europe, North America, and Australasia. The introduction of legislation in the U.K. and Australia has meant that landowners can be prosecuted if the plant spreads to adjacent land, which has led to an increase in activities attempting to control these species. Commonly used interventions include natural enemies, herbicide applications, manual and mechanical removal. Through the use of explicit systematic methodology involving comprehensive searches and detailed inclusion criteria, data from primary research are collated for each type of intervention. Meta-analyses show that 2,4-D, Asulam, Clopyralid, and MCPA are effective at reducing ragwort densities. However, when the datasets were analysed for their effectiveness against individual species, 2,4-D and MCPA were only effective against S. jacobaea, while Asulam was only effective against S. aquaticus. Natural enemies Longitarsus jacobaeae and a combination of L. jacobaeae and Tyria jacobaeae appear to have the potential to reduce S. jacobaea densities. Only applying T. jacobaeae does not appear to significantly reduce S. jacobaea densities, but does reduce the number of capitula per plant, seeds per capitula, viability of seeds, and dry weight of the plants. There is insufficient experimental evidence available to assess other interventions such as manual or mechanical removal. Further research into these types of interventions is recommended, as well as more detailed reporting of site characteristics and experimental design to allow full investigation of each intervention to explain possible reasons for variations in their effectiveness.


Patterns of primary afferent termination in the external cuneate nucleus from cervical axial muscles in the cat.
Using the method of transganglionic transport of horseradish peroxidase (HRP), the distribution of primary afferent projections was examined in the external cuneate nucleus (ECN) from different muscle groups in the forequarter of the cat. The terminal zones of afferent fibers from three shoulder muscles--clavotrapezius, acromiotrapezius, and spinotrapezius--were compared to projections from suboccipital muscles, dorsal neck extensors, and muscles of the proximal forelimb. Each muscle group had a labelled terminal zone that occupied a different subvolume of the ECN. The zone labelled from trapezius muscles formed a continuous column in the ECN running from the caudal pole of the nucleus to a level 3.0 mm rostral to the obex. Terminal zones of suboccipital muscles and dorsal neck extensors formed longer columns that extended into the most rostral tip of the ECN, while those of proximal forelimb muscles formed shorter columns confined to the caudal two-thirds of the ECN. At comparable cross-sectional levels in the caudal and middle portions of the ECN, terminal zones from proximal limb muscles were located most dorsomedially, while those from shoulder muscles, dorsal neck muscles, and suboccipital muscles were located in progressively more ventral and lateral regions. The subvolume of the ECN occupied by projections from cervical axial muscles was estimated to be more than 40% of the volume of the nucleus, suggesting that the ECN has a major role in the transmission of sensory information from axial musculature to the cerebellum. Following exposure of all muscle nerves to tracer, a second labelled zone was also identified close to the ECN in the descending vestibular nucleus at transverse levels 2.0-3.0 mm rostral to the obex. Here, reaction product was concentrated around a circumscribed collection of medium-sized, multipolar cells.


Linearized fiber-optic link with a high spurious free dynamic range over a wide frequency range.
An all-optical linearized fiber-optic link is presented. It solves the problem in most reported structures where a high spurious free dynamic range (SFDR) can only be obtained in a limited frequency range. The link only involves a laser, an optical modulator, and a photodetector. The novel design in the modulator bias setting enables the third-order intermodulation distortion to be suppressed by controlling only one bias voltage of a dual-parallel Mach-Zehnder modulator (DPMZM) while the other two bias voltages are set to bias the sub-MZM and the main MZM of the DPMZM at the standard peak and null point, respectively. The link has a very simple structure and does not require any electrical component, and hence a high SFDR can be obtained over a wide frequency range. Techniques are proposed using off-the-shelf components for stabilizing the modulator bias setting to maintain high SFDR performance when the link is operated in practice. Measured results demonstrate a high SFDR of 120.5 dB⋅Hz4/5±1.6 dB over a 2-20 GHz frequency range in an unamplified linearized fiber-optic link. To our knowledge, this is the first report of a linearized fiber-optic link with around 120 dB⋅Hz4/5 over such a wide frequency range.


Reduced Frontal Nogo-N2 With Uncompromised Response Inhibition During Transcutaneous Vagus Nerve Stimulation-More Efficient Cognitive Control?
We have previously shown invasive vagus nerve stimulation to improve attention and working memory and alter emotion-attention interaction in patients with refractory epilepsy, suggesting that VNS might be useful in the treatment of cognitive impairment. The current research focuses on whether non-invasive, transcutaneous vagus nerve stimulation (tVNS) has similar effects to VNS. Furthermore, we aimed to assess whether tVNS has an impact on cognitive control in general or on underlying brain physiology in a task that mimics everyday life demands where multiple executive functions are engaged while encountering intervening emotional stimuli. Event-related potentials (ERP) evoked in such a task, specifically centro-parietal P3 and frontal N2 were used as biomarkers for attention allocation and cognitive control required to carry out the task. A single-blinded, sham-controlled, within-subject study on healthy subjects (n = 25) was conducted using Executive Reaction Time Test (RT-test), a Go/NoGo task engaging multiple executive functions along with intervening threat-related distractors while EEG was recorded. tVNS at the left tragus and sham stimulation at the left ear lobe was alternately delivered throughout the task. To assess the impact of tVNS on neural activity underlying attention and cognitive control, centro-parietal P3 and frontal N2 peak amplitudes were measured in Go and NoGo conditions. Task performance was assessed with RTs and different error types reflecting cognitive control in general and distinct executive functions, such as working memory and response inhibition.No significant effects due to tVNS on performance in the Executive RT-test were observed. For N2 there was a main effect of stimulator status and a significant interaction of trial type (Go, NoGo) and stimulator status. Post hoc analysis revealed that tVNS resulted in a significant reduction of frontal N2 only in the NoGo condition. No significant effects were observed for P3 nor were there any effects of emotion. Diminished NoGo-N2 potential along with unaltered task performance during tVNS suggests fewer cognitive control resources were required to successfully withhold a prepotent response. Though caution is warranted, we suggest that tVNS may lead to more efficient neural processing with fewer resources needed for successful cognitive control, providing promise for its potential use in cognitive enhancement.


Ample genetic variation but no evidence for genotype specificity in an all-parthenogenetic host-parasitoid interaction.
Antagonistic coevolution between hosts and parasites can result in negative frequency-dependent selection and may thus be an important mechanism maintaining genetic variation in populations. Negative frequency-dependence emerges readily if interactions between hosts and parasites are genotype-specific such that no host genotype is most resistant to all parasite genotypes, and no parasite genotype is most infective on all hosts. Although there is increasing evidence for genotype specificity in interactions between hosts and pathogens or microparasites, the picture is less clear for insect host-parasitoid interactions. Here, we addressed this question in the black bean aphid (Aphis fabae) and its most important parasitoid Lysiphlebus fabarum. Because both antagonists are capable of parthenogenetic reproduction, this system allows for powerful tests of genotype x genotype interactions. Our test consisted of exposing multiple host clones to different parthenogenetic lines of parasitoids in all combinations, and this experiment was repeated with animals from four different sites. All aphids were free of endosymbiotic bacteria known to increase resistance to parasitoids. We observed ample genetic variation for host resistance and parasitoid infectivity, but there was no significant host clone x parasitoid line interaction, and this result was consistent across the four sites. Thus, there is no evidence for genotype specificity in the interaction between A. fabae and L. fabarum, suggesting that the observed variation is based on rather general mechanisms of defence and attack.


Usability testing of MySkinSelfie: a mobile phone application for skin self-monitoring.
Teledermatology generally involves doctors taking images of patients; however, patients increasingly want to own or have easy access to their health data. MySkinSelfie ( http://myskinselfie.com) is a mobile phone application (app) designed to improve the quality, consistency and accessibility of patient-held photos, and was developed to give patients the ability to generate and hold their own skin images to help guide their skin care. This study assessed the usability of this app in a cohort of patients attending a National Health Service Dermatology clinic. Patients were asked to use the app but were not given specific tasks to achieve. Of the 102 patients recruited, 32 downloaded the app and registered an account, 21 took at least one photo (median 5, range 1-103) and 19 completed the usability questionnaire. The majority of questionnaire respondents found the app easy to use but were more neutral on whether it really helped them to manage their skin problem. MySkinSelfie has been shown to be easy to use. Self-monitoring of skin problems may be useful for a subset of patients, and this is likely to depend on diagnosis, age and other patient factors.


Personal omics profiling reveals dynamic molecular and medical phenotypes.
Personalized medicine is expected to benefit from combining genomic information with regular monitoring of physiological states by multiple high-throughput methods. Here, we present an integrative personal omics profile (iPOP), an analysis that combines genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles from a single individual over a 14 month period. Our iPOP analysis revealed various medical risks, including type 2 diabetes. It also uncovered extensive, dynamic changes in diverse molecular components and biological pathways across healthy and diseased conditions. Extremely high-coverage genomic and transcriptomic data, which provide the basis of our iPOP, revealed extensive heteroallelic changes during healthy and diseased states and an unexpected RNA editing mechanism. This study demonstrates that longitudinal iPOP can be used to interpret healthy and diseased states by connecting genomic information with additional dynamic omics activity.


Scaling-up coverage with insecticide-treated nets against malaria in Africa: who should pay?
Insecticide-treated nets (ITNs) have been shown to reduce the burden of malaria in African villages by providing personal protection and, if coverage of a community is comprehensive, by reducing the infective mosquito population. We do not accept the view that scaling-up this method should be by making villagers pay for nets and insecticide, with subsidies limited so as not to discourage the private sector. We consider that ITNs should be viewed as a public good, like vaccines, and should be provided via the public sector with generous assistance from donors. Our experience is that teams distributing free ITNs, replacing them after about 4 years when they are torn and retreating them annually, have high productivity and provide more comprehensive and equitable coverage than has been reported for marketing systems. Very few of the free nets are misused or sold. The estimated cost would be an annual expenditure of about US$295 million to provide for all of rural tropical Africa where most of the world's malaria exists. This expenditure is affordable by the world community as a whole, but not by its poorest members. Recently, funding of this order of magnitude has been committed by donor agencies for malaria control.


The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population (NHANES 1999-2004).
The prevalence and correlates of obese individuals who are resistant to the development of the adiposity-associated cardiometabolic abnormalities and normal-weight individuals who display cardiometabolic risk factor clustering are not well known. The prevalence and correlates of combined body mass index (normal weight, < 25.0; overweight, 25.0-29.9; and obese, > or = 30.0 [calculated as weight in kilograms divided by height in meters squared]) and cardiometabolic groups (metabolically healthy, 0 or 1 cardiometabolic abnormalities; and metabolically abnormal, > or = 2 cardiometabolic abnormalities) were assessed in a cross-sectional sample of 5440 participants of the National Health and Nutrition Examination Surveys 1999-2004. Cardiometabolic abnormalities included elevated blood pressure; elevated levels of triglycerides, fasting plasma glucose, and C-reactive protein; elevated homeostasis model assessment of insulin resistance value; and low high-density lipoprotein cholesterol level. Among US adults 20 years and older, 23.5% (approximately 16.3 million adults) of normal-weight adults were metabolically abnormal, whereas 51.3% (approximately 35.9 million adults) of overweight adults and 31.7% (approximately 19.5 million adults) of obese adults were metabolically healthy. The independent correlates of clustering of cardiometabolic abnormalities among normal-weight individuals were older age, lower physical activity levels, and larger waist circumference. The independent correlates of 0 or 1 cardiometabolic abnormalities among overweight and obese individuals were younger age, non-Hispanic black race/ethnicity, higher physical activity levels, and smaller waist circumference. Among US adults, there is a high prevalence of clustering of cardiometabolic abnormalities among normal-weight individuals and a high prevalence of overweight and obese individuals who are metabolically healthy. Further study into the physiologic mechanisms underlying these different phenotypes and their impact on health is needed.


Toward better management of merkel cell carcinoma using a consensus staging system, new diagnostic codes and a recently discovered virus.
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a higher propensity for recurrence and metastasis than melanoma or squamous cell carcinoma. Despite aggressive behavior and the tripling of its reported incidence in the past 20 years, there is extensive confusion about how MCC should be managed. Here we address two issues that have impeded optimal MCC management: lack of a consensus staging system and lack of unique diagnostic codes for MCC. Five conflicting systems currently used to stage MCC will be replaced by one system in 2010 that will diminish confusion about prognosis and management among physicians and patients. The diagnostic bundling of MCC with numerous less aggressive skin cancers leads to care refusals by insurance and an inability to track MCC care costs. Worldwide adoption in 2009 of specific diagnostic codes for MCC will also improve understanding and management of this often-lethal skin cancer.


Fibrinolytic therapy and bleeding complications: risk predictors from RIKS-HIA.
Fibrinolytic treatment for ST-elevation myocardial infarction is associated with increased bleeding risk but is still widely used world wide, mainly because of limited access to primary PCI. To analyse contemporary fibrinolytic treatment patterns, in-hospital bleeding risk and prognosis during 2001 to 2006 in unselected Swedish patients. The RIKS-HIA registry covers almost all Swedish patients treated for acute coronary syndromes. Major in-hospital bleeding was defined as lethal or intracranial bleeding or bleeding requiring surgery or blood transfusion. Survival status of the 15 373 patients was obtained from the National Cause of Death Register. The number of patients receiving fibrinolysis as reperfusion therapy decreased from 4336 patients in 2001 to 733 in 2006. Cases of major in-hospital bleeding increased from 1.2% (including 0.7% lethal or intracranial) in 2001 to 4.0% (1.1%) in 2006, p<0.001. Higher age, female gender, hypertension, kidney failure, clopidogrel treatment before admission, pre-hospital administration of fibrinolysis and fibrin-specific fibrinolytic agents were identified as predictors for bleeding. Major in-hospital bleeding was the strongest predictor of adverse prognosis with a more than threefold increase in 1-year mortality. During 2001 to 2006 the use of fibrinolytic treatment markedly decreased while the incidence of major bleeding complications more than doubled. The latter might in part be explained by increasing use concomitant antiplatelet therapy, pre-hospital treatment and fibrin-specific fibrinolytic agents. Future close monitoring of bleeding complications is warranted, especially when considering the increased use of various combinations of antithrombotic drugs in conjunction with fibrinolysis and the great impact of bleeding on long-term mortality.


Problematic eating behaviours, changes in appetite, and weight gain in Major Depressive Disorder: The role of leptin.
Appetite and weight changes are core symptoms of Major Depressive Disorder (MDD), and those with MDD are at increased risk of obesity, cardiovascular disease and metabolic disorders. Leptin promotes satiety, with leptin dysregulation and resistance noted in obesity. However, the role of leptin in weight changes in MDD is not established. This study investigates leptin levels in relation to appetite and weight changes and problematic eating behaviours in MDD. Plasma leptin levels, psychopathology and biometrics were compared between participants meeting DSM-5 diagnostic criteria for MDD (n = 63) and healthy controls (n = 60). Depressed participants were also sub-categorised according to increased, decreased or unchanged appetite and weight. The Dutch Eating Behaviour Questionnaire and Yale Food Addiction Scale were examined in a subset of participants with MDD. Females with increased appetite/weight had higher leptin levels than those with stable or reduced appetite/weight, however males showed the opposite effect. Leptin levels were positively correlated with problematic eating behaviours. One quarter of the depressed subset, all females, met the Yale criteria for food addiction, approximately double the rates reported in general community samples. The study is limited by a cross sectional design and a small sample size in the subset analysis of eating behaviours. The results provide new information about associations between leptin, sex-specific weight and appetite changes and problematic eating behaviours, which may be risk factors for cardiovascular and metabolic diseases in MDD, particularly in females. Future longitudinal research investigating leptin as a risk factor for weight gain in MDD is warranted, and may lead to early interventions aimed at preventing weight gain in at-risk individuals.


Hydrogen gas reduces chronic intermittent hypoxia-induced hypertension by inhibiting sympathetic nerve activity and increasing vasodilator responses via the antioxidation.
Molecular hydrogen is reported to be used medically to ameliorate various systemic pathological conditions. This study aimed to investigate the effect of hydrogen (H2 ) gas on hypertension induced by intermittent hypoxia in rats. The adult rats were exposed to chronic intermittent hypoxia (CIH) 8 hours/day for 5 weeks and/or H 2 gas 2 hours/day. We found that the systolic and diastolic blood pressure (BP) increased significantly in rats exposed to intermittent hypoxia, both of which were markedly attenuated after H treatment. Furthermore, intermittent hypoxia exposure elevated renal sympathetic nerve activity, consistent with plasma norepinephrine. Additionally, H 2 gas significantly improved CIH-induced abnormal vascular relaxation. Nevertheless, inhalation of H 2 gas alone did not cause such changes. Moreover, H 2 gas-treated rats exposed to CIH showed a significant reduction in 8-hydroxy-2 deoxyguanosine content and increases in superoxide dismutase activity, indicating improved oxidative stress. Taken together, these results indicate that H 2 gas has significant effects on the reduction of BP without any side effects. Mechanistically, inhibition of sympathetic activity and reduction of systemic vascular resistance may participate in this process via the antioxidant activity of H 2 .


GPs' views on transfer of information about terminally ill patients to the out-of-hours co-operative.
In the Netherlands, the increase in of out-of-hours care that is provided by GP co-operatives is challenging the continuity of care for the terminally ill in general practice. Aim of this study is to investigate the views of general practitioners (GPs) on the transfer of information about terminally ill patients to the GP co-operatives. GPs were asked to give their view from two different perspectives: as a GP in their daily practice and as a locum in the GP co-operative. Retrospective web based questionnaire sent to all 424 GPs in the Amsterdam region. With a response rate of 42%, 177 physicians completed the questionnaire. Transfer of information to the GP co-operative about most of their terminally ill patients was reported by 82% of the GPs and 5% did not do so for any of their patients. A faster than foreseen deterioration of the patient's situation was the most frequently reported reason for not transferring information. Of those who transferred information to the GP co-operative, more than 95% reported that they provided information about the diagnosis and terminally ill status of the patient. Information about medication, patient wishes regarding treatment, and prognosis was reported by respectively 90%, 87%, and 74% of the GPs. Less than 50% of the GPs reported that they transferred information about the patient's awareness of both the diagnosis and the prognosis, about the psychosocial context, and intolerances. In their role as locum, over 90% of the GPs wanted to receive information about the diagnosis, the terminally ill status of the patient, the medication and the patient's wishes regarding treatment. Although most GPs reported that they transferred information about their terminally ill patients to the GP co-operative, the content of this information varies considerably. Only 21% of the GPs, working out of hours as a locum, were satisfied with the quality of the information transferred.


External validation of the modified Glasgow prognostic score for renal cancer.
The modified Glasgow prognostic Score (mGPS) incorporates C-reactive protein and albumin as a clinically useful marker of tumor behavior. The ability of the mGPS to predict metastasis in localized renal cell carcinoma (RCC) remains unknown in an external validation cohort. Patients with clinically localized clear cell RCC were followed for 1 year post-operatively. Metastases were identified radiologically. Patients were categorized by mGPS score as low-risk (mGPS = 0 points), intermediate-risk (mGPS = 1 point) and high-risk (mGPS = 2 points). Univariate, Kaplan-Meier and multivariate Cox regression analyses examined Recurrence -free survival (RFS) across patient and disease characteristics. Of the 129 patients in this study, 23.3% developed metastases. Of low, intermediate and high risk patients, 10.1%, 38.9% and 89.9% recurred during the study. After accounting for various patient and tumor characteristics in multivariate analysis including stage and grade, only mGPS was significantly associated with RFS. Compared with low-risk patients, intermediate- and high-risk patients experienced a 4-fold (hazard ratios [HR]: 4.035, 95% confidence interval [CI]: 1.312-12.415, P = 0.015) and 7-fold (HR: 7.012, 95% CI: 2.126-23.123 P < 0.001) risk of metastasis, respectively. mGPS is a robust predictor of metastasis following potentially curative nephrectomy for localized RCC. Clinicians may consider mGPS as an adjunct to identify high-risk patients for possible enrollment into clinical trials or for patient counseling.


On-surface synthesis of single-layered two-dimensional covalent organic frameworks via solid-vapor interface reactions.
Surface covalent organic frameworks (SCOFs), featured by atomic thick sheet with covalently bonded organic building units, are promised to possess unique properties associated with reduced dimensionality, well-defined in-plane structure, and tunable functionality. Although a great deal of effort has been made to obtain SCOFs with different linkages and building blocks via both "top-down" exfoliation and "bottom-up" surface synthesis approaches, the obtained SCOFs generally suffer a low crystallinity, which impedes the understanding of intrinsic properties of the materials. Herein, we demonstrate a self-limiting solid-vapor interface reaction strategy to fabricate highly ordered SCOFs. The coupling reaction is tailored to take place at the solid-vapor interface by introducing one precursor via vaporization to the surface preloaded with the other precursor. Following this strategy, highly ordered honeycomb SCOFs with imine linkage are obtained. The controlled formation of SCOFs in our study shows the possibility of a rational design and synthesis of SCOFs with desired functionality.


Molecular characterization of cryptic and sympatric lymnaeid species from the Galba/Fossaria group in Mendoza Province, Northern Patagonia, Argentina.
Freshwater lymnaeid snails can act as the intermediate hosts for trematode parasites such as the liver fluke Fasciola hepatica, that cause significant economic and biomedical burden worldwide, particularly through bovine fascioliasis. Transmission potential is tightly coupled to local compatibility with snail hosts, so accurate identification of lymnaeid species is crucial for understanding disease risk, especially when invasive species are encountered. Mendoza Province, in Argentina, is a center of livestock production and also an area of endemic fascioliasis transmission. However, the distribution of lymnaeid species in the region is not well known. This study examined lymnaeid snails from seven localities in the Department of Malarguë, Mendoza Province, using morphological and molecular analyses and also describing ecological variables associated with snail presence. While morphological characters identified two species of lymnaeid, Galba truncatula and G. viatrix, molecular data revealed a third, cryptic species, G. neotropica, which was sympatric with G. viatrix. G. truncatula was exclusively found in high altitude (>1900 meters above sea level [masl]) sites, whereas mixed G. neotropica/G. viatrix localities were at middle elevations (1300-1900 masl), and G. viatrix was found alone at the lowest altitude sites (<1300 masl). Phylogenetic analysis using two mitochondrial markers revealed G. neotropica and G. viatrix to be closely related, and given their morphological similarities, their validities as separate taxonomic entities should be questioned. This study highlights the need of a robust taxonomic framework for the identification of lymnaeid snails, incorporating molecular, morphological and ecological variables while avoiding nomenclature redundancy. As the three species observed here, including one alien invasive species, are considered hosts of varying susceptibility to Fasciola parasites, and given the economic importance of fascioliasis for livestock production, this research has critical importance for the ultimate aim of controlling disease transmission.


Cluster analysis of multiplex ligation-dependent probe amplification data in choroidal melanoma.
To determine underlying correlations in multiplex ligation-dependent probe amplification (MLPA) data and their significance regarding survival following treatment of choroidal melanoma (CM). MLPA data were available for 31 loci across four chromosomes (1p, 3, 6, and 8) in tumor material obtained from 602 patients with CM treated at the Liverpool Ocular Oncology Center (LOOC) between 1993 and 2012. Data representing chromosomes 3 and 8q were analyzed in depth since their association with CM patient survival is well-known. Unsupervised k-means cluster analysis was performed to detect latent structure in the data set. Principal component analysis (PCA) was also performed to determine the intrinsic dimensionality of the data. Survival analyses of the identified clusters were performed using Kaplan-Meier (KM) and log-rank statistical tests. Correlation with largest basal tumor diameter (LTD) was investigated. Chromosome 3: A two-cluster (bimodal) solution was found in chromosome 3, characterized by centroids at unilaterally normal probe values and unilateral deletion. There was a large, significant difference in the survival characteristics of the two clusters (log-rank, p<0.001; 5-year survival: 80% versus 40%). Both clusters had a broad distribution in LTD, although larger tumors were characteristically in the poorer outcome group (Mann-Whitney, p<0.001). Threshold values of 0.85 for deletion and 1.15 for gain optimized the classification of the clusters. PCA showed that the first principal component (PC1) contained more than 80% of the data set variance and all of the bimodality, with uniform coefficients (0.28±0.03). Chromosome 8q: No clusters were found in chromosome 8q. Using a conventional threshold-based definition of 8q gain, and in conjunction with the chromosome 3 clusters, three prognostic groups were identified: chromosomes 3 and 8q both normal, either chromosome 3 or 8q abnormal, and both chromosomes 3 and 8q abnormal. KM analysis showed 5-year survival figures of approximately 97%, 80%, and 30% for these prognostic groups, respectively (log-rank, p<0.001). All MLPA probes within both chromosomes were significantly correlated with each other (Spearman, p<0.001). Within chromosome 3, the strong correlation between the MLPA variables and the uniform coefficients from the PCA indicates a lack of evidence for a signature gene that might account for the bimodality we observed. We hypothesize that the two clusters we found correspond to binary underlying states of complete monosomy or disomy 3 and that these states are sampled by the complete ensemble of probes. Consequently, we would expect a similar pattern to emerge in higher-resolution MLPA data sets. LTD may be a significant confounding factor. Considering chromosome 8q, we found that chromosome 3 cluster membership and 8q gain as traditionally defined have an indistinguishable impact on patient outcome.


Evaluation of tele-ultrasound as a tool in remote diagnosis and clinical management at the Amundsen-Scott South Pole Station and the McMurdo Research Station.
Abstract Background: A large number of Antarctic stations do not utilize ultrasound for medical care. Regular use of ultrasound imaging at South Pole and McMurdo Stations first began in October 2002. To date, there has been no evaluation of medical events requiring ultrasound examination from this remote environment. Additionally, the importance of tele-ultrasound for clinical management in Antarctica has not yet been assessed. We therefore conducted a retrospective analysis of all ultrasound exams performed at South Pole and McMurdo Stations between October 2002 and October 2003. Radiology reports and patient charts were reviewed for pre- and post-ultrasound diagnosis and treatment. Sixty-six ultrasound exams were conducted on 49 patients. Of the exams, 94.0% were interpreted by the store-and-forward method, whereas 6.0% were interpreted in "real-time" format. Abdominal, genitourinary, and gynecology ultrasound exams accounted for 63.6% of exams. Ultrasound examination prevented an intercontinental aeromedical evacuation in 25.8% of cases, and had a significant effect on the diagnosis and management of illness in patients at South Pole and McMurdo research stations. These findings indicate that diagnostic ultrasound has significant benefits for medical care at Antarctic stations and that tele-ultrasound is a valuable addition to remote medical care for isolated populations with limited access to tertiary-healthcare facilities.


The treatment of premenstrual syndrome with preparations of Vitex agnus castus: a systematic review and meta-analysis.
Premenstrual syndrome is characterized by the cyclic occurrence of physical, behavioral and psychological symptoms during the luteal phase of the menstrual cycle disappearing within a few days of the onset of menstruation. Generally symptoms are mild, but 5-8% of women suffer from severe PMS. Apart from conventional drugs, like serotonin reuptake inhibitors and oral contraceptives, complementary and alternative medicines such as Vitex agnus castus are used by many women experiencing PMS. Our objective was to determine the efficacy, tolerability, and acceptability of Vitex agnus castus preparations for treatment of premenstrual syndrome. All journals in the Ovid software from inception through January 2016 were searched, including the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and PsycINFO. Gray literature was searched by Google Scholar and manufacturers of Vitex agnus castus preparations were contacted for information about unpublished trials. We included randomized controlled trials with Vitex agnus castus in women with premenstrual syndrome and/or premenstrual dysphoric disorder with a minimal duration of 2 menstrual cycles. The eligibility of the manuscripts was assessed by 2 reviewers independently. The data abstracted included characteristics of the study design, characteristics of the patient population, intervention details, type of comparator, method of diagnosis, and outcome measures. We adhered to the PRISMA guidelines. We found 17 randomized controlled trials of Vitex agnus castus in the treatment of premenstrual syndrome. Fourteen of these could be included in the quantitative analysis. Thirteen of 14 studies with placebo, dietary supplements, or herbal preparations as controls reported positive effects of Vitex agnus castus on total premenstrual syndrome symptoms. Unfortunately most of the trials are associated with a high risk of bias. The pooled effect of Vitex agnus castus in placebo-controlled trials was large (Hedges g, -1.21; 95% confidence interval, -1.53 to -0.88), but heterogeneity was extremely high (I2, 91%). We were unable to single out factors that could explain this heterogeneity satisfactorily. The funnel plot and Egger tests suggest the presence of publication bias. Although meta-analysis shows a large pooled effect of Vitex agnus castus in placebo-controlled trials, the high risk of bias, high heterogeneity, and risk of publication bias of the included studies preclude a definitive conclusion. The pooled treatment effects should be viewed as merely explorative and, at best, overestimating the real treatment effect of Vitex agnus castus for premenstrual syndrome symptoms. There is a clear need for high-quality trials of appropriate size examining the effect of standardized extracts of Vitex agnus castus in comparison to placebo, selective serotonin reuptake inhibitors, and oral contraceptives to establish relative efficacy.


Population structure and coalescence in pedigrees: Comparisons to the structured coalescent and a framework for inference.
Contrary to what is often assumed in population genetics, independently segregating loci do not have completely independent ancestries, since all loci are inherited through a single, shared population pedigree. Previous work has shown that the non-independence between gene genealogies of independently segregating loci created by the population pedigree is weak in panmictic populations, and predictions made from standard coalescent theory are accurate for populations that are at least moderately sized. Here, we investigate patterns of coalescence in pedigrees of structured populations. We find that the pedigree creates deviations away from the predictions of the structured coalescent that persist on a longer timescale than in the case of panmictic populations. Nevertheless, we find that the structured coalescent provides a reasonable approximation for the coalescent process in structured population pedigrees so long as migration events are moderately frequent and there are no migration events in the recent pedigree of the sample. When there are migration events in the recent sample pedigree, we find that distributions of coalescence in the sample can be modeled as a mixture of distributions from different initial sample configurations. We use this observation to motivate a maximum-likelihood approach for inferring migration rates and mutation rates jointly with features of the pedigree such as recent migrant ancestry and recent relatedness. Using simulation, we show that our inference framework accurately recovers long-term migration rates in the presence of recent migration events in the sample pedigree.


Primate phylogenomics: developing numerous nuclear non-coding, non-repetitive markers for ecological and phylogenetic applications and analysis of evolutionary rate variation.
Genetic analyses are often limited by the availability of appropriate molecular markers. Markers from neutrally evolving genomic regions may be particularly useful for inferring evolutionary histories because they escape the constraints of natural selection. For the majority of taxa however, obtaining such markers is challenging. Advances in genomics have the potential to alleviate the shortage of neutral markers. Here we present a method to develop numerous markers from putatively neutral regions of primate genomes. We began with the available whole genome sequences of human, chimpanzee and macaque. Using computational methods, we identified a total of 280 potential amplicons from putatively neutral, non-coding, non-repetitive regions of these genomes. Subsequently we amplified, using experimental methods, many of these amplicons from diverse primate taxa, including a ring-tailed lemur, which is distantly related to the genomic resources. Using a subset of 10 markers, we demonstrate the utility of the developed markers in phylogenetic and evolutionary rate analyses. Particularly, we uncovered substantial evolutionary rate variation among lineages, some of which are previously not reported. We successfully developed numerous markers from putatively neutral regions of primate genomes using a strategy combining computational and experimental methods. Applying these markers to phylogenetic and evolutionary rate variation analyses exemplifies the utility of these markers. Diverse ecological and evolutionary analyses will benefit from these markers. Importantly, methods similar to those presented here can be applied to other taxa in the near future.


Effect of aquatic exercise on the multiple sclerosis patients' quality of life.
The appearance of a new innovation in medical science named aquatic exercise has faded the effects of other preventive exercises in patients with multiple sclerosis to a large extent. Since exercise is one of the beneficial factors in enhancement of quality of life, researchers decided to investigate the role of aquatic exercise on the patients' quality of life. This study is a semi experimental research that was performed on 22 patients chosen by simple random sampling. The standard SF-36 questionnaire was used and data was gathered by interview before and after aquatic exercise. Data was analyzed by paired t test via SPSS software version 10. The mean age of participants was 32.86 years. 68.2% of participants were married and 45.5% of them were high school graduates. The paired t test showed the significant differences between different aspects of quality of life before and after aquatic exercise. The findings of this research revealed that aquatic exercise has enhanced the aspects of multiple sclerosis patients' quality of life; therefore the program of this exercise is suggested to be used for the patients with multiple sclerosis along with other methods of treatment for improvement in quality of their lives.


Expression, immunolocalization and processing of fertilins ADAM-1 and ADAM-2 in the boar (Sus domesticus) spermatozoa during epididymal maturation.
Fertilin alpha (ADAM-1) and beta (ADAM-2) are integral membrane proteins of the ADAM family that form a fertilin complex involved in key steps of the sperm-oocyte membrane interaction. In the present work, we analyzed the presence of ADAM-1 and ADAM-2 mRNAs, the spermatozoa proteins' processing and their sub-cellular localization in epididymal samples from adult boars. ADAM-1 and ADAM-2 mRNAs were highly produced in the testis, but also in the vas efferens and the epididymis. On immunoblots of sperm extracts, ADAM-1 subunit appeared as a main reactive band of ~50-55 kDa corresponding to occurrence of different isoforms throughout the epididymal duct, especially in the corpus region where isoforms ranged from acidic to basic pI. In contrast, ADAM-2 was detected as several bands of ~90 kDa, ~75 kDa, ~50-55 kDa and ~40 kDa. The intensity of high molecular mass bands decreased progressively in the distal corpus where lower bands were also transiently observed, and only the ~40 kDa was observed in the cauda. The presence of bands of different molecular weights likely results from a proteolytic processing occurring mainly in the testis for ADAM-1, and also throughout the caput epididymis for ADAM-2. Immunolocalization showed that fertilin migrates from the acrosomal region to the acrosomal ridge during the sperm transit from the distal corpus to the proximal cauda. This migration is accompanied by an important change in the extractability of a part of ADAM-1 from the sperm membrane. This suggests that the fertilin surface migration may be triggered by the biochemical changes induced by the epididymal post-translational processing of both ADAM1 and ADAM-2. Different patterns of fertilin immunolocalization then define several populations of spermatozoa in the cauda epididymis. Characterization of such fertilin complex maturation patterns is an important step to develop fertility markers based on epididymal maturation of surface membrane proteins in domestic mammals.


Production of biopharmaceutical proteins by yeast: advances through metabolic engineering.
Production of recombinant proteins for use as pharmaceuticals, so-called biopharmaceuticals, is a multi-billion dollar industry. Many different cell factories are used for the production of biopharmaceuticals, but the yeast Saccharomyces cerevisiae is an important cell factory as it is used for production of several large volume products. Insulin and insulin analogs are by far the dominating biopharmaceuticals produced by yeast, and this will increase as the global insulin market is expected to grow from USD12B in 2011 to more than USD32B by 2018. Other important biopharmaceuticals produced by yeast are human serum albumin, hepatitis vaccines and virus like particles used for vaccination against human papillomavirus. Here is given a brief overview of biopharmaceutical production by yeast and it is discussed how the secretory pathway can be engineered to ensure more efficient protein production. The involvement of directed metabolic engineering through the integration of tools from genetic engineering, systems biology and mathematical modeling, is also discussed.


Epigenetic Regulation of Fanconi Anemia Genes Implicates PRMT5 Blockage as a Strategy for Tumor Chemosensitization.
Strengthened DNA repair pathways in tumor cells contribute to the development of resistance to DNA-damaging agents. Consequently, targeting proteins in these pathways is a promising strategy for tumor chemosensitization. Here, we show that the expression of a subset of Fanconi anemia (FA) genes is attenuated in glioblastoma tumor cells deficient in methylthioadenosine phosphorylase (MTAP), a common genetic alteration in a variety of cancers. Subsequent experiments in cell line models of different cancer types illustrate that this reduced transcription of FA genes can be recapitulated by blockage of Protein Arginine Methyltransferase 5 (PRMT5), a promising therapeutically targetable epigenetic regulator whose enzymatic activity is compromised in MTAP-deficient cells. Further analyses provide evidence to support that PRMT5 can function as an epigenetic regulator that contributes to the increased expression of FA genes in cancer cells. Most notably and consistent with the essential roles of FA proteins in resolving DNA damage elicited by interstrand crosslinking (ICL) agents, PRMT5 blockage, as well as MTAP loss, sensitizes tumor cells to ICL agents both in vitro and in xenografts. Collectively, these findings reveal a novel epigenetic mechanism underlying the upregulated expression of FA genes in cancer cells and suggest that therapeutically targeting PRMT5 can have an additional benefit of chemosensitizing tumor cells to ICL agents. IMPLICATIONS: PRMT5 positively regulates the expression of FA genes. Inhibition of PRMT5 attenuates FA-dependent DNA repair pathway and sensitizes tumor cells to ICL agents.


A group IIA-secreted phospholipase A2 from snake venom induces lipid body formation in macrophages: the roles of intracellular phospholipases A2 and distinct signaling pathways.
We investigated the ability of the sPLA(2), known as MT-III, isolated from the viperid snake Bothrops asper, to induce LB formation in macrophages and the major cellular signaling pathways involved in this process. The effects of MT-III on ADRP localization and expression and macrophage ultrastructure were assessed. Our results showed that this sPLA(2) induced a marked increase in LB numbers in macrophages, induced the recruitment of ADRP in macrophages, and up-regulated ADRP expression. Ultrastructural analysis showed the presence of weakly and strongly osmiophilic LBs in sPLA(2)-stimulated cells. Enlargement of the ER and Golgi cisterns was also observed. Pretreatment of cells with H7 or staurosporine (PKC inhibitors), LY294002 or wortmannin (PI3K inhibitors), SB202190 or PD98059 (p38(MAPK) and ERK1/2 inhibitors, respectively), or Pyr-2 or Bel (cPLA(2) and iPLA(2) inhibitors, respectively) significantly reduced sPLA(2)-induced LB formation. Herbimycin (a PTK inhibitor) and indomethacin or etoricoxib (COX inhibitors) failed to alter sPLA(2)-induced effects. In conclusion, our results show for the first time the ability of a venom sPLA(2) to induce the formation of LBs and the expression of ADRP in macrophages. Venom PLA(2)-induced LB formation is dependent on PKC, PI3K, p38(MAPK), ERK1/2, cPLA(2), and iPLA(2) signaling pathways but not on PTK, COX-1, or COX-2 pathways. Activation of the ER and Golgi complex may play an important role in the formation of LBs induced by this sPLA(2) in macrophages.