Expression mapping, quantification, and complex formation of GluD1 and GluD2 glutamate receptors in adult mouse brain.
In the cerebellum, GluD2 is exclusively expressed in Purkinje cells, where it regulates synapse formation and regeneration, synaptic plasticity, and motor learning. Delayed cognitive development in humans with GluD2 gene mutations suggests extracerebellar functions of GluD2. However, extracerebellar expression of GluD2 and its relationship with that of GluD1 are poorly understood. GluD2 mRNA and protein were widely detected, with relatively high levels observed in the olfactory glomerular layer, medial prefrontal cortex, cingulate cortex, retrosplenial granular cortex, olfactory tubercle, subiculum, striatum, lateral septum, anterodorsal thalamic nucleus, and arcuate hypothalamic nucleus. These regions were also enriched for GluD1, and many individual neurons coexpressed the two GluDs. In the retrosplenial granular cortex, GluD1 and GluD2 were selectively expressed at PSD-95-expressing glutamatergic synapses, and their coexpression on the same synapses was shown by SDS-digested freeze-fracture replica labeling. Biochemically, GluD1 and GluD2 formed coimmunoprecipitable complex formation in HEK293T cells and in the cerebral cortex and hippocampus. We further estimated the relative protein amount by quantitative immunoblotting using GluA2/GluD2 and GluA2/GluD1 chimeric proteins as standards for titration of GluD1 and GluD2 antibodies. Intriguingly, the relative amount of GluD2 was almost comparable to that of GluD1 in the postsynaptic density fraction prepared from the cerebral cortex and hippocampus. In contrast, GluD2 was overwhelmingly predominant in the cerebellum. Thus, we have determined the relative extracerebellar expression of GluD1 and GluD2 at regional, neuronal, and synaptic levels. These data provide a molecular-anatomical basis for possible competitive and cooperative interactions of GluD family members at synapses in various brain regions.


Lentinan modulates intestinal microbiota and enhances barrier integrity in a piglet model challenged with lipopolysaccharide.
The intestinal microbiota plays a vital role in metabolism, pathogen resistance, and immune development in host cells, and is modifiable by dietary change. Lentinan (LNT), a type of mushroom polysaccharide, is known to ameliorate intestinal inflammation with the potential of therapeutic effect on digestive diseases. We hypothesized that LNT could alleviate Escherichia coli lipopolysaccharide (LPS)-induced intestinal injury via regulating the composition and metabolites of intestinal microbiota in a piglet model. Twenty-four weaned piglets were used in a 2 × 2 factorial design, and the main factors included a dietary treatment (basal or LNT diet) and immunological challenge (LPS or saline). After feeding basal or LNT diet for 21 days, pigs were injected with LPS or saline. At 4 h post-injection, pigs were killed and jejunum, ileum and cecal digesta were collected. LNT improved intestinal morphology and barrier function. LNT also inhibited inflammatory signaling pathways (toll-like receptor 4 and nucleotide binding oligomerization domain protein) and pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β and interleukin-6) expression, as well as up-regulated the heat shock protein 70 expression in small intestine. In addition, LNT enhanced the concentrations of propionate, butyrate, isobutyrate and isovalerate in cecal digesta, resulting in a significant increase in histone acetylation without affecting the protein level of G protein-coupled receptor 41 (GPR41), a short chain fatty acid receptor. Bacterial 16S rRNA gene pyrosequencing showed that LNT had a great impact on gut microbiota composition at different taxonomic levels. Moreover, the correlation analysis revealed some potential relationships between cecal metabolites and certain intestinal microbiota. These results indicate that LNT promotes intestinal health, in part, through altering intestinal microbiota composition and increasing the short chain fatty acid synthesis, which subsequently lead to a reduction in inflammation and hyper-acetylation of histones.


Do phosphorus requirements for RNA limit genome size in crustacean zooplankton?
As for most other organisms, genome size in zooplankton differs widely. This may have a range of consequences for growth rate, development, and life history strategies, yet the causes of this pronounced variability are not settled. Here we propose that small genome size may be an evolutionary consequence of phosphorus (P) allocation from DNA to RNA under P deficiency. To test this hypothesis we have compared the two major groups of zooplankton, copepods and cladocerans, that have overlapping niches and body size. Relative to the cladocerans, copepods have a more complex life history and a lower mass-specific P content, while cladocerans tend to have higher P and RNA contents and higher specific growth rates and frequently experience P-limited growth, likely due to a shortage of P for ribosome synthesis. Cladocerans also generally have smaller genomes than copepods (1C = 0.17-0.63 pg DNA.cell(-1) vs. 1C = 0.10-10 pg DNA.cell(-1)). Furthermore, cladocerans have a higher slope of the relationship of body size with DNA content (1.5 vs. 0.28 in copepods) and present almost 15-fold higher RNA:DNA ratios (24.8 in cladocerans vs. 1.6 in copepods). Hence, small genome size in cladocerans could reflect an evolutionary pressure towards "efficient" genomes to conserve a key element needed to maximize growth rate. We do not claim that this is a universal cause of genome size variability, but propose that streamlining of genomes could be related to P conservation rather than energy conservation. This could be relevant for a range of organisms that may suffer P-limited growth rates.


Monocytic cell necrosis is mediated by potassium depletion and caspase-like proteases.
Apoptosis is a physiological cell death that culminates in mitochondrial permeability transition and the activation of caspases, a family of cysteine proteases. Necrosis, in contrast, is a pathological cell death characterized by swelling of the cytoplasm and mitochondria and rapid plasma membrane disruption. Necrotic cell death has long been opposed to apoptosis, but it now appears that both pathways involve mitochondrial permeability transition, raising the question of what mediates necrotic cell death. In this study, we investigated mechanisms that promote necrosis induced by various stimuli (Clostridium difficile toxins, Staphylococcus aureus alpha toxin, ouabain, nigericin) in THP-1 cells, a human monocytic cell line, and in monocytes. All stimuli induced typical features of necrosis and triggered protease-mediated release of interleukin-1beta (IL-1beta) and CD14 in both cell types. K+ depletion was actively implicated in necrosis because substituting K+ for Na+ in the extracellular medium prevented morphological features of necrosis and IL-1beta release. N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum caspase inhibitor, prevented morphological features of necrosis, plasma membrane destruction, loss of mitochondrial membrane potential, IL-1beta release, and CD14 shedding induced by all stimuli. Thus, in monocytic cells, necrosis is a cell death pathway mediated by passive K+ efflux and activation of caspase-like proteases.


[Nanoparticles in the environment and their effect on hydrobionts].
This paper summarizes the data on the effect of engineered nanoparticles on aquatic organisms. The issues of penetration and accumulation of nanoparticles in the body of hydrobionts and their toxic effect, biotransformation, and migration along food chains are considered. It is demonstrated that the behavior of nanomaterials in the environment and their effect on living organisms have been studied insufficiently and require close attention, because their release into the environment will increase in the very near future.


Twin anemia-polycythemia sequence in a case of monoamniotic twins.
Twin anemia-polycythemia sequence (TAPS) complicates up to 6% of monochorionic diamniotic twin pregnancies, typically in the late second or third trimester. The presence of only a few and very small arteriovenous vascular anastomoses characterizes the underlying angioarchitecture at the chorionic plate in cases of TAPS. In monoamniotic twins, large vascular anastomoses can usually be seen at the placental vascular equator, and therefore one would not expect the development of TAPS in monoamniotic twins. We report a case of TAPS in a monoamniotic pregnancy at 26 + 5 weeks' gestation which responded favorably to fetoscopic laser coagulation of the small placental anastomoses, resolving severe anemia in one twin and polycythemia in the other. The pregnancy continued until 32 + 5 weeks, when worsening cord entanglement with increased resistance and the development of postsystolic notches in the umbilical artery of one twin prompted delivery by Cesarean section. There was only a moderate difference in neonatal hemoglobin concentrations, with the former polycythemic twin needing a single partial volume exchange transfusion. The postnatal course of the neonates was uneventful, according to their gestational age at birth. To our knowledge this is the first case report describing successful laser therapy for TAPS in monoamniotic twins.


Impact of Visually Induced Motion Sickness from VR Depending on Viewing Patterns, View Movement, and Background Motion.
The impact of visually induced motion sickness from virtual reality (VR) because of viewing patterns, view movements, and background global motion was investigated experimentally through classification into four categories.Each of the ten subjects underwent watching four patterns with bio-signal measurements, such as electrocardiogram and respiration, answering a subjective questionnaire.The results of the subjective evaluation of biological effects indicate that the VR viewing pattern has a significantly lower influence on visually induced motion sickness than other patterns, such as viewing with global background motion or sight motion by operating the controller.Clinical Relevance- This study aimed to reduce the effects of visually induced motion sickness in VR viewing, particularly to reduce the burden on the eyes and body.


Treatment switching in idiopathic pulmonary fibrosis: from triple therapy to enrollment into a clinical investigational drug trial.
A number of pharmacological agents have been the focus of clinical trials over the past years. Although no single pharmacological agent is recommended by current guidelines, preliminary negative findings regarding the safety of a triple therapy regimen consisting of prednisone, azathioprine and N-acetylcysteine have raised the question of whether it is no longer a treatment option. More recent data have resulted in the approval of pirfenidone in Europe. Pirfenidone shows a favourable risk-benefit profile and a beneficial effect in reducing the decline in lung function in patients with IPF. This case study describes the diagnosis and initial treatment of a patient with IPF with triple therapy of prednisone, azathioprine and N-acetylcysteine (NAC) followed by inclusion into a double-blind, randomised, placebo-controlled study and subsequent open-label extension trial of pirfenidone in IPF.


Angiotensin peptides acting at rostral ventrolateral medulla contribute to hypertension of TGR(mREN2)27 rats.
We have previously demonstrated that microinjections of the selective angiotensin-(1-7) [ANG-(1-7)] antagonist, A-779, into the rostral ventrolateral medulla (RVLM) produces a significant fall in mean arterial pressure (MAP) and heart rate (HR) in both anesthetized and conscious rats. In contrast, microinjection of angiotensin II (ANG II) AT(1) receptor antagonists did not change MAP in anesthetized rats and produced dose-dependent increases in MAP when microinjected into the RVLM of conscious rats. In the present study, we evaluated whether endogenous ANG-(1-7) and ANG II acting at the RVLM contribute to the hypertension of transgenic rats harboring the mouse renin Ren-2 gene, TGR(mREN2)27. Unilateral microinjection of A-779 (0.1 nmol) produced a significant fall in MAP (-25 +/- 5 mmHg) and HR (-57 +/- 20 beats/min) of awake TGR rats. The hypotensive effect was greater than that observed in Sprague-Dawley (SD) rats (-9 +/- 2 mmHg). Microinjection of the AT(1) antagonist CV-11974 (0.2 nmol) produced a fall in MAP in TGR rats (-14 +/- 4 mmHg), contrasting with the pressor effect observed in SD rats (33 +/- 9 mmHg). These results indicate that endogenous ANG-(1-7) exerts a significant pressor action in the RVLM, contributing to the hypertension of TGR(mREN2)27 transgenic rats. The role of ANG II at the RVLM seems to be dependent on its endogenous level in this area.


Causes and evolutionary significance of genetic convergence.
Convergent phenotypes provide extremely valuable systems for studying the genetics of new adaptations. Accumulating studies on this topic have reported surprising cases of convergent evolution at the molecular level, ranging from gene families being recurrently recruited to identical amino acid replacements in distant lineages. Together, these different examples of genetic convergence suggest that molecular evolution is in some cases strongly constrained by a combination of limited genetic material suitable for new functions and a restricted number of substitutions that can confer specific enzymatic properties. We discuss approaches for gaining further insights into the causes of genetic convergence and their potential contribution to our understanding of how the genetic background determines the evolvability of complex organismal traits.


Anatomy of microvascular anastomosis in the neck.
Structural and morphometric investigations of the vessels of the neck region were carried out on 30 cadavers (15 male and 15 female in the age range of 45 to 93 years old) to gain more knowledge of the anatomy for microvascular surgery. Our results briefly are as follows: (1) The non-common-truck type of the external carotid artery (in which each branch arises separately from the external carotid artery) was found in 76.6 percent of cases, the truncus linguofacialis type was found in 21.7 percent, and the truncus thyrolingualis type was found in 1.7 percent. (2) The smallest internal diameter (the average was 1.2 mm) was found in the superficial cervical artery. (3) The largest internal diameter (4.4 mm) was measured in the external carotid artery. (4) The longest arterial section (127.8 mm) was measured between the clavicle and mandibular margin. This vascular section or stem consisted of three parts: the supraclavicular part of the common carotid artery, the proximal section of the external carotid artery, and the first 3 cm of the facial artery. (5) In 46.6 percent of cases, the facial, lingual, and superior thyroid veins joined together and formed a thyrolinguofacialis vein. (6) The type with one external jugular vein accounted for 83.0 percent of cases, and the type with one anterior jugular vein for 67.4 percent of cases. (7) The middle thyroid vein exhibited the smallest internal diameter (average of 2.0 mm). (8) The largest internal diameter (7.9 mm) was measured in the internal jugular vein. (9) The longest vessel to receive a vascular pedicle vein was the external jugular vein, the average length of which was 99.7 mm. (10) The frequency and location of valves in the facial vein were also determined.


Alendronate-Modified Polymeric Micelles for the Treatment of Breast Cancer Bone Metastasis.
Although the prognosis of patients with breast cancer continues to improve, breast cancer metastasis to bones remains high in incidence and challenging to manage. Here, we report the development of bone-homing alendronate (ALN)-anchored biodegradable polymeric micelles for the targeted treatment of metastatic cancer to bone. These micelles exhibited bone protective capacity including the recruitment, differentiation, and resorption activity of the osteoclasts. Encapsulation of docetaxel (DTX), the first-line chemotherapeutic for treatment of metastatic breast cancer, in ALN-modified micelles results in a sustained release, enhanced cytotoxicity, and improved pharmacokinetics. In the syngeneic animal model of late-stage disseminated breast cancer bone metastasis, the treatment with targeted DTX-loaded micelles attenuated the tumorigenesis and significantly improved animal lifespan compared to the conventional surfactant-based formulation (free DTX). These findings indicate potential applications of the osteotropic nanomedicines for bone metastasis treatment.


Energy efficient 3D printed column type feed spacer for membrane filtration.
Modification of the feed spacer design significantly influences the energy consumption of membrane filtration processes. This study developed a novel column type feed spacer with the aim to reduce the specific energy consumption (SEC) of the membrane based water filtration system. The proposed spacer increases the clearance between the filament and the membrane (reducing the spacer filament diameter) while keeping the same flow channel thickness as compared to a standard non-woven symmetric spacer. Since the higher clearance reduces the flow unsteadiness, column type nodes were added in the spacer structure as additional vortex shading bodies. Fluid flow behaviour in the channel for this spacer was numerically simulated by 3D CFD studies and then compared with the standard spacer. The numerical results showed that the proposed spacer substantially reduced the pressure drop, shear stress at the constriction region and shortened the dead zone. Finally, these findings were confirmed experimentally by investigating the filtration performances using the 3D printed prototypes of these spacers in a lab-scale filtration module. It is observed that the column spacer reduced the pressure drop by three times and doubled the specific water flux. 2D OCT (Optical Coherence Tomography) scans of the membrane surface acquired after the filtration revealed much lower biomass accumulation using the proposed spacer. Consequently, the SEC for the column spacer was found about two folds lower than the standard spacer.


TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers.
TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.


Effect of focused cardiopulmonary ultrasonography on clinical outcome of septic shock: a randomized study.
To investigate the effect of focused ultrasonography on clinical outcomes of septic shock. Patients with septic shock were randomized into an integrated cardiopulmonary ultrasonography (ICUS) group and conventional (CON) group. Within 1 hour of admission, the ICUS group underwent ICUS examination for hemodynamic decision-making, while the CON group received standard treatment. The primary endpoint was 28-day mortality after admission. The secondary endpoints were cumulative fluid administration in the first 6, 24, and 72 hours; use of vasoactive drugs; lactate clearance; duration of ventilation; and ICU stay. Ninety-four qualified patients were enrolled (ICUS group, 49; CON group, 45). ICUS showed no significant effect on 28-day mortality. Within the initial 6 hours, the ICUS group tended to have a higher fluid balance and fluid intake than the CON group. The duration of vasopressor support was shorter in the ICUS group. There were no differences in the cumulative fluid infusion within 24 or 72 hours, lactate clearance, ICU stay, or duration of ventilation. The initially focused ICUS did not affect the clinical outcomes of septic shock, but it tended to be associated with a higher fluid balance within the initial 6 hours and shorter duration of vasopressor support.


Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropic hormone.
Relapses in multiple sclerosis (MS) are disruptive and frequently disabling for patients, and their treatment is often a challenge to clinicians. Despite progress in the understanding of the pathophysiology of MS and development of new treatments for long-term management of MS, options for treating relapses have not changed substantially over the past few decades. Corticosteroids, a component of the hypothalamic-pituitary-adrenal axis that modulate immune responses and reduce inflammation, are currently the mainstay of relapse treatment. Adrenocorticotropic hormone (ACTH) gel is another treatment option. Although it has long been assumed that the efficacy of ACTH in treating relapses depends on the peptide's ability to increase endogenous corticosteroid production, evidence from research on the melanocortin system suggests that steroidogenesis may only partly account for ACTH influences. Indeed, the melanocortin peptides [ACTH and α-, β-, γ-melanocyte-stimulating hormones (MSH)] and their receptors (Melanocortin receptors, MCRs) exert multiple actions, including modulation of inflammatory and immune mediator production. MCRs are widely distributed within the central nervous system and in peripheral tissues including immune cells (e.g., macrophages). This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. An increased understanding of the role of the melanocortin system, particularly ACTH, in the immune and inflammatory processes underlying relapses may help to improve relapse management.


Applications and Trends of Machine Learning in Genomics and Phenomics for Next-Generation Breeding.
Crops are the major source of food supply and raw materials for the processing industry. A balance between crop production and food consumption is continually threatened by plant diseases and adverse environmental conditions. This leads to serious losses every year and results in food shortages, particularly in developing countries. Presently, cutting-edge technologies for genome sequencing and phenotyping of crops combined with progress in computational sciences are leading a revolution in plant breeding, boosting the identification of the genetic basis of traits at a precision never reached before. In this frame, machine learning (ML) plays a pivotal role in data-mining and analysis, providing relevant information for decision-making towards achieving breeding targets. To this end, we summarize the recent progress in next-generation sequencing and the role of phenotyping technologies in genomics-assisted breeding toward the exploitation of the natural variation and the identification of target genes. We also explore the application of ML in managing big data and predictive models, reporting a case study using microRNAs (miRNAs) to identify genes related to stress conditions.


Phylogenetics and the evolution of terrestriality in mudskippers (Gobiidae: Oxudercinae).
The initial vertebrate conquest of land by stegocephalians (Sarcopterygia) allowed access to new resources and exploitation of untapped niches precipitating a major phylogenetic diversification. However, a paucity of fossils has left considerable uncertainties about phylogenetic relationships and the eco-morphological stages in this key transition in Earth history. Among extant actinopterygians, three genera of mudskippers (Gobiidae: Oxudercinae), Boleophthalmus, Periophthalmus and Periophthalmodon are the most terrestrialized, with vertebral, appendicular, locomotory, respiratory, and epithelial specializations enabling overland excursions up to 14 h. Unlike early stegocephalians, the ecologies and morphologies of the 45 species of oxudercines are well known, making them viable analogs for the initial vertebrate conquest of land. Nevertheless, they have received little phylogenetic attention. We compiled the largest molecular dataset to date, with 29 oxudercine species, and 5 nuclear and mitochondrial loci. Phylogenetic and comparative analyses revealed strong support for two independent terrestrial transitions, and a complex suit of ecomorphological forms in estuarine environments. Furthermore, neither Oxudercinae nor their presumed sister-group the eel gobies (Amblyopinae, a group of elongated gobies) were monophyletic with respect to each other, requiring a merging of these two subfamilies and revealing an expansion of phenotypic variation within the "mudskipper" clade. We did not find support for the expected linear model of ecomorphological and locomotory transition from fully aquatic, to mudswimming, to pectoral-aided mudswimming, to lobe-finned terrestrial locomotion proposed by earlier morphological studies. This high degree of convergent or parallel transitions to terrestriality, and apparent divergent directions of estuarine adaptation, promises even greater potential for this clade to illuminate the conquest of land. Future work should focus on these less-studied species with "transitional" and other mud-habitat specializations to fully resolve the dynamics of this diversification.


Evaluation of Colloids and Activation Agents for Determination of Melamine Using UV-SERS.
UV-SERS measurements offer a great potential for environmental or food (detection of food contaminats) analytics. Here, the UV-SERS enhancement potential of various kinds of metal colloids, such as Pd, Pt, Au, Ag, Au-Ag core-shell, and Ag-Au core-shell with different shapes and sizes, were studied using melamine as a test molecule. The influence of different activation (KF, KCl, KBr, K(2)SO(4)) agents onto the SERS activity of the nanomaterials was investigated, showing that the combination of a particular nanoparticle with a special activation agent is extremely crucial for the observed SERS enhancement. In particular, the size dependence of spherical nanoparticles of one particular metal on the activator has been exploited. By doing so, it could be shown that the SERS enhancement increases or decreases for increasing or decreasing size of a nanoparticle, respectively. Overall, the presented results demonstrate the necessity to adjust the nanoparticle size and the activation agent for different experiments in order to achieve the best possible UV-SERS results.


Late ureteral obstruction after injection of dextranomer/hyaluronic acid copolymer.
Various biological and artificial materials have been introduced for endoscopic treatment of vesicoureteral reflux. Over the past years, dextranomer combined with hyaluronic acid (Dx/Ha) has been established as the most commonly used tissue-augmenting substance for subureteral injection because of its biocompatibility. Nevertheless, the histopathologic analysis of failed Dx/Ha injections showed changes in consistency and volume of the deposit and granulomatous reactions of the adjacent tissue. We report a case of late-onset obstruction 2 years after the injection of Dx/Ha. In the current literature, this potential long-term complication is hardly mentioned.


Update on infantile colic and management options.
Infant colic is a common but poorly defined and understood clinical entity and, while several causative factors have been suggested, a unifying theory of its pathogenesis is still required. Food hypersensitivity/allergy and gut dysmotility are the lead contenders for causative factors of infantile colic. Additional confounders and covariables include psychological and social factors. Although the available data fail to provide insight into the exact triggers of infantile colic, these do allow for the hypothesis that certain infants are predisposed to dietary protein intolerance and disturbed gut motility, such as visceral hypersensitivity/ hyperalgesia, in the first few weeks of life. These processes lead to distress and altered perceptions, where normal stimuli (ie, intestinal distension) are misinterpreted as painful events. This review discusses a number of interventions, including pharmacological agents, which are based on the perceived pathogenesis; however, it is likely that infants with colic will require a multifactorial management strategy. Healthcare providers must offer support, reassurance and empathy to the caregiver, and adopt a biopsychosocial approach to the infants and their families by considering any underlying medical diseases in addition to examining the family unit. In a small subset of infants with colicky behavior, a specific medical disorder such as gastroesophageal reflux or milk protein allergy may be identified. While the vast majority of infants with colic will recover uneventfully, some may be at risk for the later development of behavioral problems and atopy/allergy.


Study of Protein-protein Interactions in Autophagy Research.
Protein-protein interactions are important for understanding cellular signaling cascades and identifying novel pathway components and protein dynamics. The majority of cellular activities require physical interactions between proteins. To analyze and map these interactions, various experimental techniques as well as bioinformatics tools were developed. Autophagy is a cellular recycling mechanism that allows the cells to cope with different stressors, including nutrient deprivation, chemicals, and hypoxia. In order to better understand autophagy-related signaling events and to discover novel factors that regulate protein complexes in autophagy, we performed protein-protein interaction screens. Validation of these screening results requires the use of immunofluorescence and immunoprecipitation techniques. In this system, specific autophagy-related protein-protein interactions that we discovered were tested in Neuro2A (N2A) and HEK293T cell lines. Details of the technical procedures used are explained in this visualized experiment paper.


Variables influencing medical usage rates, injury patterns, and levels of care for mass gatherings.
Mass gatherings create difficult environments for which to plan emergency medical responses. The purpose of this study was to identify those variables that are associated with increased medical usage rates (MURs) and certain injury patterns that can be used to facilitate the planning process. Patient information collected at three types of mass gatherings (professional American football and baseball games and rock concerts) over a three-year period was reviewed retrospectively. Specific variables were abstracted: (1) event type; (2) gender; (3) age; (4) weather; and (5) attendance. All 216 events (total attendance 9,708,567) studied were held in the same metropolitan region. All MURs are reported as patients per 10,000 (PPTT). The 5,899 patient encounters yielded a MUR of 6.1 PPTT. Patient encounters totaled 3,659 for baseball games (4.85 PPTT), 1,204 for football games (6.75 PPTT), and 1,036 for rock concerts (30 PPTT). The MUR for Location A concerts (no mosh pits) was 7.49 PPTT, whereas the MUR for the one Location B concert (with mosh pits) was 110 PPTT. The MUR for Location A concerts was higher than for baseball, but not football games (p = 0.005). Gender distribution was equal among patrons seeking medical care. The mean values for patient ages were 29 years at baseball games, 33 years at football games, and 20 years at concerts. The MUR at events held when the apparent temperature was 80 degrees F significantly lower statistically than that at events conducted at temperatures <80 degrees F were (18 degrees C) (4.90 vs. 8.10 PPTT (p = 0.005)). The occurrence of precipitation and increased attendance did not predict an increased MUR. Medical care was sought mostly for minor/basic-level care (84%) and less so for advanced-level care (16%). Medical cases occurred more often at sporting events (69%), and were more common than were cases with traumatic injuries (31%). Concerts with precipitation and rock concerts had a positive association with the incidence of trauma and the incidence of injuries; whereas age and gender were not associated with medical or traumatic diagnoses. Event type and apparent temperature were the variables that best predicted MUR as well as specific injury patterns and levels of care.


Prehistoric cultural ecology in southern jordan.
Research in the mountains of southern Jordan resulted in the discovery of 109 archaeological sites that are from the Lower Paleolithic to the Chalcolithic period [150 to 6 thousand years ago (ka)]. Beginning with the Middle Paleolithic (70 ka) two site types (long-term and ephemeral camps) are recognized. Long-term sites have larger areas, thicker deposits, higher artifact densities, and more abundant archaeological features than ephemeral sites. Their natural settings (elevation and exposure) and associated seasonal evidence (phytolith and cementum increment data) indicate that long-term sites were occupied during the winter, wet season and ephemeral sites during the warm, dry season. These differences in site use and seasonality likely reflect an adaptive strategy of transhumance that persisted to modern Bedouin times. At the end of the Pleistocene, the onset of warmer, drier conditions induced a shift of the long-term winter camps from relatively low (800 to 1000 meters above sea level) to high (1000 to 1250 meters above sea level) elevations and largely reversed the earlier transhumant pattern.


Interleukin-1 receptor-related protein ST2 suppresses the initial stage of bleomycin-induced lung injury.
Acute lung injury has a range of causes, and occasionally leads to lethal respiratory failure. Despite advances in treatment, acute lung injury continues to have a high mortality rate, and thus a new therapeutic approach is needed. ST2 is an interleukin (IL)-1 receptor-related protein, and its expression is induced by various inflammatory responses. Recently, ST2 has been speculated to exert anti-inflammatory effects; therefore, we investigated the role of the ST2 in the murine model of acute lung injury. To elucidate the function of ST2 in vivo, mice that transiently overexpressed ST2 protein were prepared using the hydrodynamic gene transfer method, and lung injury was induced by intratracheal administration of bleomycin. In bleomycin-treated ST2-overexpressing mice, the increase of neutrophils in the bronchoalveolar lavage fluid (BALF) was markedly suppressed. Additionally, the levels of tumour necrosis factor-alpha and IL-6, as well as the concentration of albumin, in BALF were reduced compared with those of controls. Furthermore, the pulmonary architecture in ST2-overexpressing mice remained almost normal, and the survival rate was significantly improved. From these results, we concluded that ST2 has the potential to suppress the initial stage of acute lung injury, and therefore it may be a useful reagent for the treatment of acute lung injury.


Effectiveness of electro-acupuncture compared to sedo-analgesics in relieving pain during shockwave lithotripsy.
The aim of this study was to compare the clinical efficacy of electro-acupuncture (EA) with the combination of tramadol+midazolam (TM) for pain relief during outpatient extracorporeal shockwave lithotripsy (ESWL). A total of 35 patients (20 men, 15 women) with stones located in the pelvicalyceal system of the kidney were randomized prospectively to undergo lithotripsy with a third generation lithotriptor (Stone Lith, smart PCK) after receiving either EA (n=17) or TM (n=18) for sedation and analgesia. EA treatment was applied to patients by the same licensed acupuncturist 30 min prior to ESWL in group EA. Tramadol (1.5 mg/kg) 30 min before the start of lithotripsy and midazolam (0.06 mg/kg) 5 min prior to ESWL were given as a sedo-analgesic intravenously to group TM. During ESWL, blood pressure, heart rate, pain and sedation levels were measured at baseline and every 15 min thereafter. The pain intensity perceived during lithotripsy was evaluated using a visual analog scale (VAS). There was no statistical differences in the diameters of the stones and age of the patients between groups (P=0.590; P=0.568, respectively). In the EA group, the median of maximum energy level achieved was 16.0 kV (range 10-23 kV), while it was 18.0 kV (range 10-20 kV) in the TM group. There was no statistically significant difference between the maximum energy levels applied to the patients during ESWL (P=0.613). The median numbers of shockwaves were 2,114 (range 1,100-3,800) and 2,200 (range 1,500-3,200) in the EA and TM groups, respectively. In the TM group, the numbers of shockwaves used were higher than in group EA during ESWL. However, this difference was not significant (P=0.732). VAS scores were consistently lower in the EA group compared with the TM group throughout the ESWL procedure. The median VAS score was 5.0 (range 1-10) in the EA group while it was 8.0 (range 2-10) in the TM group. The patients who underwent EA had lower median scores of VAS than patients who took only conservative treatment, but this difference was not significant (P=0.245). When both groups were compared for stone-free rates, no significant difference was found [82.3% (14/17) for group EA, 88.8% (16/18) for group TM] (P=0.658). Durations of ESWL procedures were similar in both groups [median 27.4 min (range 15.7-34.3) in group EA vs 27.1 min (range 16.1-33.6) in group TM] (P=0.517). No side effects was seen in any patient who received EA. Side effects such as mild orthostatic hypotension and dizziness occurred in patients given sedo-analgesia, but these were not severe enough to require any patient to be excluded from the study. Our study shows that EA is an effective method for inducing sedation with analgesia without any demonstrable side effects.


Which outcomes matter in Alzheimer disease and who should define them?
The identification of salient outcomes depends on the conceptual map of the disease and its consequences. Early attention focuses on cognition. Cognitive losses can lead to behavioral problems, which may be exacerbated by treatment. Behavioral problems can create a need for supervision. Client functioning can require another form of supervision, cuing. Because Alzheimer disease affects families as much as patients, many outcomes are directed at measures of caregiver burden and stress. A therapeutic model of chronic care management, which aims at producing results at least as good as might be reasonably expected (i.e., slowing decline), creates a different mind set from a compensatory model of care, which seeks primarily to meet dependency needs. In the latter, good care is equivalent to meeting needs without incurring adverse events. Outcomes and locus of decision-making intersect around issues of quality of life. Assumptions about the ability of a patient with Alzheimer disease to express positive feelings or to indicate preferences for care need to be explored carefully. Although the use of agents or proxies may be necessary when making decisions about care, proxies serve poorly to convey information about another person's quality of life.


Political economy of tobacco control policy on public health in Japan.
Tobacco use, particularly smoking, remains the number one cause of preventable disease and mortality in Japan. This review of the tobacco control policy and public health is the first to offer a composite review of the subject within Japan. This review attempts to evaluate the most important aspects of the current political economy of the tobacco control policy, and concludes that more effective control policies must be employed to minimize the impact of smoking on the public's health in Japan. Further the article attempts to place the approaches in the larger context of tobacco control, providing a vision for the future of tobacco prevention and control based on current knowledge. Tobacco use will remain the leading cause of preventable illness and death in Japan, until tobacco prevention and control efforts are commensurate with the harm caused by tobacco. Taken together, the results of various studies have clearly shown that control measures can influence tobacco smoking patterns, and in turn, the rate of tobacco-related problems. Government tobacco taxes have not kept pace with inflation for years. Availability of tobacco is virtually unlimited with easy access and the prices being very low due to the strong currency of Japan. Thus Japan must be one of the most tobacco accessible countries. It is important to ensure that people are not conditioned to smoke tobacco by an unduly favourable economic and commercial environment. For that reason, prevention advocates have called for substantial regulation of tobacco products and appeal for both tobacco tax increases and tobacco taxes to be indexed to inflation. In this review, present tobacco related public health policies in Japan are discussed with implication for prevention of tobacco related problems. Continued research in this area will be necessary to determine the most effective policies of reducing tobacco related problems in Japan.


Skeletal muscle fibrosis develops in response to desmin deletion.
Skeletal muscle is a dynamic composite of proteins that responds to both internal and external cues to facilitate muscle adaptation. In cases of disease or altered use, these messages can be distorted resulting in myopathic conditions such as fibrosis. In this work, we describe a mild and progressive fibrotic adaptation in skeletal muscle lacking the cytoskeletal intermediate filament protein desmin. Muscles lacking desmin become progressively stiffer, accumulate increased collagen, and increase expression of genes involved in extracellular matrix turnover. Additionally, in the absence of desmin, skeletal muscle is in an increased state of inflammation and regeneration as indicated by increased centrally nucleated fibers, elevated inflammation and regeneration related gene expression, and increased numbers of inflammatory cells. These data suggest a potential link between increased cellular damage and the development of fibrosis in muscles lacking the cytoskeletal support of the desmin filament network.


Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.
To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).


RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1.
Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.


Dynamics of endothelial cell behavior in sprouting angiogenesis.
The vertebrate body contains an extensive blood vessel network that forms, with a few exceptions, by endothelial sprouting from the existing vasculature. This process, termed angiogenesis, involves complex and highly dynamic interactions between endothelial cells and their environment. Pro-angiogenic signals, such as VEGF, promote endothelial motility, filopodia extension and proliferation, and, together with Notch signaling, controls whether specific endothelial cells become lead tip cells or trailing stalk cells. Sprouts then convert into endothelial tubules and form connections with other vessels, which requires the local suppression of motility and the formation of new cell-cell junctions. We here review the dynamics of angiogenesis in the context of key molecules and pathways controlling tip cell selection, sprouting and the formation of new vessels.


Survey of sterile product compounding practices in Canadian hospital pharmacies.
Improper preparation of sterile products by hospital or community pharmacies may have serious consequences. Recent reports of deaths or injury to patients as a result of receiving products that were contaminated during their preparation in a pharmacy have highlighted the importance of maintaining good sterile compounding practices. Efforts are now underway to develop revised guidelines for the compounding of sterile products in order to minimize the potential for future recurrence of similar incidents. This survey study was undertaken to provide background data on current sterile products compounding practices and procedures in Canadian hospital pharmacies. It was also anticipated that these data would be helpful in identifying issues that needed to be addressed in the new guidelines. Surveys were distributed to 700 Canadian hospitals with 50 or more beds. Responses from returned surveys were entered into and analyzed using the database program RBase. A total of 306 hospital pharmacies responded, with 200 indicating that sterile products were compounded within their department. The information provided by respondents provides insight into the types of sterile products being prepared in Canadian hospitals, the training background of staff involved in sterile product preparation, the type of facilities and equipment used for compounding these preparations, and the quality control/quality assurance procedures that are in place in hospital pharmacies. The information arising from this survey underscores the need for comprehensive guidelines or standards with respect to sterile product compounding, and the need for improved training of personnel involved in sterile product compounding. The results should be of interest to hospital pharmacy administrators, pharmacy regulatory bodies, and government agencies responsible for assuring the safety of pharmaceutical products used in patient care.


Results of a national neurosurgery resident survey on duty hour regulations.
The Accreditation Council for Graduate Medical Education (ACGME) duty hour standards that began July 2011 will further limit resident duty hours. To survey neurosurgery residents in the United States on duty hour violations under the current system and the predicted effects on education and patient safety of the new regulations. Surveys were mailed to every neurosurgery training program in the United States and Puerto Rico. Program directors and coordinators were asked to distribute surveys to their residents. Three hundred seventy-seven neurosurgery residents mailed surveys back to the study center (34% response rate). More than one-third of respondents reported violating the 80-hour rule occasionally or frequently (36%). Thirty-one residents (8%) reported having been involved in a motor vehicle collision or life-threatening event and 20 (6%) reported having made a medical error resulting in patient harm after an extended shift. Eighty-three percent disagreed with the 16-hour proposed regulation for postgraduate year 1. The majority of respondents thought that the new standards will have a negative or strongly negative effect on their residency training (72%). This national duty hour survey of neurosurgical residents reveals considerable concern over the new ACGME proposed standards. The majority of respondents believe that the new standards will have a negative effect on their residency training. Furthermore, this survey indicates an overwhelming negative attitude toward mandated duty hour regulations among neurosurgical residents. Duty hour violations reported in this survey may be a more honest depiction of true violations than previous surveys and are higher than expected.


Proinflammatory properties of coplanar PCBs: in vitro and in vivo evidence.
So-called coplanar polychlorinated biphenyls (PCBs), as well as other environmental contaminants that are aryl hydrocarbon receptor (AhR) agonists, may compromise the normal functions of vascular endothelial cells by activating oxidative stress-sensitive signaling pathways and subsequent proinflammatory events critical in the pathology of atherosclerosis and cardiovascular disease. To test this hypothesis, porcine endothelial cells were exposed to PCB 153 and to three coplanar PCBs (PCB 77, PCB 126, or PCB 169). In contrast to PCB 153, which is not a ligand for the Ah receptor (AhR), all coplanar PCBs disrupted endothelial barrier function. All coplanar PCBs increased expression of the CYP1A1 gene, oxidative stress (DCF fluorescence), and the DNA-binding activity of nuclear factor kappaB (NF-kappaB). PCB-induced oxidative stress was concentration-dependent, with PCB 126 exhibiting a maximal response at the lowest concentration (0.5 microM) tested. The increase in NF-kappaB-dependent transcriptional activity was confirmed in endothelial cells by a luciferase reporter gene assay. In contrast to PCB 153, coplanar PCBs that are AhR ligands increased endothelial production of interleukin-6. At 3.4 microM, expression of the adhesion molecule VCAM-1 was most sensitive to PCB 77 and 169. We also provide in vivo evidence, suggesting that binding to the AhR is critical for the proinflammatory properties of PCBs. Twenty hours after a single administration of PCB 77, VCAM-1 expression was increased only in wild-type mice, while mice lacking the AhR gene showed no increased staining for VCAM-1. These data provide evidence that coplanar PCBs, agonists for the AhR, and inducers of cytochrome P450 1A1, produce oxidative stress and an inflammatory response in vascular endothelial cells. An intact AhR may be necessary for the observed PCB-induced responses. These findings suggest that activation of the AhR can be an underlying mechanism of atherosclerosis mediated by certain environmental contaminants.


Roles of work of adhesion between carbon blacks and thermoplastic polymers on electrical properties of composites.
The effect of the work of adhesion between carbon blacks and different thermoplastic polymers on the positive temperature coefficient (PTC) of composites was investigated. Thermoplastic polymers, such as EVA, LDPE, LLDPE, HDPE, and PP, were used with the addition of 30 wt% of carbon blacks. The work of adhesion based on the surface free energy of a composite was studied in the context of two-liquid contact angle measurements using deionized water and diiodomethane. It was observed that the resistivity on PTC behavior was greatly increased near the crystalline melting temperature, due to the thermal expansion of polymeric matrix. It was shown that the PTC intensity defined as the ratio of the maximum resistivity (rho(max)) to the resistivity at room temperature (rho(RT)) had the largest value on CB/HDPE composites. From the experimental results, the decrease in the work of adhesion induced by interactions between carbon black surfaces and polymer chains is an important factor in the fabrication of a PTC composite.


Effect of isolation-rearing on conditioned dopamine release in vivo in the nucleus accumbens of the rat.
Intracerebral microdialysis in conjunction with HPLC coupled to electrochemical detection was used to investigate the effect of isolation-rearing in the rat on extracellular dopamine (DA) and its metabolites in vivo, in the shell region of the nucleus accumbens, in response to footshock and in relation to a conditioned emotional response. Male Lister hooded rats were reared from weaning for 6-8 weeks in either social isolation or groups of five. In the training phase, rats were exposed to a novel environment for 10 min where they experienced mild footshock. Footshock caused an immediate increase in basal extracellular DA levels in both rearing groups relative to control rats. However, the increase in extracellular DA was prolonged in the case of the isolation-reared rats and significantly greater than in group-reared rats. Exposure to the novel environment without shock (control groups) did not significantly alter basal extracellular DA in the nucleus accumbens shell; 140 min later rats were returned to the testing box (contextual stimulus) without receiving footshock. The contextual stimulus increased basal extracellular DA in the nucleus accumbens of both groups of rats with respect to controls; however, this increase was significantly greater and more prolonged in isolates. Extracellular levels of the metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid did not differ between isolation- and group-reared rats, and they were not significantly affected by either footshock or the contextual stimulus. These results suggest that exposure to footshock and a contextual stimulus are associated with increases in basal extracellular DA levels in the nucleus accumbens shell. The results also support evidence in favour of an isolation-induced enhancement in dopaminergic activity in the nucleus accumbens, which probably underlies aspects of the behavioural syndrome associated with isolation.


Variation by state in outcomes classification for deliveries less than 500 g in the United States.
The purpose of this study is to explore state-level fetal death rates and <24 h infant mortality rates for deliveries less than 500 g in order to estimate outcomes classification differences at the edge of viability. We selected singleton deliveries to US resident mothers born <500 g and >20 weeks gestation from the NCHS live birth-infant death and fetal death files for 1999-2002 (n = 37,813). Infant deaths within 24 h of birth were selected to estimate odds of classification as a fetal death versus a live birth/infant death by state. Logistic regression was used to derive odds of classification as a fetal death and to adjust for maternal characteristics, calculating unadjusted and adjusted odds ratios. We identified 37,813 outcomes from 48 states reporting in this birthweight category. Unadjusted odds of classification of outcomes as a fetal death versus a live birth/death within 24 h by state ranged from OR = 0.38 (95% CI = 0.24-0.59) to OR = 2.93 (95% CI = 2.26-3.78); adjusted for maternal age and race, the range narrowed slightly to a OR = 0.31 (95% CI = 0.20-0.48) to aOR = 2.54 (95% CI = 1.96-3.30). Six states were more likely to classify outcomes as a live birth/infant death, while 14 states were more likely to classify as a fetal death, when compared to a large reference state. The remaining states did not differ significantly in their outcomes. The fraction of outcomes classified as fetal deaths varied by state during the years studied. This study suggests fetal death and early infant death outcomes reported for babies less than 500 g reflect differential classification thus influencing the validity of these vital statistics data at the state level. Further studies are needed to explore the factors that influence these differences.


A bottom-up approach for recurrence detection based on sampling distance.
One of the major problems faced in the recurrence analysis of dynamical systems is the tangential motion effect affecting the structures in recurrence plots and their quantification. This issue roots to the choice of a threshold for recurrence, making it a crucial parameter for such analyses. It has been shown that a variable threshold following the dynamical changes of the system is more suited to the analysis of non-stationary data as it mitigates this effect. We study here the use of the distance separating successive points in the phase space as a reference for the recurrence threshold. The method relies on a single parameter while qualitatively and quantitatively providing stable recurrence structures as the previously suggested threshold based on the local maximum pairwise distance. This complete bottom-up approach is shown to be beneficial in the presence of abrupt transitions. It is also fairly noise-resistant and is not dependent on the sampling frequency in its normalized formulation. Furthermore, the sampling distance provides a clear reference for the occurrence of the tangential motion effect, allowing to define a default value for the threshold parameter to avoid it.


Periodontal diseases and its association with disease activity in ankylosing spondylitis/SpA: A systematic review.
A close association between periodontal disease (PD) and ankylosing spondylitis (AS) has long been speculated. Both diseases are characterized by dysregulation of the host inflammatory response, leading to further destruction of the soft and hard connective tissue. There is evidence of increased levels of tumor necrosis factor-alpha and various interleukins in both patients of AS and periodontitis. This study aimed to conduct a systematic review exploring the relationship between AS and PD. We searched MEDLINE - Embase databases (from their inception till October 2019) using appropriate combinations of the following search items with limits '(English, Human)': Ankylosing spondylitis, spondyloarthritis, spondyloarthropathies, spondyloarthritides, spinal disease, musculoskeletal disease, rheumatic disease and periodontitis, PD, periodontoses, parodontoses, chronic periodontitis, gum disease, gingivitis, oral health, dental health, plaque index (PI), bleeding on probing (BOP), probing pocket depth (PPD), and clinical attachment loss (CAL). This search was supplemented by the manual search of bibliographies of the selected articles and conference proceedings of the European League against Rheumatism. Only the reviews and observational studies of cross-sectional, cohort, or case-control type on adult patients with AS were selected. Data were extracted from a predesigned PROforma. A total of 984 articles were identified, and 12 were selected for a detailed appraisal. All the identified studies were of the case-control type. The prevalence of periodontitis ranged from 38% to 88% in patients with AS and 26% to 71% in the control group. Of the 12 studies, 2 showed significant changes in PI, 2 showed altered PPD, 3 showed significantly increased CAL, and 2 showed increased BOP. In 7 studies, periodontitis was seen in a significant number of patients with AS (p<0.05). All the studies reported that the prevalence of PD in patients with AS was higher than that in patients without AS. Our systematic review found an association between AS and PD. Patients with AS show a higher prevalence of periodontitis and poor oral hygiene than the healthy controls.


Prolonged cross-bridge binding triggers muscle dysfunction in a Drosophila model of myosin-based hypertrophic cardiomyopathy.
K146N is a dominant mutation in human β-cardiac myosin heavy chain, which causes hypertrophic cardiomyopathy. We examined how Drosophila muscle responds to this mutation and integratively analyzed the biochemical, physiological and mechanical foundations of the disease. ATPase assays, actin motility, and indirect flight muscle mechanics suggest at least two rate constants of the cross-bridge cycle are altered by the mutation: increased myosin attachment to actin and decreased detachment, yielding prolonged binding. This increases isometric force generation, but also resistive force and work absorption during cyclical contractions, resulting in decreased work, power output, flight ability and degeneration of flight muscle sarcomere morphology. Consistent with prolonged cross-bridge binding serving as the mechanistic basis of the disease and with human phenotypes, 146N/+ hearts are hypercontractile with increased tension generation periods, decreased diastolic/systolic diameters and myofibrillar disarray. This suggests that screening mutated Drosophila hearts could rapidly identify hypertrophic cardiomyopathy alleles and treatments.


Topology of Learning in Feedforward Neural Networks.
Understanding how neural networks learn remains one of the central challenges in machine learning research. From random at the start of training, the weights of a neural network evolve in such a way as to be able to perform a variety of tasks, such as classifying images. Here, we study the emergence of structure in the weights by applying methods from topological data analysis. We train simple feedforward neural networks on the MNIST data set and monitor the evolution of the weights. When initialized to zero, the weights follow trajectories that branch off recurrently, thus generating trees that describe the growth of the effective capacity of each layer. When initialized to tiny random values, the weights evolve smoothly along 2-D surfaces. We show that natural coordinates on these learning surfaces correspond to important factors of variation.


B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis.
In melanoma, the RAS/RAF/MEK/ERK signalling pathway is an area of great interest, because it regulates tumor cell proliferation and survival. A varying mutation rate has been reported for B-RAF and N-RAS, which has been largely attributed to the differential source of tumor DNA analyzed, e.g., fixed tumor tissues or in vitro propagated melanoma cells. Notably, this variation also interfered with interpreting the impact of these mutations on the clinical course of the disease. Consequently, we investigated the mutational profile of B-RAF and N-RAS in biopsies and corresponding cell lines from metastatic tumor lesions of 109 melanoma patients (AJCC stage III/IV), and its respective impact on survival. 97 tissue biopsies and 105 biopsy-derived cell lines were screened for B-RAF and N-RAS mutations by PCR single strand conformation polymorphism and DNA sequencing. Mutations were correlated with patient survival data obtained within a median follow-up time of 31 months. B-RAF mutations were detected in 55% tissues and 51% cell lines, N-RAS mutations in 23% tissues and 25% cell lines, respectively. There was strong concordance between the mutational status of tissues and corresponding cell lines, showing a differing status for B-RAF in only 5% and N-RAS in only 6%, respectively. Patients with tumors carrying mutated B-RAF showed an impaired median survival (8.0 versus 11.8 months, p = 0.055, tissues; 7.1 versus 9.3 months, p = 0.068, cell lines), whereas patients with N-RAS-mutated tumors presented with a favorable prognosis (median survival 12.5 versus 7.9 months, p = 0.084, tissues; 15.4 versus 6.8 months, p = 0.0008, cell lines), each in comparison with wildtype gene status. Multivariate analysis qualified N-RAS (p = 0.006) but not B-RAF mutation status as an independent prognostic factor of overall survival. Our findings demonstrate that B-RAF and N-RAS mutations are well preserved during short term in vitro propagation and, most importantly, differentially impact the outcome of melanoma patients.


Predictive role of Trimprob associated with multiparametric MRI in the diagnosis of prostate cancer.
To evaluate the predictive value of TRIMprob test to detect prostate cancer (PCa) in patients referred to prostate biopsy (PB). Patients with PSA <10ng/mL and rectal exam without findings suggestive of prostate cancer were selected for TRIMprob evaluation. Exam was performed by a single operator through transperineal approach. Patients admitted for the study were submitted to TRIMprob and multiparametric magnetic resonance (mpMRI) and posteriorly to PB. In total, 77 patients were included. TRIMprob showed evidences of PCa in 25 (32.5%) and was negative in 52 patients (67.5%). The rate of detection of prostate cancer at biopsy was higher in patients with positive TRIMprob (16/25; 64.0%) than in patients with negative TRIMprob (11/52; 21.1%; p<0.001). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of TRIMprob were respectively 61.5%, 82.0%, 64.0%, 80.3% and 74.0%. ROC curve showed the following areas under the curve values for TRIMprob, mpMRI and combination of TRIMprob + mpMRI: 0.706; 0.662 and 0.741 respectively. At combined analysis, when both TRIMprob and mpMRI were negative for prostate cancer, accuracy was 96.3% or only 1 in 27 PB was positive (3.7%). Trimprob had similar predictive value for PCa in patients submitted to PB as mpMRI. Combined TRIMprob and mpMRI showed higher accuracy than when performed singly.


Sleep Quality, Fatigue, and Postpartum Depression of Mother at Six Months after Delivery.
This study was correlation study to identify the factors influencing sleep quality, fatigue, and postnatal depression in mothers who have given birth during the past 6 months. The study was conducted using a survey with questionnaires to 329 mothers who visited E University Medical Center, or three local clinics located in D city, between August and October 2013. Collected data were analyzed using the SPSS/WIN 20.0 program. Out of 329 subjects, 18.2% showed that they had mild postnatal depression whereas 24.3% had severe postnatal depression. Accordingly, 42.5% reported having postnatal depression. Postnatal depression had a significant correlation with sleep hours after childbirth (r=-.16, p=.003), spousal support (r=-.28, p<.001), sleep quality (r=-.35, p<.001), physical fatigue (r=.66, p<.001), psychological fatigue (r=.69, p<.001), and neurosensory fatigue (r=.56, p<.001). Factors influencing postnatal depression include psychological fatigue, sleep quality, number of child births, and neurosensory fatigue, and these accounted for 53% of postnatal depression. Results indicate that factors influencing postnatal depression involve psychological fatigue, sleep quality, number of child births, and neurosensory fatigue. Therefore for nursing intervention for postpartum mothers, it is necessary to assess the level of depression, fatigue, and sleep quality, and to provide interventions to relieve depression.


Brain energetics plays a key role in the coordination of electrophysiology, metabolism and hemodynamics: Evidence from an integrated computational model.
The energetic needs of brain cells at rest and during elevated neuronal activation has been the topic of many investigations where mathematical models have played a significant role providing a context for the interpretation of experimental findings. A recently proposed mathematical model, comprising a double feedback between cellular metabolism and electrophysiology, sheds light on the interconnections between the electrophysiological details associated with changes in the frequency of neuronal firing and the corresponding metabolic activity. We propose a new extended mathematical model comprising a three-way feedback connecting metabolism, electrophysiology and hemodynamics. Upon specifying the time intervals of higher neuronal activation, the model generates a potassium based signal leading to the concomitant increase in cerebral blood flow with associated vasodilation and metabolic changes needed to sustain the increased energy demand. The predictions of the model are in good qualitative and quantitative agreement with experimental findings reported in the literature, even predicting a slow after-hyperpolarization of a duration of approximately 16 s matching experimental observations.


Patients' health-related quality-of-life and health state values for motor neurone disease/amyotrophic lateral sclerosis.
Motor neurone disease (MND) has a severe impact on patient quality of life, especially in later stages of the disease. This study assesses the health-related quality of life (HRQL) of MND patients, and for the first time elicits health state values from patients for their present health state. A structured interview was conducted with 77 patients. Patients completed a disease specific health status measure (ALSAQ-40), a generic health status measure (EuroQol EQ-5D), a visual analogue scale (VAS) and a standard gamble (SG) exercise. The ALSAQ-40 was sensitive to disease severity. Patients' mean VAS rating of their own health ranged from 0.74 for stage 1 (early) disease severity (n = 15), to 0.37 for stage 4 (late stage) disease severity (n = 19). Utilities elicited via SG varied from a mean of 0.79 for stage 1 disease severity to a mean of 0.45 for stage 4 disease severity. The EQ-5D derived single index ranged from a mean of 0.63 for stage 1 disease severity to a mean of -0.01 for stage 4 disease severity. This study demonstrates that it is feasible and practical to obtain health state values from MND patients and it provides evidence that patients place a high value on their HRQL, even in cases where health status is very poor.


Flexible versus common technology to estimate economies of scale and scope in the water and sewerage industry: an application to England and Wales.
The water industry presents several structures in different countries and also within countries. Hence, several studies have been conducted to evaluate the presence of economies of scope and scale in the water industry leading to inconclusive results. The lack of a common methodology has been identified as an important factor contributing to divergent conclusions. This paper evaluates, for the first time, the presence of economies of scale and scope in the water industry using a flexible technology approach integrating operational and exogenous variables of the water companies in the cost functions. The empirical application carried out for the English and Welsh water industry evidenced that the inclusion of exogenous variables accounts for significant differences in economies of scale and scope. Moreover, completely different results were obtained when the economies of scale and scope were estimated using common and flexible technology methodological approaches. The findings of this study reveal the importance of using an appropriate methodology to support policy decision-making processes to promote sustainable urban water activities.


Caspase-dependent apoptosis induces reactivation and gliogenesis of astrocytes in adult mice.
Astrocytes play an important role in increasing synaptic plasticity, regulating endogenous homeostasis, and contributing to neuroprotection but become overactivated or apoptotic in persistent neuroinflammatory responses or pathological conditions. Although gliogenesis under these conditions may be essential for neuronal protection, much remains unknown. Here, we generated new conditional transgenic mice (cTg) that can induce apoptosis via Cre-dependent active caspase-3 (taCasp3-2A-TEVp) without pathological conditions. We induced apoptosis of hippocampal CA1 astrocytes in cTg mice using GFAP promoter-driven adeno-associated virus (AAV) containing Cre recombinase. Activated caspase-3 was detected in astrocytes of the hippocampal CA1, and the number of astrocytes decreased sharply at 1 week but recovered at 2 weeks and was maintained until 4 weeks. Nuclear factor 1A (NF1A) mRNA, an important transcription factor for hippocampal reactive astrocytes, was significantly increased only at week 1. Interestingly, all reactive markers (pan, A1, A2) increased despite the decreased number of astrocytes at week 1, and there was no change in monoamine oxidase B (MAOB) observed in astrocytes of animal models of degenerative brain disease. Extensive CA1 astrocyte depletion at week 1 induced cognitive deficits; however, both recovered at weeks 2 and 4. Overall, transient hippocampal astrocyte depletion caused by apoptosis restored cell number and function within 2 weeks and did not induce significant neurotoxicity. Therefore, cTg mice are valuable as an in vivo animal model for studying gliogenesis in multiple regions of the adult brain.


Identification of a placental-specific enhancer in the rat placental lactogen II gene that contains binding sites for members of the Ets and AP-1 (activator protein 1) families of transcription factors.
We previously identified a 3-kb proximal 5'-flanking region of the rat placental lactogen (rPLII) gene that is important for reporter gene transcription in the rat trophoblast cell line, Rcho, and targets expression to the placentas of transgenic mice. In our current studies we have used further deletion analysis and transfection studies in Rcho and GC cells to map more precisely the locations of regulatory elements involved in this placental expression. We show that sequences between - 1435 and -765 are necessary for minimal expression in Rcho cells and that there are negative regulatory elements between -3031 to -2838 and -1729 to -1435. Most importantly, we have identified a fragment between -1793 to -1729 that is essential for expression levels characteristic of the complete 3-kb 5'-region. When linked to the herpes simplex thymidine kinase minimal promoter, this fragment acts as an enhancing element in Rcho but not GC cells. Deoxyribonuclease I (DNAse I) protection and electrophoretic mobility shift assays with nuclear extracts and in vitro translated proteins identify binding sites for members of the activator protein-1 (AP-1) and Ets families of transcription factors. Site-directed mutagenesis of the individual AP-1- and Ets-binding sites leads to a partial loss of the enhancing activity; a double AP-1/Ets mutation leads to a complete loss of activity, demonstrating the functional importance of these sites. By these criteria, putative GATA-binding sites located within the enhancing fragment are not active. These new data suggest an important role for this enhancing fragment in rPLII placental giant cell expression and are the first to implicate a member of the Ets family in the regulation of this gene family.


Cytokinin and auxin interaction in root stem-cell specification during early embryogenesis.
Plant stem-cell pools, the source for all organs, are first established during embryogenesis. It has been known for decades that cytokinin and auxin interact to control organ regeneration in cultured tissue. Auxin has a critical role in root stem-cell specification in zygotic embryogenesis, but the early embryonic function of cytokinin is obscure. Here, we introduce a synthetic reporter to visualize universally cytokinin output in vivo. Notably, the first embryonic signal is detected in the hypophysis, the founder cell of the root stem-cell system. Its apical daughter cell, the precursor of the quiescent centre, maintains phosphorelay activity, whereas the basal daughter cell represses signalling output. Auxin activity levels, however, exhibit the inverse profile. Furthermore, we show that auxin antagonizes cytokinin output in the basal cell lineage by direct transcriptional activation of ARABIDOPSIS RESPONSE REGULATOR genes, ARR7 and ARR15, feedback repressors of cytokinin signalling. Loss of ARR7 and ARR15 function or ectopic cytokinin signalling in the basal cell during early embryogenesis results in a defective root stem-cell system. These results provide a molecular model of transient and antagonistic interaction between auxin and cytokinin critical for specifying the first root stem-cell niche.


Dual regulation by the Hunchback gradient in the Drosophila embryo.
The regulation of segmentation gene expression is investigated by computational modeling using quantitative expression data. Previous tissue culture assays and transgene analyses raised the possibility that Hunchback (Hb) might function as both an activator and repressor of transcription. At low concentrations, Hb activates gene expression, whereas at high concentrations it mediates repression. Under the same experimental conditions, transcription factors encoded by other gap genes appear to function as dedicated repressors. Models based on dual regulation suggest that the Hb gradient can be sufficient for establishing the initial Kruppel (Kr) expression pattern in central regions of the precellular embryo. The subsequent refinement of the Kr pattern depends on the combination of Hb and the Giant (Gt) repressor. The dual-regulation models developed for Kr also explain some of the properties of the even-skipped (eve) stripe 3+7 enhancer. Computational simulations suggest that repression results from the dimerization of Hb monomers on the DNA template.


Fractures of the clavicle in the adult. Epidemiology and classification.
From 1988 to 1994 a consecutive series of 1000 fractures of the adult clavicle was treated in the Orthopaedic Trauma Clinic of the Royal Infirmary of Edinburgh. In males, the annual incidence was highest under 20 years of age, decreasing in each subsequent cohort until the seventh decade. In females, the incidence was more constant, but relatively frequent in teenagers and the elderly. In young patients, fractures usually resulted from road-traffic accidents or sport and most were diaphyseal. Fractures in the outer fifth were produced by simple domestic falls and were more common in the elderly. A new classification was developed based on radiological review of the anatomical site and the extent of displacement, comminution and articular extension. There were satisfactory levels of inter- and intraobserver variation for reliability and reproducibility. Fractures of the medial fifth (type 1), undisplaced diaphyseal fractures (type 2A) and fractures of the outer fifth (type 3A) usually had a benign prognosis. The incidence of complications of union was higher in displaced diaphyseal (type 2B) and displaced outer-fifth (type 3B) fractures. In addition to displacement, the extent of comminution in type-2B fractures was a risk factor for delayed and nonunion.


Coexpression of the KCNA3B gene product with Kv1.5 leads to a novel A-type potassium channel.
Shaker-related voltage-gated potassium (Kv) channels may be heterooligomers consisting of membrane-integral alpha-subunits associated with auxiliary cytoplasmic beta-subunits. In this study we have cloned the human Kvbeta3.1 subunit and the corresponding KCNA3B gene. Identification of sequence-tagged sites in the gene mapped KCNA3B to band p13.1 of human chromosome 17. Comparison of the KCNA1B, KCNA2B, and KCNA3B gene structures showed that the three Kvbeta genes have very disparate lengths varying from >/=350 kb (KCNA1B) to approximately 7 kb (KCNA3B). Yet, the exon patterns of the three genes, which code for the seven known mammalian Kvbeta subunits, are very similar. The Kvbeta1 and Kvbeta2 splice variants are generated by alternative use of 5'-exons. Mouse Kvbeta4, a potential splice variant of Kvbeta3, is a read-through product where the open reading frame starts within the sequence intervening between Kvbeta3 exons 7 and 8. The human KCNA3B sequence does not contain a mouse Kvbeta4-like open reading frame. Human Kvbeta3 mRNA is specifically expressed in the brain, where it is predominantly detected in the cerebellum. The heterologous coexpression of human Kv1.5 and Kvbeta3.1 subunits in Chinese hamster ovary cells yielded a novel Kv channel mediating very fast inactivating (A-type) outward currents upon depolarization. Thus, the expression of Kvbeta3.1 subunits potentially extends the possibilities to express diverse A-type Kv channels in the human brain.


Synthesis, structure, and photophysics of copper(i) triphenylphosphine complexes with functionalized 3-(2'-pyrimidinyl)-1,2,4-triazole ligands.
A series of new mononuclear and dinuclear copper(i) triphenylphosphine complexes with functionalized 3-(2'-pyrimidinyl)-1,2,4-triazole ligands have been synthesized and characterized, in which functionalized 3-(2'-pyrimidinyl)-1,2,4-triazole adopts neutral mono- and bis-chelating coordination modes and a mono-anionic bis-chelating binding manner due to the 1,2,4-triazolyl-NH deprotonation. All these Cu(i) complexes display a relatively weak low-energy absorption in a CH2Cl2 solution, ascribed to the charge-transfer transitions with appreciable MLCT character, as suggested by TD-DFT analyses. These Cu(i) complexes are all emissive in solution and in the solid state at ambient temperature, and their luminescence properties can be well modulated via the addition of the second {Cu(PPh3)2} unit and modification of 3-(2'-pyrimidinyl)-1,2,4-triazole involving the N-H deprotonation and the substituent variation of the 1,2,4-triazolyl ring. It is also demonstrated that introducing the trifluoromethyl group into the 1,2,4-triazolyl ring is helpful for enhancing the solid-state luminescence properties of the 1,2,4-triazole-based Cu(i) complexes, whereas the introduction of the tert-butyl group into the 1,2,4-triazolyl ring, the 1,2,4-triazolyl-NH deprotonation, and the use of the pyrimidinyl ring instead of the pyridyl ring are all unfavorable.


Mapping of Drug-like Chemical Universe with Reduced Complexity Molecular Frameworks.
The emergence of the DNA-encoded chemical libraries (DEL) field in the past decade has attracted the attention of the pharmaceutical industry as a powerful mechanism for the discovery of novel drug-like hits for various biological targets. Nuevolution Chemetics technology enables DNA-encoded synthesis of billions of chemically diverse drug-like small molecule compounds, and the efficient screening and optimization of these, facilitating effective identification of drug candidates at an unprecedented speed and scale. Although many approaches have been developed by the cheminformatics community for the analysis and visualization of drug-like chemical space, most of them are restricted to the analysis of a maximum of a few millions of compounds and cannot handle collections of 108-1012 compounds typical for DELs. To address this big chemical data challenge, we developed the Reduced Complexity Molecular Frameworks (RCMF) methodology as an abstract and very general way of representing chemical structures. By further introducing RCMF descriptors, we constructed a global framework map of drug-like chemical space and demonstrated how chemical space occupied by multi-million-member drug-like Chemetics DNA-encoded libraries and virtual combinatorial libraries with >1012 members could be analyzed and mapped without a need for library enumeration. We further validate the approach by performing RCMF-based searches in a drug-like chemical universe and mapping Chemetics library selection outputs for LSD1 targets on a global framework chemical space map.


Efficacy of home-based lymphoedema management in reducing acute attacks in subjects with lymphatic filariasis in Burkina Faso.
One of the two main goals of the Global Programme to Eliminate Lymphatic Filariasis (LF) is to provide care for those suffering from the devastating clinical manifestations of this filarial infection. Among the 120 million infected people worldwide, up to 16 million have lymphoedema. The WHO strategy for managing lymphoedema is based on rigorous skin hygiene, exercise, antibiotics and antifungals when indicated. The aim is to reduce acute attacks of adenolymphangitis and cellulitis responsible for lymphoedema progression and disability. The objective of our study was to assess the effectiveness of home-based lymphoedema management implemented by the national health system of Burkina Faso. Any patient was eligible to participate in the study if suffering from LF-related lymphoedema of a lower limb at any stage, and receiving care as part of the health education and washing project between April 2005 and December 2007. The primary readout was the occurrence of an acute attack in the month preceding the consultation reported by the patient or observed by the care-giver. In all, 1089 patients were enrolled in the study. Before lymphoedema management intervention, 78.1% (95%CI: 75.5-80.5) of the patients had an acute attack in the month preceding the consultation; after four and half months of lymphoedema management, this was reduced to 39.1% (95%CI: 36.2-42.1). A reduction of acute attacks related to the number of consultations or related to the patients' age and gender was not observed. Our results suggest that the home-based lymphoedema management programme in the primary health care system of Burkina Faso is effective in reducing morbidity due to LF in the short-term (4.5 months). The lymphoedema management requires no additional human resources, but whether its effect can be sustained remains to be seen.


Classification of High-Grade Glioma into Tumor and Nontumor Components Using Support Vector Machine.
Current imaging assessment of high-grade brain tumors relies on the Response Assessment in Neuro-Oncology criteria, which measure gross volume of enhancing and nonenhancing lesions from conventional MRI sequences. These assessments may fail to reliably distinguish tumor and nontumor. This study aimed to classify enhancing and nonenhancing lesion areas into tumor-versus-nontumor components. A total of 140 MRI scans obtained from 32 patients with high-grade gliomas and 6 patients with brain metastases were included. Classification of lesion areas was performed using a support vector machine classifier trained on 4 components: enhancing and nonenhancing, tumor and nontumor, based on T1-weighted, FLAIR, and dynamic-contrast-enhancing MRI parameters. Classification results were evaluated by 2-fold cross-validation analysis of the training set and MR spectroscopy. Longitudinal changes of the component volumes were compared with Response Assessment in Neuro-Oncology criteria. Normalized T1-weighted values, FLAIR, plasma volume, volume transfer constant, and bolus-arrival-time parameters differentiated components. High sensitivity and specificity (100%) were obtained within the enhancing and nonenhancing areas. Longitudinal changes in component volumes correlated with the Response Assessment in Neuro-Oncology criteria in 27 patients; 5 patients (16%) demonstrated an increase in tumor component volumes indicating tumor progression. These changes preceded Response Assessment in Neuro-Oncology assessments by several months. Seven patients treated with bevacizumab showed a shift to an infiltrative pattern of progression. This study proposes an automatic classification method: segmented Response Assessment in Neuro-Oncology criteria based on advanced imaging that reliably differentiates tumor and nontumor components in high-grade gliomas. The segmented Response Assessment in Neuro-Oncology criteria may improve therapy-response assessment and provide earlier indication of progression.


[Dengue outbreak in Buenos Aires, Argentina, 2016: Clinical and hematological features in children].
Dengue is the human arbovirus with the highest morbidity and mortality in the world. The largest outbreak of dengue in Buenos Aires, Argentina, occurred during 2016. To describe clinical and hematological features in children with confirmed dengue infection. Cross sectional study that included children attended since January 18th to April 15th 2016 at Hospital de Niños "Dr. Ricardo Gutiérrez". among 156 registered cases, 82 confirmed cases by virology test; 130 (83 %) autochthonous cases. The most frequent clinical manifestations were fever, headache and retro-ocular pain. Laboratory abnormalities were leukopenia, thrombocytopenia and increased liver enzymes. Thirty-five children were hospitalized (23 %), 25 (16 %) with warning signs. In our study, no cases of severe dengue occurred. early recognition of warning signs and hematological monitoring is essential in order to detect patients at risk and offer them adequate early treatment.


Stable chromosome aberration frequencies in men occupationally exposed to radiation.
The introduction of fluorescence in situ hybridisation techniques to cytogenetic biodosimetry has enabled the detection of stable aberrations, e.g. translocations, which can provide an integrated measure of radiation exposure. The opportunity to study stable aberration frequencies in lymphocyte cultures from occupationally exposed workers with well-documented dosimetry records enables the establishment of dose-response relationships which can be compared with those obtained from studies of populations with high acute exposures. Since there is good mechanistic evidence for the role of translocations in oncogenesis, this provides an insight into the risks associated with low-dose exposure for which no direct epidemiological evidence is available. This paper provides preliminary data on a group of 98 individuals with cumulative occupational doses > 500 mSv and 96 controls with doses < 50 mSv. An increased frequency of translocations was found for the high-dose group (20.50 +/- 0.78 x 10(-3) per genome equivalent) in comparison with the control group (11.71 +/- 0.59 x 10(-3) per genome equivalent). Further analysis of the control group revealed increasing frequencies of translocations with increasing age. An increase associated with ever-smoking status was found for the control group which appeared to be driven by the lower age groups but no overall effect of smoking was seen in the > 500 mSv group.


Overweight and obesity in preschool children in Turkey: A multilevel analysis.
Childhood obesity/overweight is a worldwide concern and its prevalence is increasing in many countries. The first aim of this study is to analyse the trends in overweight and obesity among children under the age of five in Turkey based on the new World Health Organization (WHO) standards, using data from the 'five-round of the Turkey Demographic and Health Surveys' (TDHSs). The second aim is to examine whether or not the maternal/household and individual-level factors are associated with overweight/obesity using TDHS 2003, 2008, and 2013 datasets. A total sample of 14,231 children under the age of five were extracted from the TDHS in 1993, 1998, 2003, 2008, and 2013 to determine the prevalence of the trend. Pooled data from 8,812 children were included in the analysis to examine factors associated with overweight/obesity. Taking into account the clustered data structure, multilevel logistic regression models were utilised. In 1993, 1998, 2003, 2008, and 2013 the prevalence of overweight children was 5.3%, 4.9%, 10.0%, 11% and 11.6%, respectively. The factors that were independently associated with overweight/obesity were as follows: living in single-parent households (adjusted odds ratio (aOR) = 2.27, 95%CI = 1.21-4.26), compared to living in dual-parent households; having an obese mother (aOR = 4.25, 95%CI = 1.73-10.44), overweight mother (aOR = 3.15, 95%CI = 1.29-7.69), and a normal-weight mother (aOR = 2.70, 95%CI = 1.11-6.59) compared to having an underweight mother; being aged between 13-24 months (aOR = 1.72, 95%CI = 1.30 to 2.27), compared to being aged 0-12 months; male gender (aOR = 1.30, 95%CI = 1.11 to 1.53); being stunted (aOR = 2.18, 95%CI = 1.74 to 2.73); high birth weight (aOR = 1.55, 95%CI = 1.08 to 2.23) compared to low birth weight. In addition, overweight was higher in children of mothers who had completed primary school (aOR = 1.21, 95%CI = 1.01 to 1.59) than children of mothers who had not completed primary school. These findings reveal that, over the years, there has been a substantial increase in obesity/overweight among children which demonstrates the importance of evaluating the overweight indicators at the maternal/household level.


Overt Thyroid Dysfunction and Anti-Thyroid Antibodies Predict Response to Anti-PD-1 Immunotherapy in Cancer Patients.
Background: Thyroid dysfunction is among the most common adverse effects during anti-programmed cell death 1 (PD-1) immunotherapy, and alongside correlations with elevated anti-thyroid antibodies (ATAb), studies have found correlations with survival. However, the exact relations remain to be clarified. We, therefore, aimed at clarifying the relationship between thyroid dysfunction, ATAbs, and survival in anti-PD-1 treated cancer patients. Methods: We included 168 patients with nonsmall-cell lung carcinoma, renal cell carcinoma, and metastatic melanoma treated with nivolumab or pembrolizumab. Thyrotropin and free T4 (fT4) levels were measured before each anti-PD-1 infusion. ATAb levels (anti-thyroid peroxidase [TPO] and anti-thyroglobulin [Tg]) were measured at baseline and after two months of treatment. Although the vast majority of patients had detectable levels of ATABs, only a few patients had positive ATAbs when using conventional cut-offs. To study the consequences of detectable ATABs, the cut-off levels were a priori set at the median concentrations at baseline in the study population. Tumor progression was classified according to RECIST v1.1. Results: Patients who acquired overt thyroid dysfunction during treatment had significantly higher overall survival (OS) (hazard ratio [HR] = 0.18 confidence interval [CI: 0.04-0.76]; p = 0.020) and progression-free survival (PFS) (HR = 0.39 [0.15-0.998]; p = 0.050) than patients without thyroid dysfunction with 1-year OS rates of 94% vs. 59% and 1-year PFS rates of 64% vs. 34%. During treatment, patients with ATAb levels above the median had a higher OS (HR = 0.39 [0.21-0.72]; p = 0.003) and PFS (HR = 0.52 [0.33-0.81]; p = 0.004) than patients with ATAb levels below the median, with 1-year OS rates of 83% vs. 49% and PFS rates of 54% vs. 20%, respectively. When analyzing ATAb levels over time, patients with a persistent ATAb level above the median had a higher OS (HR = 0.41 [0.19-0.89], p = 0.025) and PFS (HR = 0.54 [0.31-0.95], p = 0.032) compared with patients with a persistent ATAb level below the median. Patients whose ATAb levels increased above the median during treatment had an improved OS (HR = 0.27 [0.06-1.22], p = 0.088) and PFS (HR = 0.24 [0.07-0.77], p = 0.017) compared with patients whose ATAb levels decreased below the median. Conclusions: Acquired overt thyroid toxicity and above median ATAb levels during anti-PD-1 treatment are associated with improved PFS and OS. In addition, our results suggest that ATAb levels at baseline are of clinical relevance for PFS and OS.


Genetic control of melatonin synthesis in the pineal gland of the mouse.
Pineal melatonin may play an important role in regulation of vertebrate circadian rhythms and in human affective disorders. In some mammals, such as hamsters and sheep, melatonin is involved in photoperiodic time measurement and in control of reproduction. Although wild mice (Mus domesticus) and some wild-derived inbred strains of mice have melatonin in their pineal glands, several inbred strains of laboratory mice (for example, C57BL/6J) were found not to have detectable melatonin in their pineal glands. Genetic analysis suggests that melatonin deficiency in C57BL/6J mice results from mutations in two independently segregating, autosomal recessive genes. Synthesis of melatonin from serotonin in the pineal gland requires the enzymes N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT). Pineal glands from C57BL/6J mice have neither NAT nor HIOMT activity. These results suggest that the two genes involved in melatonin deficiency are responsible for the absence of normal NAT and HIOMT enzyme activity.