The effect of monocyte chemoattractant protein-1/CC chemokine ligand 2 on aqueous humor outflow facility.
To investigate the effect of monocyte chemoattractant protein-1 (MCP-1)/CC chemokine ligand 2 on aqueous humor outflow facility. Aqueous humor outflow facility was measured in enucleated porcine eyes in a constant pressure perfusion system with or without MCP-1 (1600 ng/mL). Expression of CCR2, an MCP-1 receptor, in Schlemm's canal endothelial (SCE) cells was examined by reverse transcription-polymerase chain reaction (RT-PCR) assay. The effect of MCP-1 (0-1600 ng/mL) on SCE cell viability was evaluated using a WST-8 assay. The effect of MCP-1 (0-800 ng/mL) on SCE-cell monolayer permeability was evaluated with or without a CCR2 antagonist (10 nM) by measuring transendothelial electrical resistance (TEER). The intracellular localization of the gap junction protein ZO-1 was analyzed by immunofluorescence staining of SCE cells. The aqueous humor outflow facility increased significantly from basal levels at 80 minutes after perfusion with MCP-1 compared with control eyes (21.2% ± 6.6% [MCP-1] vs. 5.7 ± 2.5% [control]; P = 0.048). CCR2 was detected by RT-PCR. Cell viability was not affected by MCP-1 treatment. TEER of SCE-cell monolayer at 3 hours after treatment with 800 ng/mL MCP-1 decreased by 21.6 ± 1.7% compared with controls (P = 0.014), and the TEER-decreasing effects of MCP-1 were attenuated by a CCR2 antagonist. Immunocytochemical staining revealed a modest disruption of ZO-1 in MCP-1-treated SCE cells. The present results revealed that MCP-1 increased aqueous humor outflow facility and decreased TEER via CCR2. These findings suggest that MCP-1 modulates aqueous humor outflow through the conventional pathway.


DNA-protein cross-links in different organs of mice induced by the combined action of zinc and gamma-irradiation.
Fractional whole-body gamma-irradiation of mice at total doses of 0. 5-1.5 Gy induces increased DNA-protein cross-links (DPCs) in thymus, spleen, and brain, whereas in liver no DPCs are detected. Chronic administration of zinc ions in drinking water at concentration 10 mg/liter for 20-30 days increased DPCs in thymus, spleen, brain, and liver of mice. The combined action of zinc ions and gamma-radiation produced a significantly lower amount of DPCs than was induced by the separate action of these agents.


Bias in self-reported parasite data from the salmon farming industry.
Many industries are required to monitor themselves in meeting regulatory policies intended to protect the environment. Self-reporting of environmental performance can place the cost of monitoring on companies rather than taxpayers, but there are obvious risks of bias, often addressed through external audits or inspections. Surprisingly, there have been relatively few empirical analyses of bias in industry self-reported data. Here, we test for bias in reporting of environmental compliance data using a unique data set from Canadian salmon farms, where companies monitor the number of parasitic sea lice on fish in open sea pens, in order to minimize impacts on wild fish in surrounding waters. We fit a hierarchical population-dynamics model to these sea-louse count data using a Bayesian approach. We found that the industry's monthly counts of two sea-louse species, Caligus clemensi and Lepeophtheirus salmonis, increased by a factor of 1.95 (95% credible interval: 1.57, 2.42) and 1.18 (1.06, 1.31), respectively, in months when counts were audited by the federal fisheries department. Consequently, industry sea-louse counts are less likely to trigger costly but mandated delousing treatments intended to avoid sea-louse epidemics in wild juvenile salmon. These results highlight the potential for combining external audits of industry self-reported data with analyses of their reporting to maintain compliance with regulations, achieve intended conservation goals, and build public confidence in the process.


Genetic and molecular analysis of a simple disjunctional system in Drosophila melanogaster.
The basic aspects of the achiasmate distributive segregation system in Drosophila are briefly reviewed. Specific attention is given to the role of homology in specifying the patterns of distributive segregation. The genetic and molecular analysis of mutations affecting the system is also discussed. Finally, a consideration of the available evidence allows the presentation of a revised model of meiosis in Drosophila.


Aromatherapy benefits autonomic nervous system regulation for elementary school faculty in taiwan.
Workplace stress-related illness is a serious issue, and consequently many stress reduction methods have been investigated. Aromatherapy is especially for populations that work under high stress. Elementary school teachers are a high-stress working population in Taiwan. In this study, fifty-four elementary school teachers were recruited to evaluate aromatherapy performance on stress reduction. Bergamot essential oil was used for aromatherapy spray for 10 minutes. Blood pressure and autonomic nervous system parameters were recorded 5 minutes before and after the application of the aroma spray. Results showed that there were significant decreases in blood pressure, heart rate, LF power percentage, and LF/HF while there were increases in heart rate variability and HF power percentage (P < .001(∗∗∗)) after application of the aromatherapy spray. Further analysis was investigated by dividing subjects into three background variables (position variables, age variables, gender variables) and anxiety degree groups. All parameters were significantly different for most subgroups, except for the substitute teachers and the light-anxiety group. Parasympathetic nervous system activation was measured after aromatherapy in this study. It encouraged further study for other stress working population by aromatherapy.


Modified cytoplasmic Ca2+ sequestration contributes to spinal cord injury-induced augmentation of nerve-evoked contractions in the rat tail artery.
In rat tail artery (RTA), spinal cord injury (SCI) increases nerve-evoked contractions and the contribution of L-type Ca2+ channels to these responses. In RTAs from unoperated rats, these channels play a minor role in contractions and Bay K8644 (L-type channel agonist) mimics the effects of SCI. Here we investigated the mechanisms underlying the facilitatory actions of SCI and Bay K8644 on nerve-evoked contractions of RTAs and the hypothesis that Ca2+ entering via L-type Ca2+ channels is rapidly sequestered by the sarcoplasmic reticulum (SR) limiting its role in contraction. In situ electrochemical detection of noradrenaline was used to assess if Bay K8644 increased noradrenaline release. Perforated patch recordings were used to assess if SCI changed the Ca2+ current recorded in RTA myocytes. Wire myography was used to assess if SCI modified the effects of Bay K8644 and of interrupting SR Ca2+ uptake on nerve-evoked contractions. Bay K8644 did not change noradrenaline-induced oxidation currents. Neither the size nor gating of Ca2+ currents differed between myocytes from sham-operated (control) and SCI rats. Bay K8644 increased nerve-evoked contractions in RTAs from both control and SCI rats, but the magnitude of this effect was reduced by SCI. By contrast, depleting SR Ca2+ stores with ryanodine or cyclopiazonic acid selectively increased nerve-evoked contractions in control RTAs. Cyclopiazonic acid also selectively increased the blockade of these responses by nifedipine (L-type channel blocker) in control RTAs, whereas ryanodine increased the blockade produced by nifedipine in both groups of RTAs. These findings suggest that Ca2+ entering via L-type channels is normally rapidly sequestered limiting its access to the contractile mechanism. Furthermore, the findings suggest SCI reduces the role of this mechanism.


5-Hydroxytryptamine selectively activates the vagal nodose C-fibre subtype in the guinea-pig oesophagus.
The afferent neurons innervating the oesophagus originate from two embryonic sources: neurons located in vagal nodose ganglia originate from embryonic placodes and neurons located in vagal jugular and spinal dorsal root ganglia (DRG) originate from the neural crest. Here, we address the hypothesis that 5-hydroxytryptamine (5-HT) differentially stimulates afferent nerve subtypes in the oesophagus. Extracellular recordings of single unit activity originating from nerve terminals were made in the isolated innervated guinea-pig oesophagus. Whole cell patch clamp recordings (35 degrees C) were made from the primary afferent neurons retrogradely labelled from the oesophagus. 5-Hydroxytryptamine (10 micromol L(-1)) activated vagal nodose C-fibres (70%) in the oesophagus but failed to activate overtly vagal jugular nerve fibres and oesophagus-specific spinal DRG neurons. The response to 5-HT in nodose C-fibre nerve terminals was mimicked by the selective 5-HT(3) receptor agonist 2-methyl-5-HT (10 micromol L(-1)) and nearly abolished by the 5-HT(3) receptor antagonists ondansetron (10 micromol L(-1)) and Y-25130 (10 micromol L(-1)). In patch clamp studies, 2-methyl-5-HT (10 micromol L(-1)) activated a proportion of isolated oesophagus-specific nodose capsaicin-sensitive neurons (putative cell bodies of nodose C-fibres). We conclude that the responsiveness to 5-HT discriminates placode-derived (vagal nodose) C-fibres from the neural crest-derived (vagal jugular and spinal DRG) afferent nerves in the oesophagus. The response to 5-HT in nodose C-fibres is mediated by the 5-HT(3) receptor in their neuronal membrane.


Navigating a set of discrete regions in body position space.
This paper defines a mathematical object that expresses physiological aspects of motor control, besides physical aspects. Based on observations in human development and rehabilitation, this paper lays a foundation for unifying discrete with continuous aspects of motor control. Discreteness in motor control arises from the fact that movements are planned by the organism, based on movement limits set by the organism, the task, and the environment, rather than following simply from physical laws. This paper defines two relations, an ordering and a contiguity relation, between discrete regions of joint space crossed with physical space, to make a d-space. Within the d-space, a particular body and physical position is represented by a completely ordered set, a coincidence. A trajectory through a continuous space is represented by a coincidence sequence. Examples are drawn mostly from human locomotion, with particular interest in balance. Only in certain regions of body and physical position space can a body maintain balance, for example, a standing human. Slow steps proceed from one balanced region to another. A poset (partially ordered set) of sets of steps and its relationship to a person's balance regions can be used in the study of development or rehabilitation.


Affective startle modulation in anticipation and perception.
Startle modulation was investigated as participants first anticipated and then viewed affective pictures in order to determine whether affective modulation of the startle reflex is similar in these different task contexts. During a 6-s anticipation period, a neutral light cue signaled whether the upcoming picture would portray snakes, erotica, or household objects; at the end of the anticipatory period, a picture in the signaled category was viewed for 6 s. Male participants highly fearful of snakes were recruited to maximize emotional arousal during anticipation and perception. Results indicated that the startle reflex was potentiated when anticipating either unpleasant (phobic) or pleasant (erotic) pictures, compared to neutral stimuli, whereas during perception, reflexes were potentiated when viewing unpleasant stimuli, and reduced when viewing pleasant pictures. The startle reflex is modulated by hedonic valence in picture perception, and by emotional arousal in a task context involving picture anticipation.


The effects of dynein inhibition on the autophagic pathway in glioma cells.
Autophagy has multiple physiological functions, including protein degradation, organelle turnover and the response of cancer cells to chemotherapy. Because autophagy is implicated in a number of diseases, a better understanding of the molecular mechanisms of autophagy is needed for therapeutic purposes, including rational design of drugs. Autophagy is a process that occurs in several steps as follows: formation of phagophores, formation of mature autophagosomes, targeting and trafficking of autophagosomes to lysosomes, formation of autolysosomes by fusion between autophagosomes and lysosomes, and finally, degradation of the autophagic bodies within the lysosomes. It has been suggested that autophagosome formation is driven by molecular motor machineries, and, once formed, autophagosomes need to reach lysosomes, enriched perinuclearly around the microtubule-organizing centre. While it is recognized that all these steps require the cytoskeletal network, little is known about the mechanisms involved. Here we assessed the role of cytoplasmic dynein in the autophagic process of human glioma cells to determine the part played by dynein in autophagy. We observed that chemical interference with dynein function led to an accumulation of autophagosomes, suggesting impaired autophagosome-lysosome fusion. In contrast, we found that overexpression of dynamitin, which disrupts the dynein complex, reduced the number of autophagosomes, suggesting the requirement of the dynein-dynactin interaction in the early membrane trafficking step in autophagosome formation. These results suggest that dynein plays a variety of crucial roles during the autophagic process in glioma cells.


Extracorporeal Shock Wave Therapy Provides Limited Therapeutic Effects on Carpal Tunnel Syndrome: A Systematic Review and Meta-Analysis.
Night wrist splinting has been a conservative treatment for carpal tunnel syndrome. The addition of extracorporeal shock wave therapy provides an alternative treatment. However, strong evidence on the clinical effectiveness of extracorporeal shock wave therapy for carpal tunnel syndrome is still lacking. This study aimed to investigate the effectiveness and safety of extracorporeal shock wave therapy compared with treatments of night wrist splints alone for patients with carpal tunnel syndrome. In this systematic review and meta-analysis, no limitation criteria were used for study selection. All available articles that compare the effectiveness between extracorporeal shock wave therapy combined with night wrist splint and night wrist splint alone for treating carpal tunnel syndrome published up to 20 January 2022 were identified from the databases of PubMed, Embase, and Cochrane Central Register of Controlled Trials Central. The primary outcomes were a standard mean difference with a 95% confidence interval on the improvement of symptom severity and functional impairment between the two groups. In an attempt to analyze trends over time in studies that report repeated measurements, an all time-points meta-analysis (ATM) was undertaken. Seven randomized controlled trials with a total of 376 participants were included in this study. Significant improvements in functional impairment and symptom remission were only observed in the extracorporeal shock wave group at four weeks post-treatment. Extracorporeal shock wave therapy did not demonstrate superior efficacy compared to treatment with night wrist splint alone at 8-10 and 12-14 weeks post-treatment, or through the ATM approach. In conclusion, the therapeutic effect of extracorporeal shock wave therapy is transient and mostly nonsignificant compared with using night wrist splint alone. No serious side effects were reported in all included studies. Other conservative treatments to ameliorate carpal tunnel syndrome symptoms are warranted.


Sensitivity of proximal femoral stiffness and areal bone mineral density to changes in bone geometry and density.
Areal bone mineral density (aBMD) is the most common surrogate measurement for assessing the bone strength of the proximal femur associated with osteoporosis. Additional factors, however, contribute to the overall strength of the proximal femur, primarily the anatomical geometry. Finite element analysis (FEA) is an effective and widely used computer-based simulation technique for modelling mechanical loading of various engineering structures, providing predictions of displacement and induced stress distribution due to the applied load. FEA is therefore inherently dependent upon both density and anatomical geometry. FEA may be performed on both three-dimensional and two-dimensional models of the proximal femur derived from radiographic images, from which the mechanical stiffness may be predicted. It is examined whether the outcome measures of two-dimensional FEA, two-dimensional, finite element analysis of X-ray images (FEXI), and three-dimensional FEA computed stiffness values of the proximal femur are more sensitive than aBMD to changes in trabecular bone density and femur geometry. It is assumed that if an outcome measure follows known trends with changes in density and geometric parameters, then an increased sensitivity will be indicative of an improved prediction of bone strength. All three outcome measures increased non-linearly with trabecular bone density, increased linearly with cortical shell thickness and neck width, decreased linearly with neck length, and were relatively insensitive to neck-shaft angle. For femoral head radius, aBMD was relatively insensitive, with two-dimensional FEXI and three-dimensional FEA demonstrating a non-linear increase and decrease in sensitivity respectively. For neck anteversion, aBMD decreased non-linearly, whereas both two-dimensional FEXI and three-dimensional FEA demonstrated a parabolic-type relationship, with the maximum stiffness being achieved at an angle of approximately 15 degrees. Multi-parameter analysis showed that all three outcome measures demonstrated their highest sensitivity to a change in cortical thickness. When changes in all input parameters were considered simultaneously, three and two-dimensional FEA had statistically equal sensitivities (0.41 +/- 0.20 and 0.42 +/- 0.16 respectively, p = ns) that were significantly higher than the sensitivity of aBMD (0.24 +/- 0.07; p = 0.014 and 0.002 for three-dimensional and two-dimensional FEA respectively). This simulation study suggests that since mechanical integrity and FEA are inherently dependent on anatomical geometry, FEXI stiffness, being derived from conventional two-dimensional radiographic images, may provide an improvement in the prediction of bone strength of the proximal femur than currently provided by aBMD.


Infrared spectroscopy depth profiling of organic thin films.
Organic thin films are widely used in organic electronics and coatings. Such films often feature film-depth dependent variations of composition and optoelectronic properties. State-of-the-art depth profiling methods such as mass spectroscopy and photoelectron spectroscopy rely on non-intrinsic species (vaporized ions, etching-induced surface defects), which are chemically and functionally different from the original materials. Here we introduce an easily-accessible and generally applicable depth profiling method: film-depth-dependent infrared (FDD-IR) spectroscopy profilometry based on directly measuring the intrinsic material after incremental surface-selective etching by a soft plasma, to study the material variations along the surface-normal direction. This depth profiling uses characteristic vibrational signatures of the involved compounds, and can be used for both conjugated and non-conjugated, neutral and ionic materials. A film-depth resolution of one nanometer is achieved. We demonstrate the application of this method for investigation of device-relevant thin films, including organic field-effect transistors and organic photovoltaic cells, as well as ionized dopant distributions in doped semiconductors.


Geochemical carbon dioxide removal potential of Spain.
Many countries have made pledges to reduce CO2 emissions over the upcoming decades to meet the Paris Agreement targets of limiting warming to no >1.5 °C, aiming for net zero by mid-century. To achieve national reduction targets, there is a further need for CO2 removal (CDR) approaches on a scale of millions of tonnes, necessitating a better understanding of feasible methods. One approach that is gaining attention is geochemical CDR, encompassing (1) in-situ injection of CO2-rich gases into Ca and Mg-rich rocks for geological storage by mineral carbonation, (2) ex-situ ocean alkalinity enhancement, enhanced weathering and mineral carbonation of alkaline-rich materials, and (3) electrochemical separation processes. In this context, Spain may host a notionally high geochemical CDR capacity thanks to its varied geological setting, including extensive mafic-ultramafic and carbonate rocks. However, pilot schemes and large-scale strategies for CDR implementation are presently absent in-country, partly due to gaps in current knowledge and lack of attention paid by regulatory bodies. Here, we identify possible materials, localities and avenues for future geochemical CDR research and implementation strategies within Spain. This study highlights the kilotonne to million tonne scale CDR options for Spain over the rest of the century, with attention paid to chemically and mineralogically appropriate materials, suitable implementation sites and potential strategies that could be followed. Mafic, ultramafic and carbonate rocks, mine tailings, fly ashes, slag by-products, desalination brines and ceramic wastes hosted and produced in Spain are of key interest, with industrial, agricultural and coastal areas providing opportunities to launch pilot schemes. Though there are obstacles to reaching the maximum CDR potential, this study helps to identify focused targets that will facilitate overcoming such barriers. The CDR potential of Spain warrants dedicated investigations to achieve the highest possible CDR to make valuable contributions to national reduction targets.


[Speciation and bioavailability of heavy metals in paddy soil irrigated by acid mine drainage].
Based on field investigation and laboratory analysis, the speciation and bioavailability of the heavy metals (Cd, Cu, Pb, and Zn) was studied. These metals were tested from 16 soil samples taken from paddy soils irrigated by acid mine drainage in the lower stream of Dabaoshan mine area, Guangdong Province, China. The toxicity characteristic leaching procedure (TCLP) and three-step community bureau of reference (BCR) sequential extraction procedure methods were used to analyse the bioavailability of heavy metals. TCLP is currently recognized as an international method for evaluation of heavy metal pollution in soils. Two methods were compared in bioavailability by stepwise multiple linear regression analysis. Cd was dominated mainly by the acid-extractable and residual fractions, and followed by the order of acid-extractable > residual > oxidisable > reducible. Cu was dominated mainly by the residual fraction, and decreased in the following order: residual > reducible > acid-extractable > oxidisable. Pb was dominantly released in the reducible and residual fractions, they account for 86.54% of the total contents, and decreased in the following order: reducible > residual > acid-extractable > oxidisable. Zn was dominated mainly by the residual fraction, it takes more than 50% of the total contents, and followed by the order of residual > acid-extractable > reducible > oxidisable. The levels of Cd, Cu, Pb and Zn extracted by TCLP were 0.17-0.89, 8.12-70.33, 3.16-90.33 and 10.24-106.85 mg x kg(-1), respectively, and the average concentrations of Cd, Cu, Pb and Zn were 0.41, 36.60, 15.97 and 50.78 mg x kg(-1), respectively. The concentrations of Cd, Cu, Ph and Zn in rice seeds were 0.183-0.947, 3.542-5.997, 0.285-1.532 and 17.54-41.10 mg x kg(-1), respectively. Comparing to the national standards on heavy metals in foods by the Chinese Ministry of Health, the contents of Cu and Zn in rice seeds didn't exceed the upper limit, while the contents of Cd and Pb in rice seeds exceed the upper limit by 87.50% and 81.25%, respectively. Results of the stepwise multiple linear regression analysis revealed that contents of Cd and Zn in seeds of rice were significantly influenced by contents of acid-extractable Cd and Zn, that contents of Cu in seeds of rice were significantly influenced by contents of acid-extractable and oxidisable Cu, and the contents of Pb in seeds of rice were significantly influenced by contents of reducible Pb and organic matter. Contents of four metals in seeds of rice were significantly influenced by contents of metals extracted by TCLP, and the influences of total content, pH and organic matter were not significant. In short, TCLP method was fast, simple and suitable for evaluation of bioavailability of heavy metals in sewage-irrigated paddy soils by acid mine drainage.


Renal artery Doppler compared with the cerebral placental ratio to identify fetuses at risk for adverse neonatal outcome.
Background: Current clinical practice incorporates an umbilical artery resistance index or a ratio of the middle cerebral artery (MCA PI) to the umbilical artery pulsatility index (UA PI) known as the cerebral placental ratio (CPR) to assess wellbeing in the small for gestational age fetus. Previous reports using the renal artery Doppler indices have not been consistent in regards to their design and clinical use. Our objective is to develop reference values for renal artery Doppler indices and validate their use compared with the UA PI or CPR to identify fetuses that will develop a composite neonatal outcome.Methods: We performed 9700 ultrasounds among 2852 women at 20-40 weeks of gestation at the University of Maryland between 1 June 2016 and 1 December 2016. Nomograms were first developed using one randomly selected scan from each of a subgroup of 860 women without any comorbidities. The nomograms were validated among a cohort of 550 women who subsequently delivered at the University of Maryland Medical Center. We compared the area under the receiver operating characteristic curve (AUROC) between the CPR and UA PI, and the renal artery Doppler parameters (renal artery pulsatility index (RA PI), systolic diastolic ratio (RA SDR), and peak systolic velocity (RA PSV)). The primary outcome was the development any one of the composite neonatal outcome components (death, intensive care unit admission, ventilator for more than 6 h, hypoxic ischemic encephalopathy or necrotizing enterocolitis) or admission to the neonatal intensive care unit (NICU) for any indication.Results: The renal artery Doppler indices did not improve identification of fetuses that would subsequently develop one of the components of the composite neonatal outcome (AUROC for CPR 0.54, 95% CI (0.49-0.59), versus the UA PI: 0.59 (0.54-0.64) p = .07, the RA PI: 0.51 (0.48-0.55) p = .41, RA SDR 0.54 (0.49-0.58) p = .99, or RA PSV 0.51 (0.47-0.55) p = .37). There was no difference when comparing AUROC to detect NICU admission (AUROC for CPR 0.53, 95% CI (0.49-0.58), versus the UA PI: 0.57 (0.52-0.62) p = .14, the RA PI: 0.50 (0.47-0.54) p = .44, RA SDR: 0.54 (0.50-0.59) p = .62 or RAPSV: 0.51 (0.47-0.55) p = .54).Conclusion: The renal artery indices do not improve detection of fetuses at risk for adverse neonatal outcomes compared with the CPR or the UA PI.


Legionella infection.
As specialized laboratory tests became more widely available, Legionella species were found to be common causes of nosocomial and community-acquired pneumonia. Patients with chronic lung disease and organ transplants are at greatest risk. Clinical manifestations are non-specific, although fever greater than 39 degrees C and diarrhea are common. Erythromycin remains the antibiotic of choice, although many alternative agents are available. Once cases are discovered, a search for the organism in water distribution systems and respiratory equipment can be fruitful. Disinfection of water distribution systems by superheating and flushing or by hyperchlorination is feasible.


Diagnostic evaluation, monitoring, and perioperative management of spinal cord compression in patients with Morquio syndrome.
Mucopolysaccharidosis IVA is an autosomal recessive condition caused by mutations in the GALNS gene, which encodes N-acetylgalactosamine-6-sulfatase, also called galactosamine-6-sulfatase (GALNS). A reduction in or absence of effective GALNS leads to faulty catabolism of keratan sulfate and chondroitin-6-sulfate within the lysosome; their accumulation causes cell, tissue, and organ dysfunction. The connective tissue, cartilage, ligaments, and bone of patients with Morquio A syndrome are particularly affected. Patients with Morquio A syndrome are at high risk of neurological complications because of their skeletal abnormalities; many patients are in danger of cervical myelopathy due to odontoid hypoplasia and ligamentous laxity leading to atlantoaxial subluxation. The multisystemic involvement of patients with Morquio A syndrome requires treatment by multidisciplinary teams; not all members of these teams may be aware of the potential for subluxation and quadriparesis. A multinational, multidisciplinary panel of 10 skeletal dysplasia or Morquio A syndrome specialists convened in Miami, FL on December 7 and 8, 2012 to develop consensus recommendations for early identification and effective management of spinal cord compression, for anesthesia and surgical best practices, and for effectual cardiac and respiratory management in patients with Morquio A syndrome. The target audience for these recommendations includes any physician who may encounter a patient with Morquio A syndrome, however doctors who do not have access to the full spectrum of specialists and resources needed to support patients with Morquio A syndrome should attempt to refer patients to a center that does. Physicians who manage Morquio A syndrome or comorbid conditions within specialty centers should review these expert panel recommendations and fully understand the implications of spinal cord instability for their own practices.


The Triple Step in Recreational Swing Dancers: A Kinematic Analysis.
Swing dancing is gaining popularity, yet our biomechanical understanding of swing dance remains poor, creating barriers to the development of training protocols and evaluation of performances. This study aimed to determine whether dancing with or without a partner affects the lower extremity kinematics of the triple step, and if the kinematics differ among the three steps of the dance element. Eight recreational swing dancers completed three sets of rightward triple steps with and without a partner. The angles in the sagittal, frontal and transverse planes were determined for bilateral lower limb joints and pelvis based on the kinematics collected by a motion capture system. Results illustrated that dancing with a partner has a significant effect on the angular kinematics of the lower extremity and pelvis. Dancers showed more restricted motion at the knee and hip in the sagittal and frontal planes when dancing with a partner. Additionally, differences were observed among the steps with most differences occurring between steps one and two and steps two and three in all three planes. These findings expand our knowledge of swing dancing biomechanics, possibly informing the design of future studies that will further expand our understanding of swing dancing.


Diagnostic test strategies in children at increased risk of inflammatory bowel disease in primary care.
In children with symptoms suggestive of inflammatory bowel disease (IBD) who present in primary care, the optimal test strategy for identifying those who require specialist care is unclear. We evaluated the following three test strategies to determine which was optimal for referring children with suspected IBD to specialist care: 1) alarm symptoms alone, 2) alarm symptoms plus c-reactive protein, and 3) alarm symptoms plus fecal calprotectin. A prospective cohort study was conducted, including children with chronic gastrointestinal symptoms referred to pediatric gastroenterology. Outcome was defined as IBD confirmed by endoscopy, or IBD ruled out by either endoscopy or unremarkable clinical 12 month follow-up with no indication for endoscopy. Test strategy probabilities were generated by logistic regression analyses and compared by area under the receiver operating characteristic curves (AUC) and decision curves. We included 90 children, of whom 17 (19%) had IBD (n = 65 from primary care physicians, n = 25 from general pediatricians). Adding fecal calprotectin to alarm symptoms increased the AUC significantly from 0.80 (0.67-0.92) to 0.97 (0.93-1.00), but adding c-reactive protein to alarm symptoms did not increase the AUC significantly (p > 0.05). Decision curves confirmed these patterns, showing that alarm symptoms combined with fecal calprotectin produced the diagnostic test strategy with the highest net benefit at reasonable threshold probabilities. In primary care, when children are identified as being at high risk for IBD, adding fecal calprotectin testing to alarm symptoms was the optimal strategy for improving risk stratification.


A protocol and pilot study for managing fibromyalgia with yoga and meditation.
Fibromyalgia is a chronic syndrome characterized by widespread pain, sleep disturbance, stiffness, fatigue, headache, and mood disorders. Recent research has resulted in an improved understanding of fibromyalgia and its possible causes. This article highlights some of the current research, discusses a strategy for using yoga and meditation as a therapy for fibromyalgia sufferers, and presents the results of a preliminary 8-week study using yoga and meditation to help manage fibromyalgia symptoms. The study of 11 participants found significant improvement in the overall health status of the participants and in symptoms of stiffness, anxiety, and depression. Significant improvements were also seen in the reported number of days "felt good" and number of days "missed work" because of fibromyalgia. Nonsignificant improvements were seen in measures of pain, fatigue, and how one felt in the morning. Effect sizes were medium to large for most tested areas. This study supports the benefits of yoga and meditation for individuals with fibromyalgia and encourages further research to explore their use as standard therapies for fibromyalgia.


CASP9 results compared to those of previous CASP experiments.
The quality of structure models submitted to CASP9 is analyzed in the context of previous CASPs. Comparison methods are similar to those used in previous articles in this series, with the addition of new methods looking at model quality in regions not covered by a single best structural template, alignment accuracy, and progress for template-free models. Progress in this CASP was again modest and statistically hard to validate. Nevertheless, there are several positive trends. There is an indication of improvement in overall model quality for the midrange of template-based modeling difficulty, methods for identifying the best model from a set generated have improved, and there are strong indications of progress in the quality of template-free models of short proteins. In addition, the new examination of a model quality in regions of model not covered by the best available template reveals better performance than had previously been apparent.


The paranasal sinuses and other enigmas: an aquatic evolutionary theory.
The functional role of the paranasal sinuses in man has long been in dispute and as yet no satisfactory explanation has been offered for these 'unwanted' spaces. An answer may be found by study of the comparative evolutionary development of the sinuses in man and other higher primates. Several unique physical characteristics of man not seen elsewhere in the ape family, or indeed in other terrestrial mammals, including some relating to the upper aerodigestive tract, are not satisfactorily explained by the traditionally held theory of evolutionary development of early man directly from the arboreal ape. It is argued that these developmental differences are much more logically explained by a period of aquatic adaptation at a crucial period in the evolution of pre-hominid man. A new theory is proposed which might explain the importance of the sinus air cavities as buoyancy aids for protection of the upper airway tract in such an aquatic environment. Further evidence is offered relating to a pathological condition of the external ear canal which supports this theory that man at some stage in his early development acquired an affinity for an aquatic environment. Explanation of these unique hominid characteristics in terms of an aquatic evolutionary theory may help to resolve some of the enigmatic inconsistencies between man and other higher primates, and may account for man's eventual emergence as the dominant extant species, and perhaps an explanation for the 'missing link'.


Prognostic and developmental factors in patients receiving liver transplant due to hepatocellular carcinoma: one center's experience in the north of Spain.
Hepatocellular carcinoma (HCC) is one of the most frequent types of tumor. The aim of this study was to determine the survival of patients who had received liver transplants as a result of the disease. This observational follow-up study included 150 patients who received liver transplantations from June 1994 to December 2007. The study considered epidemiological and staging variables, tumor descriptions, and follow-up variables. We employed Kaplan-Meier methodology together with a Cox multivariate regression analysis. The incidence of tumor relapse was 13.3%, with survival rates at 1, 3, and 5 years of 89.3%, 73.1%, and 61.4%, respectively. Variables that showed an independent effect to predict mortality were the degree of histological differentiation and of macrovascular invasion. Patients with poorly differentiated HCC had a 4.03 fold (95% confidence interval [CI]: 1.61-10.06) greater possibility of dying. Macrovascular involvement increased the risk of death (relative risk = 2.23), an effect that was at the limit of significance (95% CI 0.99-5.04). The survival rate was consistent with the literature. Poor tumor differentiation and macrovascular involvement were independent predictors of mortality.


Role of the kinin B1 receptor in insulin homeostasis and pancreatic islet function.
Kinins are potent vasoactive peptides generated in blood and tissues by the kallikrein serine proteases. Two distinct kinin receptors have been described, one constitutive (subtype B2) and one inducible (subtype B1), and many physiological functions have been attributed to these receptors, including glucose homeostasis and control of vascular permeability. In this study we show that mice lacking the kinin B1 receptor (B1-/- mice) have lower fasting plasma glucose concentrations but exhibit higher glycemia after feeding when compared to wild-type mice. B1-/- mice also present pancreas abnormalities, characterized by fewer pancreatic islets and lower insulin content, which leads to hypoinsulinemia and reduced insulin release after a glucose load. Nevertheless, an insulin tolerance test indicated higher sensitivity in B1-/- mice. In line with this phenotype, pancreatic vascular permeability was shown to be reduced in B1 receptor-ablated mice. The B1 agonist desArg9bradykinin injected intravenously can induce the release of insulin into serum, and this effect was not observed in the B1-/- mice or in isolated islets. Our data demonstrate the importance of the kinin B1 receptor in the control of pancreatic vascular homeostasis and insulin release, highlighting a new role for this receptor in the pathogenesis of diabetes and related diseases.


Examining the degradation of environmentally-daunting per- and poly-fluoroalkyl substances from a fundamental chemical perspective.
In this work, ground and excited-state properties were used as descriptors for probing mechanisms as well as to assess potential alternatives for tackling the elimination of perfluorobutane sulfonic acid (PFBS) - C4F9SO2OH, perfluorooctane sulfonic acid (PFOS) - C8F17SO2OH, and perfluorooctanoic acid (PFOA) - C7F15COOH. For this purpose, density functional theory (DFT) and its time-dependent formalism (TD-DFT) at both CAM-B3LYP/6-311+G(2d,2p) and M06-2X/6-311+G(2d,2p) levels of theory in water (IEF-PCM) were employed. To gauge the accuracy of the DFT approaches for the current systems, wave function methods (Møller-Plesset, MP2, coupled-cluster with single and double excitations, CCSD, CCSD with perturbative triples, CCSD(T), and equation of motion CCSD, EOM-CCSD) and aug-cc-pVXZ (X = D and T) basis sets were used. Regarding PFBS and PFOS, all the excited states probed were found to be energetically accessible only in the high-energy vacuum UV region (<200 nm ≥6.20 eV); SO2O- is released when the first low-lying excited singlet state (21A) of both compounds is accessed. On the other hand, two lowest-lying excited singlet states of PFOA were computed at considerably lower energy (5.84 eV and 5.97 eV for 21A and 31A, respectively, at the TD-DFT/CAM-B3LYP/6-311+G(2d,2p)). In addition, intramolecular OH radical formation is suggested for protonated PFOA when interacting with radiation at 7.98 eV ≈ 155 nm, as determined at the TD-DFT/CAM-B3LYP/6-311+G(2d,2p) level of theory. Such intramolecularly generated hydroxyl may contribute to a faster degradation of PFOA (or of other per- and poly-fluoroalkyl substances (PFAS) that are usually found together with PFOA).


Effects of monovalent anions of the hofmeister series on DPPC lipid bilayers Part II: modeling the perpendicular and lateral equation-of-state.
The effects of Hofmeister anions on the perpendicular and lateral equation-of-state (EOS) of the dipalmitoylphosphatidylcholine lamellar phase discussed in the companion article are here examined using appropriate free energy models for the intra- and interbilayer interactions. Minimizing the free energy with respect to the two basic geometrical parameters of the lamellar phase, which are the interbilayer water thickness, d(w), and the lipid headgroup area, a(L), provides the perpendicular (osmotic pressure balance) and lateral EOS. Standard models were used for the hydration, undulation, and Van der Waals attractive force between the bilayers in the presence of electrolytes whereas two alternative treatments of electrostatic interactions were used to obtain "binding" or "partitioning" constants of anions to the lipid bilayers both in the absence and in the presence of sodium binding. The computed binding constants depend on anion type and follow the Hofmeister series, but were found to increase with electrolyte concentration, implying that the local binding approximation cannot fit bilayer repulsion data. The partitioning model was also found inadequate at high electrolyte concentrations. The fitting attempts revealed two additional features worthy of future investigation. First, at maximum swelling in the presence of electrolytes the osmotic pressure of the bilayer system cannot be set equal to zero. Second, at high salt concentrations an additional repulsion appears to come into effect in the presence of strongly adsorbing anions such as I(-) or SCN(-). Both these phenomena may reflect an inconsistent treatment of the ion-surface interactions, which have an impact on the osmotic pressure. Alternatively, they may arise from bulk solution nonidealities that cannot be handled by the classical Poisson-Boltzmann formalism. The inability of current models to explain the "lateral" EOS by fitting the area per lipid headgroup as a function of salt type and concentration shows that current understanding of phospholipid-ion interactions is still very incomplete.


Maternal obesity epigenetically alters visceral fat progenitor cell properties in male offspring mice.
Maternal obesity reduces adipogenic progenitor density in offspring adipose tissue. The ability of adipose tissue expansion in the offspring of obese mothers is limited and is associated with metabolic dysfunction of adipose tissue when challenged with a high-fat diet. Maternal obesity induces DNA demethylation in the promoter of zinc finger protein 423, which renders progenitor cells with a high adipogenic capacity. Maternal obesity demonstrates long-term effects on the adipogenic capacity of progenitor cells in offspring adipose tissue, demonstrating a developmental programming effect. Maternal obesity (MO) programs offspring obesity and metabolic disorders, although the underlying mechanisms remain poorly defined. Progenitor cells are the source of new adipocytes. The present study aimed to test whether MO epigenetically predisposes adipocyte progenitors in the fat of offspring to adipogenic differentiation and subsequent depletion, which leads to a failure of adipose tissue plasticity under positive energy balance, contributing to adipose tissue metabolic dysfunction. C57BL/6 female mice were fed either a control diet (10% energy from fat) or a high-fat diet (45% energy from fat) for 8 weeks before mating. Male offspring of control (Con) and obese (OB) dams were weaned onto a regular (Reg) or obesogenic (Obe) diet until 3 months of age. At weaning, male OB offspring had a higher expression of Zinc finger protein 423 (zfp423), a key transcription factor in adipogenesis, as well as lower DNA methylation of its promoter in progenitors of epididymal fat compared to Con offspring, which was correlated with enhanced adipogenic differentiation. At 3 months of age, progenitor density was 30.9 ± 9.7% lower in OB/Obe compared to Con/Obe mice, accompanied by a limited expansion of the adipocyte number when challenged with a high-energy diet. This difference was associated with lower DNA methylation in the zfp423 promoter in the epididymal fat of OB/Obe offspring, which was correlated with greater macrophage chemotactic protein-1 and hypoxia-inducible factor 1α expression. In summary, MO epigenetically limits the expansion capacity of offspring adipose tissue, providing an explanation for the adipose metabolic dysfunction of male offspring in the setting of MO.


Smokeless tobacco use and oral epithelial dysplasia.
One hundred eight patients with a histologically confirmed diagnosis of epithelial dysplasia of the oral cavity and a prior history of smokeless tobacco (ST) usage were identified. The mean age at time of diagnosis for female patients was almost a decade later than for male patients (63.6 versus 51.2 years). In addition, women were more likely (P = 0.02) to have moderate or severe epithelial dysplasia than men. The two most common locations (buccal mucosa/vestibule and alveolar ridge/gingiva) accounted for 82.4% of all cases. In the 44 cases which specified both ST placement and biopsy site, 90.9% demonstrated epithelial dysplasia at the location used by the patient for holding the ST. When evaluating the histologic severity of epithelial dysplasia, a trend (P = 0.02) toward focal mild or mild was noted among ST users as compared to nonusers. No difference was found in the histologic grade of the lesions associated with either snuff or chewing tobacco.


Genome-scale measurement of off-target activity using Cas9 toxicity in high-throughput screens.
CRISPR-Cas9 screens are powerful tools for high-throughput interrogation of genome function, but can be confounded by nuclease-induced toxicity at both on- and off-target sites, likely due to DNA damage. Here, to test potential solutions to this issue, we design and analyse a CRISPR-Cas9 library with 10 variable-length guides per gene and thousands of negative controls targeting non-functional, non-genic regions (termed safe-targeting guides), in addition to non-targeting controls. We find this library has excellent performance in identifying genes affecting growth and sensitivity to the ricin toxin. The safe-targeting guides allow for proper control of toxicity from on-target DNA damage. Using this toxicity as a proxy to measure off-target cutting, we demonstrate with tens of thousands of guides both the nucleotide position-dependent sensitivity to single mismatches and the reduction of off-target cutting using truncated guides. Our results demonstrate a simple strategy for high-throughput evaluation of target specificity and nuclease toxicity in Cas9 screens.


Chemotherapy-induced modification of microRNA expression in esophageal cancer.
Neoadjuvant chemotherapy is often used in the treatment of advanced esophageal cancer. In this study, we determined the impact of chemotherapy on microRNA (miRNA) expression in esophageal cancer cells, and whether identified changes might have biological relevance. Two esophageal carcinoma cell lines (one adenocarcinoma and one squamous cell carcinoma) were treated with cisplatin or 5-fluorouracil for 24 or 72 h. RNA was extracted from cells following 24-h treatment, and used for microarray studies. Promising miRNA candidates were selected for RT-PCR validation. Target prediction using TargetScan, combined with bioinformatic analysis (Ingenuity Pathway Analysis, IPA), was performed to evaluate the implications of the altered miRNA expression. Thirteen miRNAs (miR-199a-5p, miR-302f, miR-320a, miR-342-3p, miR-425, miR-455-3p, miR-486-3p, miR-519c-5p, miR-548d-5p, miR-617, miR-758, miR-766, miR-1286) were deregulated after 24- and/or 72-h treatment in both cell lines, and most miRNAs presented similar expression changes after short- or long-term exposure. IPA revealed that the major networks which incorporate the predicted targets, include functions such as 'Cell death', 'Cell cycle', 'Cellular growth and proliferation', 'DNA replication, recombination, and repair' and 'Drug metabolism'. Cisplatin or 5-fluorouracil alter miRNA expression in esophageal cancer cells. IPA suggests that these miRNAs may target molecular pathways involved in cell survival after chemotherapy.


Laryngeal cancer mortality trends in European countries.
After a steady increase between the 1950s and the 1970s, laryngeal cancer mortality has been levelling off since the early 1980s in men from most western and southern European countries and since the early 1990s in central and eastern Europe. To update trends in laryngeal cancer mortality, we analyzed data provided by the World Health Organization over the last two decades for 34 European countries and the European Union (EU) as a whole. For major European countries, we also identified significant changes in trends between 1980 and 2012 using joinpoint regression analysis. Male mortality in the EU was approximately constant between 1980 and 1991 (annual percent change, APC=-0.5%) and declined by 3.3% per year in 1991-2012. EU age-standardized (world population) rates were 4.7/100,000 in 1990-91 and 2.5/100,000 in 2010-2011. Rates declined in most European countries, particularly over the last two decades. In 2010-11, the highest male rates were in Hungary, the Republic of Moldova, and Romania (over 6/100,000), and the lowest ones in Finland, Norway, Sweden, and Switzerland (below 1/100,000). In EU women, mortality was stable around 0.29/100,000 between 1980 and 1994 and slightly decreased thereafter (APC=-1.3%; 0.23/100,000 in 2000-01). We also considered male incidence trends for nine European countries or cancer registration areas. In most of them, declines were observed over recent decades. Laryngeal cancer mortality thus showed favourable trends over the last few decades in most Europe, following favourable changes in tobacco and, mostly for Mediterranean countries, alcohol consumption.


Sequence capture phylogenomics of eyeless Cicurina spiders from Texas caves, with emphasis on US federally-endangered species from Bexar County (Araneae, Hahniidae).
Morphological, mitochondrial, and nuclear phylogenomic data were combined to address phylogenetic and species delimitation questions in cave-limited Cicurina spiders from central Texas. Special effort was focused on specimens and cave locations in the San Antonio region (Bexar County), home to four eyeless species listed as US Federally Endangered. Sequence capture experiments resulted in the recovery of ~200-400 homologous ultra-conserved element (UCE) nuclear loci across taxa, and nearly complete COI mitochondrial DNA sequences from the same set of individuals. Some of these nuclear and mitochondrial sequences were recovered from "standard" museum specimens without special preservation of DNA material, including museum specimens preserved in the 1990s. Multiple phylogenetic analyses of the UCE data agree in the recovery of two major lineages of eyeless Cicurina in Texas. These lineages also differ in mitochondrial clade membership, female genitalic morphology, degree of troglomorphy (as measured by relative leg length), and are mostly allopatric across much of Texas. Rare sympatry was confirmed in Bexar County, where members of the two major clades sometimes co-exist in the same karst feature. Both nuclear phylogenomic and mitochondrial data indicate the existence of undescribed species from the San Antonio region, although further sampling and collection of adult specimens is needed to explicitly test these hypotheses. Our data support the two following species synonymies (Cicurina venii Gertsch, 1992 = Cicurina madla Gertsch, 1992; Cicurina loftini Cokendolpher, 2004 = Cicurina vespera Gertsch, 1992), formally proposed here. Overall, our taxonomy-focused research has many important conservation implications, and again highlights the fundamental importance of robust taxonomy in conservation research.


Effect of partially stabilized zirconia thickness on the translucency and microhardness of resin cement.
Partially stabilized zirconia has been introduced as a more translucent iteration. However, knowledge of the effect of the thickness of partially stabilized zirconia on the microhardness of resin cement is sparse. The purpose of this in vitro study was to evaluate the effect of thickness and material type on the translucency of partially stabilized zirconia and the microhardness of the resin cement polymerized beneath. Specimens were prepared from 2 translucent zirconias with different yttrium content (Ceramil Zolid HT+ [HT] and Ceramil Zolid FX [SHT]) and a lithium disilicate glass-ceramic (e.max CAD [EX]) of different thicknesses (0.5, 1, 1.5, and 2 mm) (n=10). Color coordinates were recorded by using a spectrophotometer, and the relative translucency parameter (RTP) was calculated by using the CIEDE2000 formula. The microhardness of the resin cement polymerized under ceramic specimens was measured. Two-way analysis of variance, the Tukey honestly significant difference, and independent samples t tests were used to analyze the data (α=.05). Material type (P<.001), thickness (P<.001), and their interaction significantly affected the RTP (P=.001) and hardness values (P<.001). Regardless of the thickness, EX had the highest RTP (P≤.027), and the resin cements polymerized under EX showed the highest microhardness (P≤.002). However, the difference between HT and SHT for RTP (P≥.082) and resin cement hardness (P≥.984) was not significant. Specimens of 0.5 mm resulted in higher RTP (P≤.001) and resin cement hardness (P≤.006) than the 1.5- and 2-mm specimens of each ceramic. Increasing material thickness reduced the translucency of the partially stabilized zirconia and the hardness of the resin cements polymerized beneath.


Effect of sensitization with Propionibacterium acnes on the growth of Listeria monocytogenes and Treponema pallidum in rabbits.
Sensitization of rabbits with Propionibacterium acnes, a nonspecific stimulant of the reticuloendothelial system, was investigated as a means of enhancing resistance to Treponema pallidum. A single i.v. dose of P. acnes given 3 or 7 days before challenge with Listeria monocytogenes was capable of suppressing the growth of the heterologous organism, whereas a single i.v. dose 24 hr or 14 days before challenge was not. Reactivation via i.v. elicitation with P. acnes 14 days after sensitization (1 day before challenge) caused significant suppression of listerial growth in the major organs 30 hr after i.v. challenge. A series of similar experiments was designed with T. pallidum as the challenge organism. Sensitization and repetitive elicitation with P. acnes did not change the time of appearance or progression of syphilitic chancres after i.v or i.d. challenge. Injection of P. acnes into sites of intradermal T. pallidum challenge in previously sensitized rabbits also failed to alter the evolution of syphilitic lesions. These results suggest that macrophage activation does not alter the host's ability to suppress the growth of T. pallidum.


Enhancer redundancy in development and disease.
Shadow enhancers are seemingly redundant transcriptional cis-regulatory elements that regulate the same gene and drive overlapping expression patterns. Recent studies have shown that shadow enhancers are remarkably abundant and control most developmental gene expression in both invertebrates and vertebrates, including mammals. Shadow enhancers might provide an important mechanism for buffering gene expression against mutations in non-coding regulatory regions of genes implicated in human disease. Technological advances in genome editing and live imaging have shed light on how shadow enhancers establish precise gene expression patterns and confer phenotypic robustness. Shadow enhancers can interact in complex ways and may also help to drive the formation of transcriptional hubs within the nucleus. Despite their apparent redundancy, the prevalence and evolutionary conservation of shadow enhancers underscore their key role in emerging metazoan gene regulatory networks.


The yeast MOT2 gene encodes a putative zinc finger protein that serves as a global negative regulator affecting expression of several categories of genes, including mating-pheromone-responsive genes.
The STE4 gene encodes the beta subunit of a heterotrimeric G protein that is an essential component of the pheromone signal transduction pathway. To identify downstream component(s) of Ste4, we sought pseudo-revertants that restored mating competence to ste4 mutants. The suppressor mot2 was isolated as a recessive mutation that restored conjugational competence to a temperature-sensitive ste4 mutant and simultaneously conferred a temperature-sensitive growth phenotype. The MOT2 gene encodes a putative zinc finger protein, the deletion of which resulted in temperature-sensitive growth, increased expression of FUS1 in the absence of pheromones, and suppression of a deletion of the alpha-factor receptor. On the other hand, sterility resulting from deletion of STE4 was not suppressed by the mot2 deletion. These phenotypes are similar to those associated with temperature-sensitive mutations in CDC36 and CDC39, which are proposed to encode general negative regulators of transcription rather than factors involved in the pheromone response pathway. Deletion of MOT2 also caused increased transcription of unrelated genes such as GAL7 and PHO84. Overexpression of MOT2 suppresses the growth defect of temperature-sensitive mutations in CDC36 and CDC39. These observations suggest that Mot2 functions as a general negative regulator of transcription in the same processes as Cdc36 and Cdc39.


Association between ageing, brain chemistry and white matter volume revealed with complementary MRI and FTIR brain imaging.
Magnetic resonance imaging (MRI) is the gold standard method to study brain anatomy in vivo. Using MRI, subtle alterations to white matter structures in the brain are observed prior to cognitive decline associated with the ageing process, and neurodegenerative diseases such as Alzheimer's disease. Detection of such alterations provides hope for early clinical diagnosis. While MRI is essential to detect subtle alterations to brain structure in vivo, the technique is less suited to study and image the distribution of biochemical markers within specific brain structures. Consequently, the chemical changes that drive, or are associated with MRI-detectable alterations to white matter are not well understood. Herein, we describe (to the best of our knowledge) the first application of a complementary imaging approach that incorporates in vivo MRI with ex vivo Fourier transform infrared (FTIR) spectroscopic imaging on the same brain tissue. The combined workflow is used to detect and associate markers of altered biochemistry (FTIR) with anatomical changes to brain white matter (MRI). We have applied this combination of techniques to the senescence accelerated murine prone strain 8 (SAMP8) mouse model (n = 6 animals in each group, analysed across two ageing time points, 6 and 12 months). The results have demonstrated alterations to lipid composition and markers of disturbed metabolism during ageing are associated with loss of white matter volume.


Lys05 - A Promising Autophagy Inhibitor in the Radiosensitization Battle: Phosphoproteomic Perspective.
Autophagy is a crucial factor contributing to radioresistance during radiotherapy. Although Lys05 has proven its ability to improve the results of radiotherapy through the inhibition of autophagy, molecular mechanisms of this inhibition remain elusive. We aimed to describe the molecular mechanisms involved in Lys05-induced inhibition of autophagy. Radioresistant human non-small cell lung carcinoma cells (H1299, p53-negative) and methods of quantitative phosphoproteomics were employed to define the molecular mechanisms involved in Lys05-induced inhibition of autophagy. We confirmed that at an early stage after irradiation, autophagy was induced, whereas at a later stage after irradiation, it was inhibited. The early-stage induction of autophagy was characterized mainly by the activation of biosynthetic and metabolic processes through up- or down-regulation of the critical autophagic regulatory proteins Sequestosome-1 (SQSTM1) and proline-rich AKT1 substrate 1 (AKT1S1). The late-stage inhibition of autophagy was attributed mainly to down-regulation of Unc-51 like autophagy-activating kinase 1 (ULK1) through phosphorylation at Ser638. This work contributes to emerging phosphoproteomic insights into autophagy-mediated global signaling in lung cancer cells, which might consequently facilitate the development of precision medicine therapeutics.


Biodiversity in and around Greenhouses: Benefits and Potential Risks for Pest Management.
One of the ecosystem services of biodiversity is the contribution to pest control through conservation and stimulation of natural enemies. However, whether plant diversity around greenhouses is beneficial or a potential risk is heavily debated. In this review, we argue that most greenhouse pests in temperate climates are of exotic origin and infest greenhouses mainly through transportation of plant material. For indigenous pests, we discuss the potential ways in which plant diversity around greenhouses can facilitate or prevent pest migrations into greenhouses. As shown in several studies, an important benefit of increased plant diversity around greenhouses is the stimulation of indigenous natural enemies that migrate to greenhouses, where they suppress both indigenous and exotic pests. How this influx can be supported by specific plant communities, plant characteristics, and habitats while minimising risks of increasing greenhouse pest densities, virus transmission, or hyperparasitism needs further studies. It also requires a better understanding of the underlying processes that link biodiversity with pest management. Inside greenhouses, plant biodiversity can also support biological control. We summarise general methods that growers can use to enhance pest control with functional biodiversity and suggest that it is particularly important to study how biodiversity inside and outside greenhouses can be linked to enhancement of biological pest control with both released and naturally occurring species of natural enemies.


Role of angiogenesis inhibitors in colorectal cancer: sensitive and insensitive tumors.
Angiogenesis is a key factor in the carcinogenesis process. In oncological practice, angiogenesis inhibition, mainly through the blockade of the VEGF family and its receptors, has been robustly demonstrated to produce clinical benefits and, in specific disease subsets such as colorectal cancer, to extend the overall survival of treated patients. VEGF is a multifunctional growth factor that mediates its functions through cognate receptors on endothelial cells and it has been discovered for its capability to induce macromolecule hyperpermeability in veins and venules. Several approaches have been taken to target angiogenesis in cancer: drugs that target one or more soluble ligands of the VEGF family, drugs that selectively inhibit one or more receptors of the VEGF receptor family, and drugs that inhibit VEGF receptor(s) among other, non VEGF-related targets. At present, two compounds have shown significant clinical activity, bevacizumab, Avastin® and aflibercept, Zaltrap®, and only one of these (bevacizumab) has so far been registered for use in clinical practice. In the present review, we explore and summarize the main features of the angiogenetic process, concerning in particular a common and potentially lethal disease as colorectal cancer. We overview the molecular pathways that characterize angiogenesis, focusing on VEGF family, the current applications and limitations of its blockade in oncology, and the hypothetical future perspectives of anti-angiogenic therapy.


[Mechanism of cell damage by hematoporphyrin derivative (HPD) plus light. II. Effect of HPD plus light on respiration and oxidative phosphorylation in hepatoma cells and normal liver mitochondria].
The effects of HPD plus light on energy metabolism and membrane structure of hepatoma cell and normal liver mitochondria were investigated. HPD was bound to mitochondria either in vitro or in vivo. Mitochondria bound HPD plus light increased MDA level, decreased respiratory intensity and respiratory control, dissociated phosphorylation from oxidation and enhanced mitochondria swelling on age. These effects were related to HPD concentration and exposure time but it was unchanged in the control. These results showed that the loss of function of oxidation phosphorylation was due to the mitochondrial membrane system damage under the action of singlet oxygen produced by HPD bound mitochondria following light activation.


New monitoring techniques to diagnose the cause of syncope.
Syncope is a very common clinical problem. Given the extensive differential diagnosis, we have developed a structured approach for the evaluation and management of patients with unexplained syncope. Patients with overt cardiac, neurologic, or metabolic disturbances are identified and treated accordingly. However, the remaining patients with high-risk characteristics are hospitalized for risk stratification. After excluding patients who can benefit from pacemaker or implantable cardioverter-defibrillator implantation, an implantable loop recorder (ILR) appears to be a very effective diagnostic tool. The recent availability of a small ILR that can be implanted within minutes and provides daily data wirelessly for over 3 years appears to have elevated the ILR over short-term external electrocardiography (ECG) monitoring techniques in patients with unexplained syncope. Herein, using specific case examples, we review how we use a structural pathway at our institution to guide the evaluation and management of patients presenting with unexplained syncope, identify the types of patients who benefit from long-term ECG monitoring, and show how this strategy has positively affected clinical care in these patients.


The effects of pentoxifylline treatment on bacterial translocation after hemorrhagic shock in rats.
Bacterial translocation is thought to be responsible for infectious complications after hemorrhagic shock. The aim of this study was to investigate the effects of pentoxifylline treatment on bacterial translocation in animals subjected to hemorrhagic shock. Thirty-one Wistar albino rats (280-360 g) were divided into three groups: sham (n=10), shock (n=11), and shock-pentoxifylline (n=10). Blood was not withdrawn from sham rats. Shock rats were subjected to 30 min of shock followed by reinfusion of shed blood. Shock/pentoxifylline rats received pentoxifylline after reinfusion of shed blood. After hemorrhage and reinfusion (24 h), the mesenteric lymph nodes, liver, spleen, and blood samples were evaluated using quantitative microbiological techniques, and the numbers of colony-forming units were compared between groups. Cecum was removed to evaluate the bacterial population. Ileum and cecum were examined histologically. The incidence of bacterial translocation was higher in the shocked rats (63%) than in the sham shock rats (10%). Pentoxifylline reduced the incidence of shock-induced bacterial translocation to 0%. Cecal bacterial levels were significantly higher in the shock rats than in the sham and shock/pentoxifylline rats. The histological damage caused by hemorrhagic shock was prevented by pentoxifylline treatment. In conclusion, the hemorrhagic shock triggered translocation of bacteria to the mesenteric lymph nodes, spleen, liver, and blood of rats. Pentoxifylline treatment just after shed blood transfusion significantly attenuated this phenomenon.


Glucose inhibits haemostasis and accelerates diet-induced hyperlipidaemia in zebrafish larvae.
Hyperglycaemia damages the microvasculature in part through the reduced recruitment of immune cells and interference with platelet signalling, leading to poor wound healing and accelerated lipid deposition in mammals. We investigated the utility of zebrafish larvae to model the effect of exogenous glucose on neutrophil and macrophage recruitment to a tail wound, wound-induced haemostasis, and chicken egg yolk feed challenge-induced hyperlipidaemia by supplementing larvae with exogenous glucose by immersion or injection. Neither method of glucose supplementation affected the recruitment of neutrophils and macrophages following tail transection. Glucose injection reduced thrombocyte retention and fibrin plug formation while only thrombocyte retention was reduced by glucose immersion following tail transection. We observed accelerated lipid accumulation in glucose-injected larvae challenged with high fat chicken egg yolk feeding. Our study identifies conserved and divergent effects of high glucose on inflammation, haemostasis, and hyperlipidaemia in zebrafish larvae compared to mammals.


Suicide mortality of suicide attempt patients discharged from emergency room, nonsuicidal psychiatric patients discharged from emergency room, admitted suicide attempt patients, and admitted nonsuicidal psychiatric patients.
The suicide mortality rate and risk factors for suicide completion of patients who presented to an emergency room (ER) for suicide attempt and were discharged without psychiatric admission, patients who presented to an ER for psychiatric problems other than suicide attempt and were discharged without psychiatric admission, psychiatric inpatients admitted for suicide attempt, and psychiatric inpatients admitted for other reasons were examined. The records of 3,897 patients who were treated at a general hospital in Seoul, Korea, from July 2003 to December 2006 were reviewed. Forty-three of the 3,897 subjects died by suicide during the 2.5-year observation period. Compared to the general Korean population, the suicide mortality rate was 82-fold higher for suicide attempt patients, admitted; 54-fold higher for suicide attempt patients, discharged; 21-fold higher for nonsuicidal patients, admitted; and 11-fold higher for nonsuicidal patients, discharged. In all four groups, diagnosis of a depressive disorder and suicide attempt at presentation were each significant independent risk factors for suicide completion. These results highlight the need for suicide prevention strategies for depressed patients who present to the ER or are admitted to a psychiatric ward after a suicide attempt.


Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS.
Clostridium difficile is a nosocomial bacterial pathogen causing antibiotic-associated diarrhea and fatal pseudomembranous colitis. Key virulence factors are toxin A and toxin B (TcdB), two highly related toxins that are members of the large clostridial toxin family. These large multifunctional proteins disrupt cell function using a glucosyltransferase domain that is translocated into the cytosol after vesicular internalization of intact holotoxin. Although substantial information about the biochemical mechanisms of intoxication exists, research has been hampered by limited structural information, particularly of intact holotoxin. Here, we used small-angle X-ray scattering (SAXS) methods to obtain an ab initio low-resolution structure of native TcdB, which demonstrated that this molecule is monomeric in solution and possesses a highly asymmetric shape with a maximum dimension of approximately 275 A. Combining this SAXS information with crystallographic or modeled structures of individual functional domains of TcdB reveals for the first time that the three-dimensional structure of TcdB is organized into four distinct structural domains. Structures of the N-terminal glucosyltransferase, the cysteine protease, and the C-terminal repeat region can be aligned within three domains of the SAXS envelope. A fourth domain, predicted to be involved in the translocation of the glucosyltransferase, appears as a large solvent-exposed protrusion. Knowledge of the shapes and relative orientations of toxin domains provides new insight into defining functional domain boundaries and provides a framework for understanding how potential intra-domain interactions enable conformational changes to propagate between domains to facilitate intoxication processes.


Technology and competitiveness: a key to the economic future of the United States.
The United States still is a leader in technology and innovation, but American industry has been slow to translate that advantage into commercial success. A major contributing factor is the low status accorded manufacturing in this country and a lack of teamwork among scientists, engineers, and managers. However, there are encouraging signs that these key players in the innovation cycle are recognizing the need to work together to improve products and manufacturing processes and to restore the competitive position of the United States.


Effectiveness of Telematic Behavioral Techniques to Manage Anxiety, Stress and Depressive Symptoms in Patients with Chronic Musculoskeletal Pain: A Systematic Review and Meta-Analysis.
Anxiety, depressive symptoms and stress have a significant influence on chronic musculoskeletal pain. Behavioral modification techniques have proven to be effective to manage these variables; however, the COVID-19 pandemic has highlighted the need for an alternative to face-to-face treatment. We conducted a search of PubMed, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science, APA PsychInfo, and Psychological and Behavioural Collections. The aim was to assess the effectiveness of telematic behavioral modification techniques (e-BMT) on psychological variables in patients with chronic musculoskeletal pain through a systematic review with meta-analysis. We used a conventional pairwise meta-analysis and a random-effects model. We calculated the standardized mean difference (SMD) with the corresponding 95% confidence interval (CI). Forty-one randomized controlled trials were included, with a total of 5018 participants. We found a statistically significant small effect size in favor of e-BMT in depressive symptoms (n = 3531; SMD = -0.35; 95% CI -0.46, -0.24) and anxiety (n = 2578; SMD = -0.32; 95% CI -0.42, -0.21) with low to moderate strength of evidence. However, there was no statistically significant effect on stress symptoms with moderate strength of evidence. In conclusion, e-BMT is an effective option for the management of anxiety and depressive symptoms in patients with chronic musculoskeletal pain. However, it does not seem effective to improve stress symptoms.


Dexamethasone in patients with acute lung injury from acute monocytic leukaemia.
The use of steroids is not required in myeloid malignancies and remains controversial in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We sought to evaluate dexamethasone in patients with ALI/ARDS caused by acute monocytic leukaemia (AML FAB-M5) via either leukostasis or leukaemic infiltration. Dexamethasone (10 mg every 6 h until neutropenia) was added to chemotherapy and intensive care unit (ICU) management in 20 consecutive patients between 2005 and 2008, whose data were compared with those from 20 historical controls (1994-2002). ICU mortality was the primary criterion. We also compared respiratory deterioration rates, need for ventilation and nosocomial infections. 17 (85%) patients had hyperleukocytosis, 19 (95%) had leukaemic masses, and all 20 had severe pancytopenia. All patients presented with respiratory symptoms and pulmonary infiltrates prior to AML FAB-M5 diagnosis. Compared with historical controls, dexamethasone-treated patients had a significantly lower ICU mortality rate (20% versus 50%; p = 0.04) and a trend for less respiratory deterioration (50% versus 80%; p = 0.07). There were no significant increases in the rates of infections with dexamethasone. In conclusion, in patients with ALI/ARDS related to AML FAB-M5, adding dexamethasone to conventional chemotherapy seemed effective and safe. These results warrant a controlled trial of dexamethasone versus placebo in AML FAB-M5 patients with noninfectious pulmonary infiltrates.


Cadmium Nephrotoxicity Is Associated with Altered MicroRNA Expression in the Rat Renal Cortex.
Cadmium (Cd) is a nephrotoxic environmental pollutant that causes a generalized dysfunction of the proximal tubule characterized by polyuria and proteinuria. Even though the effects of Cd on the kidney have been well-characterized, the molecular mechanisms underlying these effects have not been fully elucidated. MicroRNAs (miRNAs) are small non-coding RNAs that regulate cellular and physiologic function by modulating gene expression at the post-transcriptional level. The goal of the present study was to determine if Cd affects renal cortex miRNA expression in a well-established animal model of Cd-induced kidney injury. Male Sprague-Dawley rats were treated with subcutaneous injections of either isotonic saline or CdCl₂ (0.6 mg/kg) 5 days a week for 12 weeks. The 12-week Cd-treatment protocol resulted in kidney injury as determined by the development of polyuria and proteinuria, and a significant increase in the urinary biomarkers Kim-1, β₂ microglobulin and cystatin C. Total RNA was isolated from the renal cortex of the saline control and Cd treated animals, and differentially expressed miRNAs were identified using µParafloTM microRNA microarray analysis. The microarray results demonstrated that the expression of 44 miRNAs were significantly increased and 54 miRNAs were significantly decreased in the Cd treatment group versus the saline control (t-test, p ≤ 0.05, N = 6 per group). miR-21-5p, miR-34a-5p, miR-146b-5p, miR-149-3p, miR-224-5p, miR-451-5p, miR-1949, miR-3084a-3p, and miR-3084c-3p demonstrated more abundant expression and a significant two-fold or greater increased expression in the Cd-treatment group versus the saline control group. miR-193b-3p, miR-455-3p, and miR-342-3p demonstrated more abundant expression and a significant two-fold or greater decreased expression in the Cd-treatment group versus the saline control group. Real-time PCR validation demonstrated (1) a significant (t-test, p ≤ 0.05, N = 6 per group) increase in expression in the Cd-treated group for miR-21-5p (2.7-fold), miR-34a-5p (10.8-fold), miR-146b-5p (2-fold), miR-224-5p (10.2-fold), miR-3084a-3p (2.4-fold), and miR-3084c-3p (3.3-fold) and (2) a significant (t-test, p ≤ 0.05, N = 6 per group) 52% decrease in miR-455-3p expression in the Cd-treatment group. These findings demonstrate that Cd significantly alters the miRNA expression profile in the renal cortex and raises the possibility that dysregulated miRNA expression may play a role in the pathophysiology of Cd-induced kidney injury. In addition, these findings raise the possibility that Cd-dysregulated miRNAs might be used as urinary biomarkers of Cd exposure or Cd-induced kidney injury.


Development of fibrous biodegradable polymer conduits for guided nerve regeneration.
The technique of microbraiding with modification was employed as a novel method for the fabrication of fibrous tubular scaffolds for nerve tissue engineering purposes. The biodegradable polymers used in this study were poly(L-lactide-co-glycolide) (10:90) and chitosan. The polymeric fibers were microbraided around a Teflon mandrel to make it as a tubular construct. The conduits were then studied for their surface morphology, swelling behaviour and biocompatibility. The surface morphology was analysed by scanning electron microscope, swelling behaviour by weight increase due to water uptake and biocompatibility by in vitro cytotoxicity assessment in terms of cell morphology and cell viability by the MTT assay of polymer extract treated cells. These conduits may also be used for regeneration of tissues, which require tubular scaffolds such as blood vessel, spinal cord, intestine etc.


Absorption, distribution, metabolism, and excretion of mTOR kinase inhibitor CC-223 in rats, dogs, and humans.
1. The absorption, distribution, metabolism, and excretion of CC-223 were studied following a single oral dose of [14C]CC-223 to rats (3 mg/kg; 90 μCi/kg), dogs (1.5 mg/kg; 10 μCi/kg), and healthy volunteers (20 mg; 200 nCi). 2. CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), whereas urine (57.6%) was the major elimination route for humans. Urine and bile each contained approximately 20% administered radioactivity in rats, whereas bile (20%) played a more important role than urine (<10%) in the excretion of absorbed radioactivity in dogs. Based on excretion data, CC-223 had good absorption, with greater than 56%, 29%, and 57% of the oral dose absorbed in rats, dogs, and humans, respectively. 3. CC-223 was the prominent radioactive component in circulation of rats (>71% of the exposure to total radioactivity) and dogs (≥45.5%), whereas M1 (76.5%) was the predominant circulating metabolite in humans. M1 and M1-derived metabolites accounted for >66% of human dose. CC-223 was extensively metabolized in rats, dogs, and humans through glucuronidation, O-demethylation, oxidation, and combinations of these pathways.


Do suicide survivors suffer social stigma: a review of the literature.
One of the delineating elements found in suicide bereavement versus normal bereavement is the stigma experienced by survivors. This review of the literature will provide insight into stigma as an underlying element in suicide bereavement and point to the role of health professionals in dealing with this complex issue. Historical review and empirical studies are analyzed to provide a framework for how suicide relates to natural bereavement. The conclusion is that suicide bereavement is different from natural loss. The challenge to health care providers is to sort through the complex issues surrounding the individual and their social network to find mechanisms that lead to resolution. Suicide has a profound effect on the family, friends, and associates of the victim that transcends the immediate loss. As those close to the victim suffer through bereavement, a variety of reactions and coping mechanisms are engaged as each individual sorts through individual reactions to the difficult loss. Bereavement refers to "all the physiological, psychological, behavioral, and social response patterns displayed by an individual following the loss (usually through death) of a significant person or thing" (Dunne, Dunne-Maxim & McIntosh, 1987). Bereavement following suicide is complicated by the complex psychological impact of the act on those close to the victim. It is further complicated by the societal perception that the act of suicide is a failure by the victim and the family to deal with some emotional issue and ultimately society affixes blame for the loss on the survivors. This individual or societal stigma introduces a unique stress on the bereavement process that in some cases requires clinical intervention.


T Cell Protein Tyrosine Phosphatase in Glucose Metabolism.
T cell protein tyrosine phosphatase (TCPTP), a vital regulator in glucose metabolism, inflammatory responses, and tumor processes, is increasingly considered a promising target for disease treatments and illness control. This review discusses the structure, substrates and main biological functions of TCPTP, as well as its regulatory effect in glucose metabolism, as an attempt to be referenced for formulating treatment strategies of metabolic disorders. Given the complicated regulation functions in different tissues and organs of TCPTP, the development of drugs inhibiting TCPTP with a higher specificity and a better biocompatibility is recognized as a promising therapeutic strategy for diabetes or obesity. Besides, treatments targeting TCPTP in a specific tissue or organ are suggested to be considerably promising.


Recovery and Fatigue Behavior of Forearm Muscles during a Repetitive Power Grip Gesture in Racing Motorcycle Riders.
Despite a reduction in the maximal voluntary isometric contraction (MVCisom) observed systematically in intermittent fatigue protocols (IFP), decrements of the median frequency, assessed by surface electromyography (sEMG), has not been consistently verified. This study aimed to determine whether recovery periods of 60 s were too long to induce a reduction in the normalized median frequency (MFEMG) of the flexor digitorum superficialis and carpi radialis muscles. Twenty-one road racing motorcycle riders performed an IFP that simulated the posture and braking gesture on a motorcycle. The MVCisom was reduced by 53% (p < 0.001). A positive and significant relationship (p < 0.005) was found between MFEMG and duration of the fatiguing task when 5 s contractions at 30% MVCisom were interspersed by 5 s recovery in both muscles. In contrast, no relationship was found (p > 0.133) when 10 s contractions at 50% MVC were interspersed by 1 min recovery. Comparative analysis of variance (ANOVA) confirmed a decrement of MFEMG in the IFP at 30% MVCisom including short recovery periods with a duty cycle of 100% (5 s/5 s = 1), whereas no differences were observed in the IFP at 50% MVCisom and longer recovery periods, with a duty cycle of 16%. These findings show that recovery periods during IFP are more relevant than the intensity of MVCisom. Thus, we recommend the use of short recovery periods between 5 and 10 s after submaximal muscle contractions for specific forearm muscle training and testing purposes in motorcycle riders.


Effect of Torso and Breast Characteristics on the Perceived Fit of Body Armour Systems Among Female Soldiers: Implications for Body Armour Sizing and Design.
This study aimed to provide normative data characterising the torsos and breasts of female soldiers and to determine which torso and breast anthropometric measurements contributed to reports of poor body armour fit. Ninety-seven female Australian Army soldiers completed a questionnaire about their experience with current-issue body armour, including perceptions of fit. Participants also attended a single testing session where we took a three-dimensional scan of their breasts and torso and collected several anthropometric measurements to characterise their torso size and shape. Sixteen of the 22 breast and torso measurements collected were significantly related to the perceived fit of current-issue body armour systems. To improve perceptions of fit for female soldiers and, in turn, reduce movement interference, discomfort, and barriers to occupational performance, future body armour systems should cater to the wide range of female breast and torso shapes and sizes.


The Acute Effects of a "Reduced Sitting Preschool Day" on Executive Function and Musculoskeletal Health in Preschoolers: A Randomized Cross-Over Study.
To examine the acute effects of a reduced sitting day on executive function (EF) and musculoskeletal health in preschoolers. A sample of 29 children (54% boys; 4-5 y) participated in a randomized cross-over trial. Each child completed 2 protocols, which simulate a day at childcare in random order for 2.5 hours; a typical preschool day (50% sitting) and a reduced preschool day (25% sitting) where most sitting activities were replaced with standing activities. Sitting, standing, and stepping time were objectively assessed using an activPAL accelerometer. EF was evaluated using tablet-based EF assessments (inhibition, working memory, and task shifting). Musculoskeletal health was assessed using a handheld dynamometer and goniometer. Compared with the typical preschool day, the reduced sitting day showed no significant differences for EF scores. Effect sizes for inhibition (d = 0.04), working memory (d = 0.02), and shifting (d = 0.11) were all small. For musculoskeletal health, no significant differences were reported after the reduced preschool day. The effect sizes for the hip extension force, hamstring flexibility, gastrocnemius length, and balancing on 1 leg were all small (d = 0.21, d = 0.25, d = 0.28, and d = 0.28). This study suggests that reducing sitting time is unlikely to result in acute changes in EF and musculoskeletal health among preschoolers.


MIB-1, p53, bcl-2, and WAF-1 expression in pelvic lymph nodes and primary tumors in early stage cervical carcinomas: correlation with clinical outcome.
A complete series of 40 cervical carcinomas with pelvic lymph node metastases were analysed immunohistochemically for prognostic markers. The aims of this study were to examine whether the detection of MIB-1, p53, bcl-2, and WAF-1 could be used as a prognostic marker for tumor recurrence and survival rate. During the period of observation (mean 222, range 72-360 months) 22 (55%) recurrences were encountered and 20 patients died of the disease. There were 35 squamous cell carcinomas (87.5%), 2 adenosquamous carcinomas (5.0%), and 3 pure adenocarcinomas (7.5%). One tumor (2.5%) was well differentiated, 12 tumors (30%) were moderately differentiated, and 27 tumors (67.5%) were poorly differentiated. The primary tumor grade (P=0.037) and radicality of the surgical margins (P=0.021) were significant prognostic factors with regard to tumor recurrence. The site and number of lymph nodes with metastases had no prognostic value. P53, bcl-2, and WAF-1 were not predictive factors for recurrences or the cancer-specific survival rate. The concordant expression of WAF-1 in the primary tumor and in lymph node metastases was lower than for p53 and bcl-2. The proliferative activity (MIB-1) seemed to be lower in tumor cells metastasized to the pelvic lymph nodes than in cells of the primary tumor. Expression of MIB-1 in lymph nodes was predictive of disease-free survival in both univariate and multivariate proportional hazard Cox analyses.


Temporal changes in the epidemiology, management, and outcome from acute respiratory distress syndrome in European intensive care units: a comparison of two large cohorts.
Mortality rates for patients with ARDS remain high. We assessed temporal changes in the epidemiology and management of ARDS patients requiring invasive mechanical ventilation in European ICUs. We also investigated the association between ventilatory settings and outcome in these patients. This was a post hoc analysis of two cohorts of adult ICU patients admitted between May 1-15, 2002 (SOAP study, n = 3147), and May 8-18, 2012 (ICON audit, n = 4601 admitted to ICUs in the same 24 countries as the SOAP study). ARDS was defined retrospectively using the Berlin definitions. Values of tidal volume, PEEP, plateau pressure, and FiO2 corresponding to the most abnormal value of arterial PO2 were recorded prospectively every 24 h. In both studies, patients were followed for outcome until death, hospital discharge or for 60 days. The frequency of ARDS requiring mechanical ventilation during the ICU stay was similar in SOAP and ICON (327[10.4%] vs. 494[10.7%], p = 0.793). The diagnosis of ARDS was established at a median of 3 (IQ: 1-7) days after admission in SOAP and 2 (1-6) days in ICON. Within 24 h of diagnosis, ARDS was mild in 244 (29.7%), moderate in 388 (47.3%), and severe in 189 (23.0%) patients. In patients with ARDS, tidal volumes were lower in the later (ICON) than in the earlier (SOAP) cohort. Plateau and driving pressures were also lower in ICON than in SOAP. ICU (134[41.1%] vs 179[36.9%]) and hospital (151[46.2%] vs 212[44.4%]) mortality rates in patients with ARDS were similar in SOAP and ICON. High plateau pressure (> 29 cmH2O) and driving pressure (> 14 cmH2O) on the first day of mechanical ventilation but not tidal volume (> 8 ml/kg predicted body weight [PBW]) were independently associated with a higher risk of in-hospital death. The frequency of and outcome from ARDS remained relatively stable between 2002 and 2012. Plateau pressure > 29 cmH2O and driving pressure > 14 cmH2O on the first day of mechanical ventilation but not tidal volume > 8 ml/kg PBW were independently associated with a higher risk of death. These data highlight the continued burden of ARDS and provide hypothesis-generating data for the design of future studies.


Clinical diagnosis of dementia, not behavioral and psychologic symptoms, is associated with psychotropic drug use in community-dwelling elders classified as having dementia.
Little is known about the prevalence and correlates of psychotropic drug use in community-dwelling elders with dementia. Baseline data from 285 community-dwelling elders with a research classification of dementia enrolled in the observational Memory and Medical Care Study were analyzed. Of these, 33.3% with a research classification of dementia were clinically diagnosed, 28.8% used at least 1 psychotropic drug, and 61.8% had at least 1 behavioral or psychologic symptom of dementia. Presence of a behavioral or psychologic symptom of dementia was associated with a higher likelihood of a clinical diagnosis of dementia. A clinical diagnosis of dementia, not a behavioral or psychologic symptom of dementia, was associated with psychotropics use. Clinical recognition of dementia appears to be an intermediate step between presence of symptoms of dementia and the prescription of psychotropics. Most community-dwelling elders meeting the research criteria for dementia were not clinically diagnosed, despite contact with a physician (89%) in the previous year.


Can kidney parenchyma metabolites serve as prognostic biomarkers for long-term kidney function after nephrectomy for renal cell carcinoma? A preliminary study.
Nephrectomy, the standard of care for localized renal cell carcinoma (RCC), may lead to kidney function loss. Our goal was to identify prognostic biomarkers of postoperative renal function using metabolomics. Metabolomics data from benign kidney parenchyma were collected prospectively from 138 patients with RCC who underwent nephrectomy at a single institution. The primary endpoint was the difference between the postoperative and preoperative estimated glomerular filtration (eGFR) rate divided by the elapsed time (eGFR slope). eGFR slope was calculated ∼2 years post-nephrectomy (GFR1), and at last follow-up (GFR2). A multivariate regularized regression model identified clinical characteristics and abundance of metabolites in baseline benign kidney parenchyma that were significantly associated with eGFR slope. Findings were validated by associating gene expression data with eGFR slope in an independent cohort (n = 58). Data were compiled on 78 patients (median age 62.6 years, 65.4% males). The mean follow-up was 25 ± 3.4 months for GFR1 and 69.5 ± 23.5 months for GFR2 and 17 (22%) and 32 (41%) patients showed eGFR recovery, respectively. Nephrectomy type, blood lipids, gender and 23 metabolites from benign parenchyma were significantly associated with eGFR slope. Some metabolites associated with eGFR slope overlapped with previously reported chronic kidney disease-related processes. Subgroup analysis identified unique 'metabolite signatures' by older age, nephrectomy type and preoperative eGFR. Nephrectomy type, gender, blood lipids and benign parenchyma metabolites at nephrectomy were associated with long-term kidney function. On further study, these metabolites may be useful as potential biomarkers and to identify novel therapeutic targets for malignancy-associated renal disease.


[Cells of the metrial gland: their relation to trophoblast cells and reproductive characteristics].
Data on the origin, morphology and function of metrial gland cells are reviewed. Characteristic features of metrial gland cells are the availability of numerous eosinophilic granules lying near two round or oval nuclei and peripheral zone of the cytoplasm, generally devoid of organelles. This zone can generate pseudopodia-like projections. The notable peculiarity of metrial gland cells involves their ability to penetrate into blood vessels, to migrate towards the embryo, and to achieve the ectoplacental cone. The majority of metrial gland cells is accumulated in the decidua basalis zone where the tertiary trophoblast cells usually migrate. The metrial gland cells seem to constitute a cell population analogous to that of decidual cells. Data on the protective role of metrial gland cells are discussed. The metrial gland cells are proven to be polyploid. Polyploid nuclei are found both in mononucleate and binucleate cells. Acytokinetic mitosis is presumably a way leading to polyploidization of metrial gland cells.