Long term results of glass ionomer ossiculoplasty.
To analyze and compare the early and late post-operative results of glass ionomer bone cement (GIBC) used in ossiculoplasty. The pre-operative, early post-operative (3 months) and late post-operative (> 2 years) audiometric findings, namely the pure-tone average (PTA), bone conduction threshold (BCT) and air-bone gap (ABG) of 40 patients who underwent GIBC ossiculoplasty for different etiologies were analyzed. Early and late results were compared. Also, the patients were grouped in terms of prognostic factors and applied ossiculoplasty techniques, and the results were compared between the groups. There were statistically significant improvements in the pure-tone average and air-bone gap of the patients in the early post-operative period (PTA from 59.60 ± 15.95 to 40.37 ± 17.83 and ABG from 37.12 ± 11.18 to 19.78 ± 10.41, p < 0.001 for both). There were no statistically significant changes in any of the audiometric parameters in the late post-operative period (PTA from 40.37 ± 17.83 to 39.79 ± 17.91, ABG from 19.78 ± 10.41 to 19.32 ± 9.60, BCT from 17.99 ± 12.71 to 18.31 ± 13.99, p > 0.05 for all). Presence of tympanosclerosis was found to be the only prognostic factor to affect the outcome. GIBC is a safe and reliable material for ossiculoplasty, which maintains its ability to conduct sound in the long-term follow-up.


Regulation of mammalian cone phototransduction by recoverin and rhodopsin kinase.
Cone photoreceptors function under daylight conditions and are essential for color perception and vision with high temporal and spatial resolution. A remarkable feature of cones is that, unlike rods, they remain responsive in bright light. In rods, light triggers a decline in intracellular calcium, which exerts a well studied negative feedback on phototransduction that includes calcium-dependent inhibition of rhodopsin kinase (GRK1) by recoverin. Rods and cones share the same isoforms of recoverin and GRK1, and photoactivation also triggers a calcium decline in cones. However, the molecular mechanisms by which calcium exerts negative feedback on cone phototransduction through recoverin and GRK1 are not well understood. Here, we examined this question using mice expressing various levels of GRK1 or lacking recoverin. We show that although GRK1 is required for the timely inactivation of mouse cone photoresponse, gradually increasing its expression progressively delays the cone response recovery. This surprising result is in contrast with the known effect of increasing GRK1 expression in rods. Notably, the kinetics of cone responses converge and become independent of GRK1 levels for flashes activating more than ∼1% of cone pigment. Thus, mouse cone response recovery in bright light is independent of pigment phosphorylation and likely reflects the spontaneous decay of photoactivated visual pigment. We also find that recoverin potentiates the sensitivity of cones in dim light conditions but does not contribute to their capacity to function in bright light.


Examination of the early infection stages of koi herpesvirus (KHV) in experimentally infected carp, Cyprinus carpio L. using in situ hybridization.
Koi herpesvirus (KHV) causes a highly infectious disease afflicting common carp and koi, Cyprinus carpio L. Various molecular and antibody-based detection methods have been used to elucidate the rapid attachment and dissemination of the virus throughout carp tissues, facilitating ongoing development of effective diagnostic approaches. In situ hybridization (ISH) was used here to determine the target tissues of KHV during very early infection, after infecting carp with a highly virulent KHV isolate. Analysis of paraffin-embedded tissues (i.e. gills, skin, spleen, kidney, gut, liver and brain) during the first 8 h and following 10 days post-infection (hpi; dpi) revealed positive signals in skin mucus, gills and gut sections after only 1 hpi. Respiratory epithelial cells were positive as early as 2 hpi. Viral DNA was also detected within blood vessels of various tissues early in the infection. Notable increases in signal abundance were observed in the gills and kidney between 5 and 10 dpi, and viral DNA was detected in all tissues except brain. This study suggests that the gills and gut play an important role in the early pathogenesis of this Alloherpesvirus, in addition to skin, and demonstrates ISH as a useful diagnostic tool for confirmation of acutely infected carp.


Added value of diffusion weighted imaging in pediatric central nervous system embryonal tumors surveillance.
Diffusion weighted imaging (DWI) has an established role in primary CNS embryonal tumor (ET) characterization; however, its diagnostic utility in detecting relapse has never been determined. We aimed to compare DWI and conventional MRI sensitivity in CNS ET recurrence detection, and to evaluate the DWI properties of contrast-enhancing radiation induced lesions (RIL). Fifty-six patients with CNS ET (25 with disease relapse, 6 with RIL and 25 with neither disease relapse nor RIL) were retrospectively evaluated with DWI, conventional MRI (including both T2/FLAIR and post-contrast images), or contrast-enhanced MR imaging (CE-MRI) alone. MRI studies were independently reviewed by two neuroradiologists for detection and localization of potential brain relapses. Sensitivity for focal relapse detection was calculated for each image set on a lesion-by-lesion basis. A descriptive per subject analysis was also performed. Evaluation of follow-up MRI studies served as standard of reference. Focal recurrence detection sensitivity of DWI (96%) was significantly higher than conventional MRI (77%) and CE-MRI alone (51%) (p=0.0003 and p<0.0001). On per subject analysis there were not missed diagnoses for DWI. At the time of DWI relapse detection, conventional MRI missed 2 diagnoses, and CE-MRI 8. Analysis of medulloblastoma relapses revealed that DWI identified a higher number of focal lesions than CE-MRI in subjects with classic variant. All but one RIL did not show restricted diffusion. In conclusion, DWI is a valuable complementary technique allowing for improved detection of focal relapse in CNS ET patients, particularly in children with classic medulloblastoma, and may assist in differentiating recurrence from RIL.


Mechanisms of HBV-related hepatocarcinogenesis.
The hepatitis B virus (HBV) is a small enveloped DNA virus, which primarily infects hepatocytes and causes acute and persistent liver disease. Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma, but the molecular mechanisms underlying virally-induced tumourigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular cancer-related genes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long-term effects of viral proteins in enhancing immune-mediated liver disease. Recent genetic studies indicate that HBV-related tumours display a distinctive profile with a high rate of chromosomal alterations and low frequency of beta-catenin mutations. This review will discuss the evidence implicating chronic HBV infection as a causal risk factor of primary liver cancer. It will also discuss the molecular mechanisms that are critical for the tumourigenic process due to long lasting infection with HBV.


Type I and type IV pili of Xylella fastidiosa affect twitching motility, biofilm formation and cell-cell aggregation.
Xylella fastidiosa, an important phytopathogenic bacterium, causes serious plant diseases including Pierce's disease of grapevine. It is reported here that type I and type IV pili of X. fastidiosa play different roles in twitching motility, biofilm formation and cell-cell aggregation. Type I pili are particularly important for biofilm formation and aggregation, whereas type IV pili are essential for motility, and also function in biofilm formation. Thirty twitching-defective mutants were generated with an EZ : : TN transposome system, and several type-IV-pilus-associated genes were identified, including fimT, pilX, pilY1, pilO and pilR. Mutations in fimT, pilX, pilO or pilR resulted in a twitch-minus phenotype, whereas the pilY1 mutant was twitching reduced. A mutation in fimA resulted in a biofilm-defective and twitching-enhanced phenotype. A fimA/pilO double mutant was twitch minus, and produced almost no visible biofilm. Transmission electron microscopy revealed that the pili, when present, were localized to one pole of the cell. Both type I and type IV pili were present in the wild-type isolate and the pilY1 mutant, whereas only type I pili were present in the twitch-minus mutants. The fimA mutant produced no type I pili. The fimA/pilO double mutant produced neither type I nor type IV pili.


Maximum Plant Uptakes for Water, Nutrients, and Oxygen Are Not Always Met by Irrigation Rate and Distribution in Water-based Cultivation Systems.
Growing on rooting media other than soils in situ -i.e., substrate-based growing- allows for higher yields than soil-based growing as transport rates of water, nutrients, and oxygen in substrate surpass those in soil. Possibly water-based growing allows for even higher yields as transport rates of water and nutrients in water surpass those in substrate, even though the transport of oxygen may be more complex. Transport rates can only limit growth when they are below a rate corresponding to maximum plant uptake. Our first objective was to compare Chrysanthemum growth performance for three water-based growing systems with different irrigation. We compared; multi-point irrigation into a pond (DeepFlow); one-point irrigation resulting in a thin film of running water (NutrientFlow) and multi-point irrigation as droplets through air (Aeroponic). Second objective was to compare press pots as propagation medium with nutrient solution as propagation medium. The comparison included DeepFlow water-rooted cuttings with either the stem 1 cm into the nutrient solution or with the stem 1 cm above the nutrient solution. Measurements included fresh weight, dry weight, length, water supply, nutrient supply, and oxygen levels. To account for differences in radiation sum received, crop performance was evaluated with Radiation Use Efficiency (RUE) expressed as dry weight over sum of Photosynthetically Active Radiation. The reference, DeepFlow with substrate-based propagation, showed the highest RUE, even while the oxygen supply provided by irrigation was potentially growth limiting. DeepFlow with water-based propagation showed 15-17% lower RUEs than the reference. NutrientFlow showed 8% lower RUE than the reference, in combination with potentially limiting irrigation supply of nutrients and oxygen. Aeroponic showed RUE levels similar to the reference and Aeroponic had non-limiting irrigation supply of water, nutrients, and oxygen. Water-based propagation affected the subsequent cultivation in the DeepFlow negatively compared to substrate-based propagation. Water-based propagation resulted in frequent transient discolorations after transplanting in all cultivation systems, indicating a factor, other than irrigation supply of water, nutrients, and oxygen, influencing plant uptake. Plant uptake rates for water, nutrients, and oxygen are offered as a more fundamental way to compare and improve growing systems.


Iron involvement in multiple signaling pathways of atherosclerosis: a revisited hypothesis.
Atherosclerosis being a leading death cause in many countries is a chronic inflammatory process in which inflammation, immune activation, and oxidative stress are interactively involved. Some epidemiological and many experimental studies suggest that development of atherosclerosis is associated with the amount of iron stored in the body. Transport of electrons between different forms of iron makes it essential for many fundamental cell functions and signaling. Under pathologic conditions iron may serves as a potential catalyst, particularly in the form of redox-active iron or labile iron, for free radical reactions in oxidative stress and cell damage of atherogenesis. Emerging evidence indicates that cellular iron may participate in various cellular signaling pathways, many of which have been implicated in atherogenesis. These include iron homeostatic control signaling, iron-induced oxidative-responsive transcription factors, iron-induced activation of inflammatory cytokines, and iron-dependent signaling in cell growth and apoptosis. This review highlights research progress on atherosclerosis-relevant iron signaling and revisits our hypothesis on iron and atherosclerosis. We propose that iron may contribute to the pathogenesis of atherosclerosis not only via changes in the body iron amount but also by its regulatory roles in redox-sensitive signaling and inflammatory immune responses of atherosclerosis.


COVID-19 in 17 Italian Pediatric Emergency Departments.
Variability in presentation of children with coronavirus disease 2019 (COVID-19) is a challenge in emergency departments (EDs) in terms of early recognition, which has an effect on disease control and prevention. We describe a cohort of 170 children with COVID-19 and differences with the published cohorts. Retrospective chart reviews on children (0-18 years) evaluated in 17 Italian pediatric EDs. In our cohort (median age of 45 months; interquartile range of 4 months-10.7 years), we found a high number of patients <1 year with COVID-19 disease. The exposure happened mainly (59%) outside family clusters; 22% had comorbidities. Children were more frequently asymptomatic (17%) or with mild diseases (63%). Common symptoms were cough (43%) and difficulty feeding (35%). Chest computed tomography, chest radiograph, and point-of-care lung ultrasound were used in 2%, 36%, and 8% of cases, respectively. Forty-three percent of patients were admitted because of their clinical conditions. The minimal use of computed tomography and chest radiograph may have led to a reduced identification of moderate cases, which may have been clinically classified as mild cases. Italian children evaluated in the ED infrequently have notable disease symptoms. For pediatrics, COVID-19 may have rare but serious and life-threatening presentations but, in the majority of cases, represents an organizational burden for the ED. These data should not lower the attention to and preparedness for COVID-19 disease because children may represent a source of viral transmission. A clinically driven classification, instead of a radiologic, could be more valuable in predicting patient needs and better allocating resources.


Models of genetic drift as limiting forms of the Lotka-Volterra competition model.
The relationship between the Moran model and stochastic Lotka-Volterra competition (SLVC) model is explored via time scale separation arguments. For neutral systems the two are found to be equivalent at long times. For systems with selective pressure, their behavior differs. It is argued that the SLVC is preferable to the Moran model since in the SLVC population size is regulated by competition, rather than arbitrarily fixed as in the Moran model. As a consequence, ambiguities found in the Moran model associated with the introduction of more complex processes, such as selection, are avoided.


Machine learning and materials modelling interpretation of in vivo toxicological response to TiO2 nanoparticles library (UV and non-UV exposure).
Assessing the risks of nanomaterials/nanoparticles (NMs/NPs) under various environmental conditions requires a more systematic approach, including the comparison of effects across many NMs with identified different but related characters/descriptors. Hence, there is an urgent need to provide coherent (eco)toxicological datasets containing comprehensive toxicity information relating to a diverse spectra of NPs characters. These datasets are test benches for developing holistic methodologies with broader applicability. In the present study we assessed the effects of a custom design Fe-doped TiO2 NPs library, using the soil invertebrate Enchytraeus crypticus (Oligochaeta), via a 5-day pulse via aqueous exposure followed by a 21-days recovery period in soil (survival, reproduction assessment). Obviously, when testing TiO2, realistic conditions should include UV exposure. The 11 Fe-TiO2 library contains NPs of size range between 5-27 nm with varying %Fe (enabling the photoactivation of TiO2 at energy wavelengths in the visible-light range). The NPs were each described by 122 descriptors, being a mixture of measured and atomistic model descriptors. The data were explored using single and univariate statistical methods, combined with machine learning and multiscale modelling techniques. An iterative pruning process was adopted for identifying automatically the most significant descriptors. TiO2 NPs toxicity decreased when combined with UV. Notably, the short-term water exposure induced lasting biological responses even after longer-term recovery in clean exposure. The correspondence with Fe-content correlated with the band-gap hence the reduction of UV oxidative stress. The inclusion of both measured and modelled materials data benefitted the explanation of the results, when combined with machine learning.


Hypercard coding system for the ACR Index for Radiological Diagnoses.
We describe a computer version of the Index for Radiological Diagnoses of the American College of Radiology (ACR). This system combines a graphics interface with a search mechanism while preserving the hierarchical structure of the Index. The graphics interface allows easy selection of an anatomic part, while the search mechanism provides the code numbers associated with an entered term. The computer system and the paperback version of the ACR Index were compared by having 52 volunteers (21 radiology faculty members, 21 radiology residents, and 10 medical students) each code 30 cases with the book and a matched set of 30 cases with the computer. The average time to code cases was shorter when the computer was used (52.2 vs 64.5 sec; p less than .0001). Accuracy was higher when the computer was used (96.4% vs 90.4%; p less than .0001). The average confidence in the computer diagnosis was also higher (9.73 vs 9.51, on a scale of 1-10; p = .0016). This system demonstrates the ability of a computer program to outperform an analogous noncomputerized system.


Hospitalists as Triagists: Description of the Triagist Role across Academic Medical Centers.
From the hospitalist perspective, triaging involves the evaluation of a patient for potential admission to an inpatient service. Although traditionally done by residents, many academic hospitalist groups have assumed the responsibility for triaging. We conducted a cross-sectional survey of 235 adult hospitalists at 10 academic medical centers (AMCs) to describe the similarities and differences in the triagist role and assess the activities and skills associated with the role. Eight AMCs have a defined triagist role; at the others, hospitalists supervise residents/advanced practice providers. The triagist role is generally filled by a faculty physician and shared by all hospitalists.We found significant variability in verbal communication practices (P = .02) and electronic communication practices (P < .0001) between the triagist and the current provider (eg, emergency department, clinic provider), and in the percentage of patients evaluated in person (P < .0001). Communication skills, personal efficiency, and systems knowledge are dominant themes of attributes of an effective triagist.


[The Sorin pericardial bioprosthesis--a stentless aortic valve with very good hemodynamic performance].
The Sorin Pericarbon Freedom Stentless aortic valve has the potential to provide superior hemodynamic function and durability. In this study we assessed the hemodynamic performance of this valve and its impact on LV-mass regression after aortic valve replacement. 31 consecutive patients who received a Sorin Pericarbon Freedom Stentless aortic valve were analysed. Mean age of the patients (16 female and 15 male) was 64 +/- 17 years. Five patients had isolated aortic stenosis, three isolated aortic regurgitation and one combined aortic valve disease. Three patients had combined aortic and mitral valve disease, 14 patients concomitant coronary artery disease, one congenital aortic coarctation. Three patients had an acute aortic valve endocarditis. 18 patients were classified as high-risk patients (mean EuroSCORE 9 +/- 2). Mean left ventricular ejection fraction was 52.5 +/- 15.0%. Valve sizes from 21 mm to 29 mm were implanted. The valves were oversized by 2 mm compared to measurement. 16 patients received isolated aortic valve replacement, Three patients aortic valve replacement and mitral valve reconstruction. 12 patients had concomitant CABG. Three procedures were reoperations. Hospital mortality was 6.4% (two patients). Both deaths occurred in high-risk patients and were not valve-related. Four patients had perioperative low-output-syndrome and needed IABP. After six months a follow up echocardiography was performed. Mean and peak gradients were 9.6 +/- 4.4 and 20.6 +/- 5.9 mmHg, respectively. Significant reduction of left ventricular hypertrophy (LV mass index 126.5 +/- 27.3 vs. 189.6 +/- 45.3 g/m2, p = 0.0313) and improvement of the ejection fraction (58 +/- 9.8 vs. 52.5 +/- 15.0%, p = 0.9749) as compared with preoperative valve. The hemodynamic performance of the Sorin Pericarbon Freedom Stentless aortic valve is excellent and the patient outcome is satisfying. However the implantation technique requires longer ischemic time, the prosthesis offers very satisfying hemodynamic function and accelerates probably the LV-mass regression in the mid term follow-up. Late performance and durability of the valve have to be assessed.


Hypopituitarism following complicated child birth (Sheehan's syndrome).
We describe two patients with hypopituitarism and a history of severe bleeding or hypotensive shock at the time of child birth. Both patients had a decrease of all or some endocrine functions of the anterior pituitary. Although the frequency of Sheehan's syndrome is low in developed countries, it should still be considered in the differential diagnosis of hypopituitarism. An interval of many years between delivery and time of diagnosis does not exclude the diagnosis.


Universal Spin Diffusion Length in Polycrystalline Graphene.
Graphene grown by chemical vapor deposition (CVD) is the most promising material for industrial-scale applications based on graphene monolayers. It also holds promise for spintronics; despite being polycrystalline, spin transport in CVD graphene has been measured over lengths up to 30 μm, which is on par with the best measurements made in single-crystal graphene. These results suggest that grain boundaries (GBs) in CVD graphene, while impeding charge transport, may have little effect on spin transport. However, to date very little is known about the true impact of disordered networks of GBs on spin relaxation. Here, by using first-principles simulations, we derive an effective tight-binding model of graphene GBs in the presence of spin-orbit coupling (SOC), which we then use to evaluate spin transport in realistic morphologies of polycrystalline graphene. The spin diffusion length is found to be independent of the grain size, and it is determined only by the strength of the substrate-induced SOC. This result is consistent with the D'yakonov-Perel' mechanism of spin relaxation in the diffusive regime, but we find that it also holds in the presence of quantum interference. These results clarify the role played by GBs and demonstrate that the average grain size does not dictate the upper limit for spin transport in CVD-grown graphene, a result of fundamental importance for optimizing large-scale graphene-based spintronic devices.


Light-driven tipping points in polar ecosystems.
Some ecosystems can undergo abrupt transformation in response to relatively small environmental change. Identifying imminent 'tipping points' is crucial for biodiversity conservation, particularly in the face of climate change. Here, we describe a tipping point mechanism likely to induce widespread regime shifts in polar ecosystems. Seasonal snow and ice-cover periodically block sunlight reaching polar ecosystems, but the effect of this on annual light depends critically on the timing of cover within the annual solar cycle. At high latitudes, sunlight is strongly seasonal, and ice-free days around the summer solstice receive orders of magnitude more light than those in winter. Early melt that brings the date of ice-loss closer to midsummer will cause an exponential increase in the amount of sunlight reaching some ecosystems per year. This is likely to drive ecological tipping points in which primary producers (plants and algae) flourish and out-compete dark-adapted communities. We demonstrate this principle on Antarctic shallow seabed ecosystems, which our data suggest are sensitive to small changes in the timing of sea-ice loss. Algae respond to light thresholds that are easily exceeded by a slight reduction in sea-ice duration. Earlier sea-ice loss is likely to cause extensive regime shifts in which endemic shallow-water invertebrate communities are replaced by algae, reducing coastal biodiversity and fundamentally changing ecosystem functioning. Modeling shows that recent changes in ice and snow cover have already transformed annual light budgets in large areas of the Arctic and Antarctic, and both aquatic and terrestrial ecosystems are likely to experience further significant change in light. The interaction between ice-loss and solar irradiance renders polar ecosystems acutely vulnerable to abrupt ecosystem change, as light-driven tipping points are readily breached by relatively slight shifts in the timing of snow and ice-loss.


Analgesic Efficacy of Ultrasound Guided FICB in Patients with Hip Fracture.
Hip fractures are often encountered in the elderly and present special problems to the anaesthesiologist. Fascia iliaca compartment block is another technique with the intent to block all the three nerves like 3-in-1 nerve block. To evaluate the analgesic efficacy of ultrasound guided fascia iliaca compartment block to facilitate positioning of patients with hip fracture for spinal anaesthesia. This prospective study was conducted in 50 patients aged between 40-80 years, belonging to American Society of Anesthesiologists (ASA) physical status I-III undergoing surgery for hip fracture. All 50 patients received an ultrasound guided Fascia Iliaca Compartment Block (FICB) in the premedication room with 30 mL of 0.5% ropivacaine by 23G spinal needle. Sensory blockade was evaluated 5, 10 and 20 minutes after ropivacaine administration using loss of perception to cold in the lateral, anterior and medial part of the thigh. Visual analogue scale scores were noted before the block, 20 minutes after block and during positioning for spinal anaesthesia. Patient's acceptance for FICB was evaluated 24 hour after arriving back to the orthopaedics ward using a two-point score. Any episode of hypotension or bradycardia was noted and managed accordingly. In lateral part of thigh, at 5 minutes sensory blockade was present in 33 patients (66%) and at 10 minutes sensory blockade was present in 45 cases (90%). In anterior part of thigh, sensory blockade was present in 34 cases (68%) at 5 minutes time interval and at 10 minutes sensory blockade was present in 48 cases (96%). In medial part of thigh, 28 cases (56%) had sensory blockade at 5 minutes and at 10 minutes in 43 cases (86%). Sensory blockage was same at 20 minutes as on 10 minutes interval in all thigh parts. Before FIC block average VAS was 7.5 which was decreased to average of 2.94 at 20 minutes after block which was statistically significant (p<0.01). During positioning for spinal anaesthesia, 46 patients had VAS less than 4. Positioning during spinal anaesthesia was assessed unsatisfactory (0) in 2 cases (4%), satisfactory (1) in 5 cases (10%), good (2) in 25 cases (50%) and excellent (3) in 18 cases (36%). Ultrasound guided FICB can be performed safely without complications in controlling pain for patients with hip fracture. Performing an FICB before positioning for spinal anaesthesia provides good pain management and facilitates spinal performance with wide patient acceptance, hence improving overall quality and efficiency of care.


gurke and pasticcino3 mutants affected in embryo development are impaired in acetyl-CoA carboxylase.
Normal embryo development is required for correct seedling formation. The Arabidopsis gurke and pasticcino3 mutants were isolated from different developmental screens and the corresponding embryos exhibit severe defects in their apical region, affecting bilateral symmetry. We have recently identified lethal acc1 mutants affected in acetyl-CoA carboxylase 1 (ACCase 1) that display a similar embryo phenotype. A series of crosses showed that gk and pas3 are allelic to acc1 mutants, and direct sequencing of the ACC1 gene revealed point mutations in these new alleles. The isolation of leaky acc1 alleles demonstrated that ACCase 1 is essential for correct plant development and that mutations in ACCase affect cellular division in plants, as is the case in yeast. Interestingly, significant metabolic complementation of the mutant phenotype was obtained by exogenous supply of malonate, suggesting that the lack of cytosolic malonyl-CoA is likely to be the initial factor leading to abnormal development in the acc1 mutants.


Seasonal assessment of selected trace elements in grass carp (Ctenopharyngodon idella) blood and their effects on the biochemistry and oxidative stress markers.
Environmental pollution by anthropogenic activity is still a highly relevant global problem. Aquatic animals are a specifically endangered group of organisms due to their continuous direct contact with the contaminated environment. Concentrations of selected trace elements in the grass carp (Ctenopharyngodon idella) (n = 36) blood serum/clot were monitored. Possible effects of the elements on selected biochemical and oxidative markers were evaluated. The concentrations of trace elements (Al, Ba, Be, Bi, Cd, Co, Cr, Cu, Fe, Ga, Mn, Mo, Ni, Pb, Sr, Tl, and Zn) were analysed in the fish blood serum and blood clot by inductively coupled plasma optical emission spectrometry (ICP OES). A general scheme of decreasing concentrations of trace elements in the blood serum samples was: Zn ˃ Fe ˃ Sr ˃ Ba ˃ Ni ˃ Al ˃ Cu ˃ Be ˃ Co; < LOQ (below limit of quantification): Bi, Cd, Cr, Ga, Mn, Mo, Pb, Tl; and in the case of the blood clot, the scheme was as follows: Fe ˃ Zn ˃ Sr ˃ Al ˃ Ni ˃ Ba ˃ Cu ˃ Be ˃ Co ˃ Mn; < LOQ (below limit of quantification): Bi, Cd, Cr, Ga, Mo, Pb, Tl. Significant differences among the seasons were detected. The Spearman R correlation coefficients and linear or non-linear regression were used to evaluate direct relationships between trace elements and selected blood biomarkers. The correlation analysis between biochemical parameters (Na, K, P, Mg, AST, ALT, ALP, GGT, TAG, TP, urea, glucose) and trace elements (Al, Ba, Be, Cu, Fe, Ni, Sr, and Zn) concentrations confirmed statistically significant interactions in both seasons (summer and autumn). The regression analysis between oxidative stress markers (ROS, GPx, creatinine, uric acid, and bilirubin) and elements (Al, Ba, Co, Cu, Fe, Ni, and Sr) content confirmed statistically significant interactions. The results point to numerous connections between the observed elements and the physiological parameters of freshwater fish.


Relationships and taxonomic status of Alternaria radicina, A. carotiincultae, and A. petroselini based upon morphological, biochemical, and molecular characteristics.
Alternaria radicina, A. carotiincultae, and A. petroselini are closely related pathogens of umbelliferous crops. Relationships among these fungi were determined based on growth rate, spore morphology, cultural characteristics, toxin production, and host range. Random amplified polymorphic DNA (RAPD) analysis of these species, other species of Alternaria, and closely related fungi was also performed. A. petroselini was readily differentiated from A. radicina and A. carotiincultae on the basis of spore morphology, production of microsclerotia, host range, and RAPD analysis. Alternaria radicina and A. carotiincultae were considerably more similar to each other than to A. petroselini, but could be differentiated on the basis of growth rate, spore morphology, colony morphology, and, to a limited extent, RAPD analysis. When grown on media having a high nutritional content, A. radicina produced a diffusible yellow pigment and crystals of the fungal metabolite radicinin. In contrast, A. carotiincultae produced little or no radicinin. However, when A. carotiincultae was grown on the same medium amended with radicinin, growth rate and colony and conidial morphology were more similar to those of A. radicina. These results suggest that the morphological differences between A. radicina and A. carotiincultae are due, at least in part, to radicinin production, and that these fungi are conspecific. Therefore, we propose that A. carotiincultae be considered a synonym of A. radicina.


The elderly patient on dialysis: geriatric considerations.
The burgeoning population of older dialysis patients presents opportunities to provide personalized care. The older dialysis population has a high burden of chronic health conditions, decrements in quality of life and a high risk of death. In order to address these challenges, this review will recommend routinely establishing prognosis through the use of prediction instruments and communicating these findings to older patients. The challenges to prognosis in adults with end-stage renal disease (ESRD) include the subjective nature of clinical judgment, application of appropriate prognostic tools and communication of findings to patients and caregivers. There are three reasons why we believe these conversations occur infrequently with the dialysis population. First, there have previously been no clinically practical instruments to identify individuals undergoing maintenance hemodialysis (HD) who are at highest risk for death. Second, nephrologists have not been trained to have conversations about prognosis and end-of-life care. Third, other than hospitalizations and accrual of new diagnoses, there are no natural milestone guidelines in place for patients supported by dialysis. The prognosis can be used in shared decision-making to establish goals of care, limits on dialysis support or parameters for withdrawal from dialysis. As older adults with ESRD benefit from kidney transplantation, prognosis can also be used to determine who should be referred for evaluation by a kidney transplant team. The use of prognosis in older adults may determine approaches to optimize well-being and personalize care among older adults ranging from hospice to kidney transplantation.


INFLUENCE OF SNOWFALL ON BLOOD LEAD LEVELS OF FREE-FLYING BALD EAGLES (HALIAEETUS LEUCOCEPHALUS) IN THE UPPER MISSISSIPPI RIVER VALLEY.
Lead poisoning of scavenging raptors occurs primarily via consumption of game animal carcasses containing lead, which peaks during fall firearm hunting seasons. We hypothesized that snowfall would mitigate exposure by concealing carcasses. We categorized blood lead level (BLL) for a subsample of Bald Eagles (Haliaeetus leucocephalus) from the Upper Mississippi River Valley and described BLL with respect to age, sex, and snowfall. We captured Bald Eagles overwintering in the Upper Mississippi River Valley (n=55) between December 1999 and January 2002. Individual BLL ranged from nondetectable to 335 μg/dL, with 73% of the samples testing positive for acute exposure to lead. Eagle BLL did not significantly differ between age or sex, but levels were higher immediately following the hunting season, and they were lower when the previous month's snowfall was greater than 11 cm. This study suggests a window of time between the white-tailed deer (Odocoileus virginianus) hunting season and the onset of snow when the population experienced peak exposure to lead. Combining these findings with existing research, we offer a narrative of the annual lead exposure cycle of Upper Mississippi River Valley Bald Eagles. These temporal associations are necessary considerations for accurate collection and interpretation of BLL.


Raising awareness of sensory impairment among community nurses: a brief intervention in a remote island setting.
The prevalence of sensory impairment that includes sight and/or hearing impairment is projected to rise worldwide given the strong correlation between sensory impairment, older age and the demographic structure of the global population. Sensory impairment and associated disability is thus a significant global health concern. The prevalence rates for sensory impairment in Scotland are significant: as more people live into older age and as the age distribution in rural areas is markedly different with a higher proportion of older people, the extent of sensory impairment in the rural population will increase proportionally. In rural areas community nurses have a key role in recognising sensory impairment and directing people to sensory services to reduce the debilitating impact of sensory impairment. However, there is limited evidence about the utility of educational interventions to enhance healthcare professionals' knowledge, skills and attitudes about sensory impairment and subsequent impact on referral practices. The aim of this study was to evaluate the impact of a brief educational intervention with community nurses. The educational intervention was a training workshop that included simulation practice, information on assessment and referral pathways. The study was conducted in a remote island community health setting in the Western Isles of Scotland. The study evaluated nurses' perceptions of the training on their knowledge, attitudes and practice. Mixed method, longitudinal design was implemented in three phases. Phase 1 was a pre- and post-workshop questionnaire, phase 2 a postal questionnaire 3 months post-workshop and phase 3 a qualitative focus group interview 6 months post-workshop. Kirkpatrick's model of training evaluation provided a framework for data evaluation. A total of 41 community based healthcare professionals who were mostly nurses participated in the study. Participants described increased awareness of the potential for their patients to have a sensory impairment, greater understanding and empathy with patients who experience sensory impairment, more robust patient assessment to identify impairment, and increased likelihood to inform of, and refer to, sensory services. Community nurses are often well placed to identity disabilities and patients at risk of injury because of sensory impairment. Participation in simulation training can help to develop greater awareness of the impact of that sensory impairment. Knowledge of specialist services will increase the opportunities for referral to services and impact positively on the lives of older people living in rural settings. Provision of accessible education on sensory impairment for health and social care professionals can enhance care delivery to older people.


Emerging frontiers in nanomedicine targeted therapy for prostate cancer.
Prostate cancer is a prevalent cancer in men, often treated with chemotherapy. However, it tumor cells are clinically grows slowly and is heterogeneous, leading to treatment resistance and recurrence. Nanomedicines, through targeted delivery using nanocarriers, can enhance drug accumulation at the tumor site, sustain drug release, and counteract drug resistance. In addition, combination therapy using nanomedicines can target multiple cancer pathways, improving effectiveness and addressing tumor heterogeneity. The application of nanomedicine in prostate cancer treatment would be an important strategy in controlling tumor dynamic process as well as improve survival. Thus, this review highlights therapeutic nanoparticles as a solution for prostate cancer chemotherapy, exploring targeting strategies and approaches to combat drug resistance.


Negative mood influences default mode network functional connectivity in patients with chronic low back pain: implications for functional neuroimaging biomarkers.
The default mode network (DMN) has been proposed as a biomarker for several chronic pain conditions. Default mode network functional connectivity (FC) is typically examined during resting-state functional neuroimaging, in which participants are instructed to let thoughts wander. However, factors at the time of data collection (eg, negative mood) that might systematically impact pain perception and its brain activity, influencing the application of the DMN as a pain biomarker, are rarely reported. This study measured whether positive and negative moods altered DMN FC patterns in patients with chronic low back pain (CLBP), specifically focusing on negative mood because of its clinical relevance. Thirty-three participants (CLBP = 17) underwent resting-state functional magnetic resonance imaging scanning before and after sad and happy mood inductions, and rated levels of mood and pain intensity at the time of scanning. Two-way repeated-measures analysis of variances were conducted on resting-state functional connectivity data. Significant group (CLBP > healthy controls) × condition (sadness > baseline) interaction effects were identified in clusters spanning parietal operculum/postcentral gyrus, insular cortices, anterior cingulate cortex, frontal pole, and a portion of the cerebellum (PFDR < 0.05). However, only 1 significant cluster covering a portion of the cerebellum was identified examining a two-way repeated-measures analysis of variance for happiness > baseline (PFDR < 0.05). Overall, these findings suggest that DMN FC is affected by negative mood in individuals with and without CLBP. It is possible that DMN FC seen in patients with chronic pain is related to an affective dimension of pain, which is important to consider in future neuroimaging biomarker development and implementation.


Electrodeposition of a carbon dots/chitosan composite produced by a simple in situ method and electrically controlled release of carbon dots.
Carbon dots (CDs), a new type of fluorescent nanomaterial, have drawn considerable attention due to their attractive applications in biolabeling, bioimaging and fluorescent probes. Here, a CDs/chitosan composite that can be straightforwardly used for further electrodeposition and electrically controlled release of CDs, was produced by a simple and novel in situ method based on a one-step microwave treatment of a chitosan solution. We choose the chitosan solution as the only reactant for producing the CDs/chitosan composite, because chitosan can not only serve as the precursor for preparing the CDs, but can also be frequently used for the electrodeposition. Importantly, the prepared CDs/chitosan composite is not only endowed with multicolor fluorescence features coming from the CDs, but also retains the pH-responsive film-forming properties of chitosan. On the basis of these favorable properties, we can straightforwardly employ the CDs/chitosan composite to construct fluorescent coatings, as well as a variety of multicolor fluorescent patterns on different electrodes or substrates through the electrodeposition technique. More interestingly, the release of CDs in the electrodeposited coatings or patterns can be controlled by electrical signals. Consequently, this CDs/chitosan composite with straightforward applications in electrodeposition and electrically controlled release of CDs is promising for use in photoluminescent coatings, fluorescent patterns, fluorescent labeling, and controlled release.


Can we define and characterize the aging lower urinary tract?-ICI-RS 2015.
The prevalence of lower urinary tract (LUT) symptoms increases with age but the etiology is unknown. This article aims to identify research directions that clarify the basis of this association. The initial question is whether biological age is the variable of interest or a time-dependent accumulation of factors that impact on LUT function at rates that differ between individuals. In particular, the accumulation of conditions or agents due to inflammatory states or tissue ischemia is important. Much of the above has been concerned with changes to bladder function and morphology. However, the outflow tract function is also affected, in particular changes to the function of external sphincter skeletal muscle and associated sacral motor nerve control. Nocturia is a cardinal symptom of LUT dysfunction and is more prevalent with aging. Urine production is determined by diurnal changes to the production of certain hormones as well as arterial blood pressure and such diurnal rhythms are blunted in subjects with nocturia, but the causal links remain to be elucidated. Changes to the central nervous control of LUT function with age are also increasingly recognized, whether in mid-brain/brainstem regions that directly affect LUT function or in higher centers that determine psycho-social and emotional factors impinging on the LUT. In particular, the linkage between increasing white matter hyperintensities and LUT dysfunction during aging is recognized but not understood. Overall, a more rational approach is being developed to link LUT dysfunction with factors that accumulate with age, however, the precise causal pathways remain to be characterized. Neurourol. Urodynam. 36:854-858, 2017. © 2017 Wiley Periodicals, Inc.


A 5-kilobase pair promoter fragment of the murine epididymal retinoic acid-binding protein gene drives the tissue-specific, cell-specific, and androgen-regulated expression of a foreign gene in the epididymis of transgenic mice.
The murine epididymis synthesizes and secretes a retinoic acid-binding protein (mE-RABP) that belongs to the lipocalin superfamily. The gene encoding mE-RABP is specifically expressed in the mouse mid/distal caput epididymidis under androgen control. In transgenic mice, a 5-kilobase pair (kb) promoter fragment, but not a 0.6-kb fragment, of the mE-RABP gene driving the chloramphenicol acetyltransferase (CAT) reporter gene restricted high level of transgene expression to the caput epididymidis. No transgene expression was detected in any other male or female tissues. Immunolocalization of the CAT protein and in situ hybridization of the corresponding CAT mRNA indicated that transgene expression occurred in the principal cells of the mid/distal caput epididymidis, thereby mimicking the spatial endogenous mE-RABP gene expression. Transgene and mE-RABP gene expression was detected from 30 days and progressively increased until 60 days of age. Castration, efferent duct ligation, and hormone replacement studies demonstrated that transgene expression was specifically regulated by androgen but not by any other testicular factors. Altogether, our results demonstrate that the 5-kb promoter fragment of the mE-RABP gene contains all of the information required for the hormonal regulation and the spatial and temporal expression of the mE-RABP gene in the epididymis.


Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles.
Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.


Enhanced PDR-BLE Compensation Mechanism Based on HMM and AWCLA for Improving Indoor Localization.
This paper presents an enhanced PDR-BLE compensation mechanism for improving indoor localization, which is considerably resilient against variant uncertainties. The proposed method of ePDR-BLE compensation mechanism (EPBCM) takes advantage of the non-requirement of linearization of the system around its current state in an unscented Kalman filter (UKF) and Kalman filter (KF) in smoothing of received signal strength indicator (RSSI) values. In this paper, a fusion of conflicting information and the activity detection approach of an object in an indoor environment contemplates varying magnitude of accelerometer values based on the hidden Markov model (HMM). On the estimated orientation, the proposed approach remunerates the inadvertent body acceleration and magnetic distortion sensor data. Moreover, EPBCM can precisely calculate the velocity and position by reducing the position drift, which gives rise to a fault in zero-velocity and heading error. The developed EPBCM localization algorithm using Bluetooth low energy beacons (BLE) was applied and analyzed in an indoor environment. The experiments conducted in an indoor scenario shows the results of various activities performed by the object and achieves better orientation estimation, zero velocity measurements, and high position accuracy than other methods in the literature.


Clinical Documentation to Predict Factors Associated with Urinary Incontinence Following Prostatectomy for Prostate Cancer.
Advances in data collection provide opportunities to use population samples in identifying risk factors for urinary incontinence (UI), which occurs in up to 71% of men with prostate cancer following prostatectomy. Most studies on patient-centered outcomes use surveys or manual chart abstraction for data collection, which can be costly and difficult to scale. We sought to evaluate rates of and risk factors for UI following prostatectomy using natural language processing on electronic health record (EHR) data. We conducted a retrospective analysis of patients undergoing prostatectomy for prostate cancer between January 2008 and August 2018 using EHR data from an academic medical center. UI incidence for each patient in the cohort was assessed using natural language processing from clinical notes generated pre- and postoperatively. Multivariable logistic regression was used to evaluate potential risk factors for postoperative UI at various time points within 2 years following surgery. We identified 3792 patients who underwent prostatectomy for prostate cancer. We found a significant association between preoperative UI and UI in the first (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.24-4.28) and second (OR 2.24, 95% CI 1.04-4.83) years following surgery. Preoperative body mass index was also associated with UI in the second postoperative year (OR 1.11, 95% CI 1.02-1.21). We show that a natural language processing approach using clinical narratives can be used to assess risk for UI in prostate cancer patients. Unstructured clinical narrative text can help advance future population-level research in patient-centered outcomes and quality of care.


Expression of RUNX3 gene in pancreatic adenocarcinoma and its clinical significance.
We investigated the clinical significance of RUNX3 gene expression in human pancreatic carcinoma. Five samples of pancreatic tissues and 30 samples of pancreatic cancer tissues and paracancerous tissues were collected. RUNX3 expression was detected by real-time PCR and immunohistochemistry. The relationships between clinicopathological findings and the expression of RUNX3 were analyzed. The relative quantification level of RUNX3 mRNA expression in human pancreatic carcinoma tissues and paracancerous tissues was 2.60 (0.42-12.82) and 1.02 (0.19-3.58), respectively (P < 0.05). The percentage of positive cells expressing RUNX3 protein in human pancreatic tissues and paracancerous tissues was 45.5 ± 26.2 and 6.9 ± 6.0%, respectively (P < 0.01). The high RUNX3 group (N = 9) with 45.5% or more of the cancer cells staining for RUNX3 and the low RUNX3 group (N = 21) with less than 45.5% cancer cells staining for RUNX3. Low expression of RUNX3 correlated significantly with an advanced TNM stage (χ(2) = 6.897, P = 0.045), lymph node metastasis (χ(2) = 4.739, P = 0.029) and neural invasion (χ(2) = 5.44, P = 0.020). On the other hand, no association could be found between RUNX3 expression and clinicopathological variables including age, gender, tumor location, tumor size, tumor differentiation or the serum concentration of CEA and CA199. The expression of RUNX3 in pancreatic cancer tissues was obviously higher than that in the paracancerous tissues. Low expression of RUNX3 may have an important role in aggressiveness, lymph node metastasis and neural invasion in pancreatic cancer. In pancreatic carcinoma tissues, low expression of RUNX3 may indicate a poor prognosis.


Novel nonsense mutation in MSX1 in familial nonsyndromic oligodontia: subcellular localization and role of homeodomain/MH4.
Nonsyndromic tooth agenesis is one of the most common anomalies in human development. Part of the malformation is inherited and is associated with paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) mutations. To obtain a comprehensive understanding of the genetic and molecular mechanisms that underlie this genetic disease, we investigated six familial and seven sporadic Japanese cases of nonsyndromic tooth agenesis. Searches for mutations in these candidate genes detected a novel nonsense mutation (c.416G>A) in exon 1 of MSX1 from a family with oligodontia. This mutation co-segregated in the affected family members. Moreover, this mutation produced a termination codon in the first exon and therefore the gene product (W139X) was truncated at the C terminus, hence, the entire homeodomain/MH4, which has many functions, such as DNA binding, protein-protein interaction, and nuclear localization, was absent. We characterized the properties of this truncated MSX1 by investigating the subcellular localization of the mutant gene product in transfected cells. The wild-type MSX1 localized exclusively at the nuclear periphery of transfected cells, whereas the mutant MSX1 was stable but localized diffusely throughout the whole cell. These results indicate that W139X MSX1 is responsible for tooth agenesis.


[Behavior disorder in rats induced by Madopar and its pharmacological correction].
Administration to rats of madopar in a dose of 125 mg/kg produced stereotypy, decrease in the exploration activity in the open field test, loss of the ability to decide the extrapolation problem (escape out of acute stressful situation). The latter type of behavioral pathology alone was selectively averted by administering the classical neuroleptics fluorophenazine, haloperidol and its analog azaperone. Atypical neuroleptics and the the antidepressant imipramine were less effective and reduced but animals' motor excitation induced by madopar according to the extrapolation avoidance test. The tranquilizer phenazepam did not influence behavioral pathology in this test. The data obtained suggest that impairment of the animals' behavioral pattern in the extrapolation avoidance test on madopar administration in a dose of 125 mg/kg may serve an experimental model for evaluating the neuroleptic effect of the drugs.


Analysis of Occupational Accidents in Underground and Surface Mining in Spain Using Data-Mining Techniques.
An analysis of occupational accidents in the mining sector was conducted using the data from the Spanish Ministry of Employment and Social Safety between 2005 and 2015, and data-mining techniques were applied. Data was processed with the software Weka. Two scenarios were chosen from the accidents database: surface and underground mining. The most important variables involved in occupational accidents and their association rules were determined. These rules are composed of several predictor variables that cause accidents, defining its characteristics and context. This study exposes the 20 most important association rules in the sector-either surface or underground mining-based on the statistical confidence levels of each rule as obtained by Weka. The outcomes display the most typical immediate causes, along with the percentage of accidents with a basis in each association rule. The most important immediate cause is body movement with physical effort or overexertion, and the type of accident is physical effort or overexertion. On the other hand, the second most important immediate cause and type of accident are different between the two scenarios. Data-mining techniques were chosen as a useful tool to find out the root cause of the accidents.


[Age-specific features of the vessels of the microcirculatory bed of the conjunctiva].
The microcirculatory bed of various parts of the human bulbar conjunctiva in ontogenesis has been studied in 63 preparations of the eyeball by means of complex morphological methods. Structural peculiarities and functions of all parts of the micro-vessels have been revealed in fetuses, their conjunctiva being not yet subjected to any environmental effect, and in successive age groups of the postnatal development. The period of stabilization and differentiation for all parts of the microcirculatory bed in the eyeball conjunctiva has been stated. Certain age changes of the microcirculatory bed have been revealed in all sectors and in various parts within the sectors; these changes should be taken into account at biomicroscopy and when analysing the data obtained.


The phenotypic spectrum associated with OTX2 mutations in humans.
The transcription factor OTX2 is implicated in ocular, craniofacial, and pituitary development. We aimed to establish the contribution of OTX2 mutations in congenital hypopituitarism patients with/without eye abnormalities, study functional consequences, and establish OTX2 expression in the human brain, with a view to investigate the mechanism of action. We screened patients from the UK (n = 103), international centres (n = 24), and Brazil (n = 282); 145 were within the septo-optic dysplasia spectrum, and 264 had no eye phenotype. Transactivation ability of OTX2 variants was analysed in murine hypothalamic GT1-7 neurons. In situ hybridization was performed on human embryonic brain sections. Genetically engineered mice were generated with a series of C-terminal OTX2 variants. Two chromosomal deletions and six haploinsufficient mutations were identified in individuals with eye abnormalities; an affected relative of one patient harboured the same mutation without an ocular phenotype. OTX2 truncations led to significant transactivation reduction. A missense variant was identified in another patient without eye abnormalities; however, studies revealed it was most likely not causative. In the mouse, truncations proximal to aa219 caused anophthalmia, while distal truncations and the missense variant were tolerated. During human embryogenesis, OTX2 was expressed in the posterior pituitary, retina, ear, thalamus, choroid plexus, and partially in the hypothalamus, but not in the anterior pituitary. OTX2 mutations are rarely associated with hypopituitarism in isolation without eye abnormalities, and may be variably penetrant, even within the same pedigree. Our data suggest that the endocrine phenotypes in patients with OTX2 mutations are of hypothalamic origin.


The Bigger Picture: Why Oral Mucosa Heals Better Than Skin.
Wound healing is an essential process to restore tissue integrity after trauma. Large skin wounds such as burns often heal with hypertrophic scarring and contractures, resulting in disfigurements and reduced joint mobility. Such adverse healing outcomes are less common in the oral mucosa, which generally heals faster compared to skin. Several studies have identified differences between oral and skin wound healing. Most of these studies however focus only on a single stage of wound healing or a single cell type. The aim of this review is to provide an extensive overview of wound healing in skin versus oral mucosa during all stages of wound healing and including all cell types and molecules involved in the process and also taking into account environmental specific factors such as exposure to saliva and the microbiome. Next to intrinsic properties of resident cells and differential expression of cytokines and growth factors, multiple external factors have been identified that contribute to oral wound healing. It can be concluded that faster wound closure, the presence of saliva, a more rapid immune response, and increased extracellular matrix remodeling all contribute to the superior wound healing and reduced scar formation in oral mucosa, compared to skin.


Signaling through the TGF beta-activin receptors ALK4/5/7 regulates testis formation and male germ cell development.
The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgfβ family members has indicated that Tgfβ's are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGFβ's, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGFβ signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGFβ receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGFβ and Activin signaling during testis formation and male germ cell development.


Replacement of barley with oats and dehulled oats: Effects on milk production, enteric methane emissions, and energy utilization in dairy cows fed a grass silage-based diet.
Sixteen Nordic Red dairy cows, at 80 ± 4.6 d in milk and with an average body weight of 624 ± 91.8 kg, were used in a replicated 4 × 4 Latin square design to investigate the effects of different concentrate supplements on milk production, enteric CH4 emissions, ruminal fermentation, digestibility, and energy utilization. The cows were blocked into 4 groups based on parity and milk yield and randomly assigned to 1 of 4 experimental concentrates: (1) barley, (2) hulled oats, (3) an oat mixture consisting of hulled and dehulled oats, 50:50 on dry matter basis, and (4) dehulled oats; canola meal was a protein supplement in all 4 concentrates. The cows were fed grass silage and experimental concentrate (forage-to-concentrate ratio 60:40 on dry matter basis) ad libitum. To compare the effects of barley and oats, the barley diet was compared with the overall mean of the hulled oat, oat mixture, and dehulled oat diets. To investigate the effects of gradual replacement of hulled oats with dehulled oats, linear and quadratic contrasts were specified. Milk and energy-corrected milk (ECM) yield were higher on the oat diets compared with the barley diet but were not affected by the type of oats. Concentrations of milk constituents were not affected by grain species or type of oats, except for protein concentration, which was lower on the oat diets than on the barley diet. Feeding the oat diets led to higher milk protein yield and higher milk urea N concentrations. Feed efficiency tended to be higher on the oat diets, and linearly increased with increased inclusion of dehulled oats. Methane emissions (g/d) and CH4 yield (g/kg of dry matter intake) were unaffected by grain species but increased linearly with increasing inclusion of dehulled oats in the diet. Because of higher ECM yield, CH4 intensity (g/kg of ECM) was on average 5.7% lower from cows on the oat diets than on the barley diet. Ruminal fermentation was not affected by dietary treatment. Total-tract apparent digestibility of organic matter, crude protein, and neutral detergent fiber was unaffected by grain species but linearly increased with increasing inclusion of dehulled oats. Gross energy content was higher on the oat diets and linearly increased with increasing inclusion of dehulled oats. Feeding the oat diets led to a lower ratio of CH4 energy to gross energy intake, greater milk energy and heat production but no change in energy balance. Gradual replacement of hulled oats with dehulled oats linearly increased gross energy digestibility, CH4 energy, metabolizable energy intake, heat production, and energy balance. We observed no effect of dietary treatment on efficiency of metabolizable energy use for lactation. In conclusion, replacing barley with any type of oats increased milk and ECM yield, which led to a 5.7% decrease in CH4 intensity. In addition, dehulling of oats before feeding is unnecessary because it did not significantly improve production performance of dairy cows in positive energy balance.


Twenty-five years in the making: flecainide is safe and effective for the management of atrial fibrillation.
Atrial fibrillation (AF) is the most common arrhythmia in clinical practise and its prevalence is increasing. Over the last 25 years, flecainide has been used extensively worldwide, and its capacity to reduce AF symptoms and provide long-term restoration of sinus rhythm (SR) has been well documented. The increased mortality seen in patients treated with flecainide in the Cardiac Arrhythmia Suppression Trial (CAST) study, published in 1991, still deters many clinicians from using flecainide, denying many new AF patients a valuable treatment option. There is now a body of evidence that clearly demonstrates that flecainide has a favourable safety profile in AF patients without significant left ventricular disease or coronary heart disease. As a result of this evidence, flecainide is now recommended as one of the first-line treatment options for restoring and maintaining SR in patients with AF under current treatment guidelines. The objective of this article is to review the literature pertaining to the pharmacological characteristics, safety and efficacy of flecainide, and to place this drug in the context of current therapeutic management strategies for AF.


Differences in the length of postoperative care of endoscopic endonasal surgery in simple and complex surgical procedure groups.
Background: The rapid development of endoscopic endonasal surgery has made the procedure widely used in nasal and sinus surgery. Endoscopic endonasal surgery is a minimally invasive procedure, but the possibility of postoperative damage to the sinonasal mucosa cannot be ruled out. The aim of this study was to analyze the difference in the length of postoperative care between complex and simple endoscopic endonasal surgeries which can be used as a reference in planning postoperative care. Methods: This was a retrospective cross-sectional observational study. The participants were divided into two groups, i.e., simple, and complex surgical procedures groups. The simple procedure group consisted of middle meatal anstrostomy, uncinectomy, endoscopic septoplasty, and endoscopic turbinoplasty. The complex procedure group included frontal sinusotomy, sphenoidectomy, as well as anterior and posterior ethmoidectomy. The length of postoperative care between the two groups were measured and analyzed using the Chi-square test. Results: The median length of care in the complex procedure group was significantly longer than that in the simple procedure group (p = 0.028), 12 weeks and 9 weeks, respectively. The number of postoperative outpatient visits was significantly less in the simple procedure group compared with the complex procedure group (Median 4 vs. 5; p=0.015). There was a significant correlation between length of care and the endonasal endoscopic surgical procedure group (p = 0.023). Conclusions: The complex endoscopic endonasal surgery group required a longer length of care and more postoperative outpatient visit than the simple procedure group.


Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: Receptors, functions, and roles in diseases.
There have been extensive developments on cellular and molecular mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumor development, organ transplantation, and chronic infections during the last few years. Better understanding the functions, reciprocal regulation, and counterbalance of subsets of immune and inflammatory cells that interact through interleukins, interferons, TNF-α, and TGF-β offer opportunities for immune interventions and novel treatment modalities in the era of development of biological immune response modifiers particularly targeting these molecules or their receptors. More than 60 cytokines have been designated as interleukins since the initial discoveries of monocyte and lymphocyte interleukins (called IL-1 and IL-2, respectively). Studies of transgenic or gene-deficient mice with altered expression of these cytokines or their receptors and analyses of mutations and polymorphisms in human genes that encode these products have provided essential information about their functions. Here we review recent developments on IL-1 to IL-38, TNF-α, TGF-β, and interferons. We highlight recent advances during the last few years in this area and extensively discuss their cellular sources, targets, receptors, signaling pathways, and roles in immune regulation in patients with allergy and asthma and other inflammatory diseases.


NKp30 isoforms in patients with chronic hepatitis C virus infection.
Natural killer (NK) cells play an important role in virus infection, their action being regulated by several activating and inhibitory receptors. The NKp30 activating receptor and its isoforms have recently emerged as important determinants of efficient NK cell responses. We determined the relative proportions of NKp30 isoforms in patients with chronic hepatitis C virus (HCV) infection and healthy donors (HD). NK cell function (degranulation and cytokine production) and correlations with clinical parameters were assessed following unsupervised hierarchical clustering of patients according to isoform expression. NKp30 receptor expression on NK cells and all isoforms were reduced in HCV-infected patients. Patients were clustered into two groups: the HCV-1 group had similar isoform expression to the HD group, whereas the HCV-2 group had lower expression. The latter showed a better functional activity, and a higher proportion of the activating a isoform and of the NKp30 isoform a/c ratio compared with the HCV-1 cluster. There was a positive correlation between the activating a isoform and liver stiffness and an inverse relationship between the immunosuppressive c isoform and the fibrosis 4 score, suggesting a potentially important role of NKp30 isoforms in influencing liver damage and ensuing fibrosis.


A Bcl-xL transgene promotes malignant conversion of chemically initiated skin papillomas.
The role of apoptosis in the pathogenesis of skin cancer was analyzed in mice bearing a Bcl-xL transgene expressed under the control of the keratin 14 promoter. No spontaneous tumors developed in the skin of these transgenic mice. Bcl-xL transgenics also failed to develop skin lesions following treatment with the chemical mutagen 9,10-dimethyl-1,2-benzanthracene, or the tumor promoter O-tetradecanoylphorbol-13-acetate. However, Bcl-xL transgenics developed a two-fold greater number of benign papillomas than control littermates following treatment with the combination of 9,10-dimethyl-1,2-benzanthracene and O-tetradecanoylphorbol-13-acetate. More significantly, Bcl-xL transgenic mice developed invasive squamous cell carcinoma earlier and more frequently than wild-type controls in response to the chemical agents. These data suggest that Bcl-xL cannot functionally substitute for a mutagenic initiator or mitogenic promoter in tumorigenesis. In contrast, Bcl-xL overexpression can dramatically increase the malignant conversion rate of benign tumors, suggesting that inhibition of apoptosis can contribute to tumor progression.


Internet society, internet addiction, and pathological social withdrawal: the chicken and egg dilemma for internet addiction and hikikomori.
Internet society has made our daily life more convenient, while its negative consequences especially internet, smartphone, and gaming addiction are emerging. At the same time, the phenomenon of pathological social withdrawal called 'hikikomori' has been increasingly highlighted as a problematic behavior in Japan. Now hikikomori is becoming a global mental health issue. The interaction between internet society, internet addiction, and hikikomori has not been well clarified. A case vignette survey among psychiatrists suggested that hikikomori cases could be comorbid with internet addiction. In reality, hikikomori cases with internet addiction have been reported internationally. A recent survey among college/university students in Japan has indicated positive interactions between internet addiction, smartphone addiction, gaming internet disorder, and hikikomori-tendencies. The cause of hikikomori has not been well understood, and the emergence of internet may be one of the important contributing factors for the occurrence of hikikomori. Whether pathological social withdrawal creates internet addiction, or internet overuse creates hikikomori remains unclear. Both possibilities exist, and we herein propose the conceptual model of these hypothetical interactions. Clarifying the mechanisms of both conditions will help to solve these crucial issues for contemporary urban societies.


A novel approach to represent and compare RNA secondary structures.
Structural information is crucial in ribonucleic acid (RNA) analysis and functional annotation; nevertheless, how to include such structural data is still a debated problem. Dot-bracket notation is the most common and simple representation for RNA secondary structures but its simplicity leads also to ambiguity requiring further processing steps to dissolve. Here we present BEAR (Brand nEw Alphabet for RNA), a new context-aware structural encoding represented by a string of characters. Each character in BEAR encodes for a specific secondary structure element (loop, stem, bulge and internal loop) with specific length. Furthermore, exploiting this informative and yet simple encoding in multiple alignments of related RNAs, we captured how much structural variation is tolerated in RNA families and convert it into transition rates among secondary structure elements. This allowed us to compute a substitution matrix for secondary structure elements called MBR (Matrix of BEAR-encoded RNA secondary structures), of which we tested the ability in aligning RNA secondary structures. We propose BEAR and the MBR as powerful resources for the RNA secondary structure analysis, comparison and classification, motif finding and phylogeny.


EORTC external quality assurance program for ER and PgR measurements: trial 1998/1999. European Organisation for Research and Treatment of Cancer.
Steroid receptor assays have clinical relevance in selecting women who would benefit from endocrine intervention. As the degree of benefit from endocrine therapy is directly related to the quantity of receptor present in the tumour, the quality of the steroid receptor assays is important. Moreover, since patients entered in multi-centre trials often include stratification based on the receptor status, receptor assays should be comparable between different institutes. ER- and PgR-assays have been evaluated in quality assessment studies for almost 20 years by the EORTC Receptor and Biomarker Study Group. During the QA trial 1998/1999 results were reported by 42 participants performing the Ligand Binding Assay (LBA) and by 39 participants using the Enzyme Immuno-Assay (EIA) kit. Each participant received a set of 12 QA vials to be analysed two at a time at two-monthly intervals. The between-laboratory CVs of ER LBA and EIA amounted to 40-50%. For PgR the between-lab CVs for the EIA method are lower as compared with LBA but still are approx. 30%. Notwithstanding the high deviation in reported values and the high between-lab CVs, the consistency of the participants over the year is acceptable, which pave the way for calibration. Indeed, after normalization of assay results the mean between-lab CVs dropped to 11% for ER LBA, 14% for ER EIA, 9% for PgR LBA and 11% for PgR EIA. Such a reduction of between-laboratory CVs is an essential requirement for the use of steroid receptor data in multicentre clinical studies.


Correlation of Magnesium Level with Cardiac and Hepatic Hemosiderosis Measured by T2*MRI Technique and Age in Patients with Thalassemia Major.
Background: Given the association of hypomagnesemia with cardiac arrhythmia, the aim of this study was to investigate the relationship between serum magnesium levels with age and T2* magnetic resonance imaging (MRI) findings of the heart and liver in patients with thalassemia major (TM). Materials and Methods: In a descriptive cross-sectional study, a total of 62 patients with β-thalassemia major aged 11-48 years were selected at the Amir-Kabir Hospital, Arak, Iran. Serum magnesium, ferritin, and iron levels of patients were measured, and the rate of cardiac and hepatic hemosiderosis of patients was extracted according to the routine T2*MRI method. Results: The mean age of the patients at diagnosis was 32.6 years. The comparison of TM patients with and without hepatic/cardiac hemosiderosis demonstrated that mean levels of serum ferritin, serum iron, and age were significantly higher in TM patients with cardiac hemosiderosis than in hepatic/cardiac non-hemosiderosis (P < 0.05); however, there was no significant difference in mean levels of serum magnesium in TM patients with and without hepatic/cardiac hemosiderosis (P = 0.279). Interestingly, the correlation of age with serum magnesium levels in TM patients revealed a statistically significant and moderate inverse correlation (r = -0.56, P = 0.013). Conclusion: Hypomagnesemia may occur in a time-dependent manner. It is recommended that, in addition to cardiac and hepatic T2*MRI, serum magnesium levels be measured by using magnesium replacement if necessary.


Dapsone resistant leprosy, the western Kenya experience.
41 patients out of 804 registered lepromatous (LL) and borderline lepromatous (BL) patients were studied for possible dapsone resistance by series of biopsy specimens, skin smears and clinical examination. These patients were drawn from a pool of 4384 registered leprosy patients in the west Kenya Leprosy Control Project area. Six out of fourty one cases (14.6%) were confirmed as dapsone resistant by series of biopsy specimens taken when patients were on supervised dapsone therapy; 11 patients (26.8%) were suspected to be resistant and 24 patients (58.6%) responded well to dapsone therapy. All the confirmed cases were lepromatous leprosy cases. We therefore found that there is dapsone resistance here with a maximal prevalence rate of 7 per 1000 in all lepromatous cases and 14.6% in clinically suspicious cases.


Translating the REACH OUT dementia caregiver intervention into a primary care setting: a pilot study.
The current study translated the Resources for Enhancing Alzheimer's Caregiver Health: Offering Useful Treatments (REACH OUT), a skills-building stress and burden intervention, for the primary care setting and pilot the resulting intervention. The 16-week intervention consisted of a combination of clinic-based group and one-on-one sessions offered within a medical home, geriatrics clinic. A quasi-experimental pre- and post-test study design without a control group tested the resulting intervention. Semi-structured qualitative exit interviews evaluated program satisfaction. Twenty-five caregivers participated in one of four intervention groups; 21 caregivers completed the intervention (attended at least five of six group sessions). Caregiver burden on standardized assessments was significantly reduced between pre- and post-intervention, specifically for physical/emotional strain and caregiving uncertainty. Significant reductions were found in the frequency of reported disruptive behaviors; increased caregiver confidence in handling behavior problem frequency, depressive symptoms, disruptive behaviors, and memory-related problems; and decreased bother with respect to behavioral problem frequency and care recipient depression. Program satisfaction was high. This work suggests that the REACH OUT program can be successfully modified for use within a primary-care medical home setting.


Inhibition of lens-aldose reductase activity by brazilin and haematoxylin.
Brazilin and haematoxylin, plant pigments, were examined for their effects on the Bovine-Lens aldose reductase (LAR)-activity. About 50% inhibition was observed in a concentration of 10 (-4) M-brazilin and 10 (-4) M-haematoxylin, and above 95% inhibition was observed in a concentration of 10 (-3) M-brazilin and 10 (-3)M-haematoxylin. In order to determine the type of inhibition, kinetic studies were also conducted with brazilin and haematoxylin, in which both were found to be noncompetitive inhibitors.


Perceptions of nearly graduated fourth year midwifery students regarding a 'good midwife' in the Netherlands.
Midwifery students have the challenge to learn to be autonomous and capable midwives to ensure a safe and emotionally satisfying experience for mothers (to be) and their babies. They have to develop and acquire knowledge and skills for practice, and they have to adopt and internalize the values and norms of the midwifery profession in order to socialize as a midwife.In this study we explored conceptualisations of 'good midwives' among nearly graduated final year midwifery students as a result of their professional socialization process. A cross-sectional study consisting of an one open-ended question was undertaken. Data was analyzed qualitatively, inductively and deductively by using Halldorsdottir's theory of the primacy of a good midwife. One of three midwifery academies in the Netherlands in July 2016 were included. All midwifery students (N=67) in their final year were included. Student midwives gave broad interpretations of the features of a good midwife. Three themes - next to the themes already conceptualised by Halldorsdottir - were revealed and mentioned by nearly graduated Dutch midwifery students. They added that a good midwife has to have specific personal characteristics, organizational competences, and has to promote physiological reproductive processes in midwifery care. Students' views are broad and deep, reflecting the values they take with them to real midwifery practice. The results of this study can serve as an indicator of the level of professional socialization into the midwifery profession and highlight areas in which changes and improvements to the educational program can be made.


Herpes simplex type 1 hepatitis in renal transplantation.
Herpes simplex is a rare but usually fatal cause of acute hepatitis in adults. Most previously reported cases have occurred in debilitated or immunosuppressed patients. We report two additional fatal cases that occurred in renal transplant recipients. In case 1, there is evidence that the allograft may have been the initial nidus of infection. In case 2, dissemination from a genital infection occurred and failed to respond to vidarabine therapy that was started early in the clinical course. We also review the literature concerning previously reported cases of herpes hepatitis.


Novel inhibitors of cholesterol degradation in Mycobacterium tuberculosis reveal how the bacterium's metabolism is constrained by the intracellular environment.
Mycobacterium tuberculosis (Mtb) relies on a specialized set of metabolic pathways to support growth in macrophages. By conducting an extensive, unbiased chemical screen to identify small molecules that inhibit Mtb metabolism within macrophages, we identified a significant number of novel compounds that limit Mtb growth in macrophages and in medium containing cholesterol as the principle carbon source. Based on this observation, we developed a chemical-rescue strategy to identify compounds that target metabolic enzymes involved in cholesterol metabolism. This approach identified two compounds that inhibit the HsaAB enzyme complex, which is required for complete degradation of the cholesterol A/B rings. The strategy also identified an inhibitor of PrpC, the 2-methylcitrate synthase, which is required for assimilation of cholesterol-derived propionyl-CoA into the TCA cycle. These chemical probes represent new classes of inhibitors with novel modes of action, and target metabolic pathways required to support growth of Mtb in its host cell. The screen also revealed a structurally-diverse set of compounds that target additional stage(s) of cholesterol utilization. Mutants resistant to this class of compounds are defective in the bacterial adenylate cyclase Rv1625/Cya. These data implicate cyclic-AMP (cAMP) in regulating cholesterol utilization in Mtb, and are consistent with published reports indicating that propionate metabolism is regulated by cAMP levels. Intriguingly, reversal of the cholesterol-dependent growth inhibition caused by this subset of compounds could be achieved by supplementing the media with acetate, but not with glucose, indicating that Mtb is subject to a unique form of metabolic constraint induced by the presence of cholesterol.


Feasibility of an augmented reality cardiopulmonary resuscitation training system for health care providers.
Augmented reality (AR) has the potential to offer a novel approach to CPR training that supplements conventional training methods with gamification and a more interactive learning experience. This is done through computer-generated imagery superimposed on users' view of the real environment to simulate interactive training scenarios. We sought to test the feasibility of an AR CPR training system (CPReality) for health care providers (HCPs). In this feasibility trial, a CPR training manikin was integrated with a commercial AR device (Microsoft HoloLens) to provide participants with real-time audio-visual feedback via a holographic overlay of blood flow to vital organs dependent on CC quality. In this system, higher quality CC visually improved virtual blood circulation. HCPs performed a 2-minute cycle of hands-only CPR using only the AR system, and CC parameters were recorded. Descriptive data on participants' demographics, CC quality, and satisfaction with the training environment were reported using quantitative and qualitative analysis. Between 10/2018-11/2018, we enrolled a convenience sample of 51 HCPs. The median age of participants was 31 years (IQR 27-41), 71% (36/51) were female, and 67% (34/51) were registered nurses. CC rates (mean 126 ± 12.9 cpm), depths (median 53 mm, IQR 46-58), and percent with complete recoil (median 80%, IQR 12-100) were consistent with guideline recommendations for good quality CPR. Participants were predominantly satisfied with the system, with 82% perceiving the experience as realistic, 98% recognizing the visualizations as helpful for training, and 94% willing to use the application in future CPR training. As AR is increasingly applied in the healthcare setting, integration in CPR training offers a novel and promising educational approach. In this convenience sample of trained HCPs, high quality CC delivery was feasible using the AR CPR training system which was received favorably by most participants.


Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy.
Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teff cells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery.


Comparisons of fatigue between dialysis modalities: A cross-sectional study.
Fatigue is one of the most frequent complications in dialyzed patients and is associated with poorer patient outcomes. Multiple factors are reported to be associated with fatigue development. Of them, the impacts of dialysis modalities remain unknown. A total of 194 dialysis patients (mean age, 61±11 years; 134 males; modalities included hemodialysis (HD) in 26, online hemodiafiltration (HDF) in 74, peritoneal dialysis (PD) in 68, and combined therapy with PD and HD in 26 cases) were recruited for this cross-sectional study. Fatigue was assessed using the Profile of Mood States (POMS), a Visual Analogue Scale (VAS), and our original scale of fatigue, and depression was assessed by the Beck Depression Inventory-second edition (BDI-II). Our original scale of fatigue was administered both on dialysis and dialysis-free days to patients on HD and online HDF. The scores of the POMS, VAS, and our original scale were weakly but significantly inter-related (rho = 0.58, P<0.01; rho = 0.47, P<0.01, and rho = 0.42, P<0.01 between POMS and VAS, POMS and our original scale for fatigue, and VAS and our original scale for fatigue, respectively). The scores of these 3 tests showed no significant differences among the 4 modalities. On multivariate analysis, age, body mass index, creatinine, and employment status were associated with the presence or severity of fatigue, whereas dialysis modality was not. A similar result was obtained in 122 patients without depression. The prevalence of fatigue by our original scale was significantly lower on dialysis-free days than on dialysis days in patients on HD and online HDF. The results suggest that there is no significant association between different dialysis modalities including HD, online HDF, PD and combined therapy with PD and HD and the prevalence or severity of fatigue.


X-linked cone dysfunction syndrome with myopia and protanopia.
To perform a detailed clinical, psychophysical, and molecular assessment of members of 4 families with an unusual X-linked cone dysfunction syndrome associated with myopia. Affected and unaffected members of 4 British nonconsanguineous families. Subjects underwent both detailed clinical examination and psychophysical testing. After informed consent was obtained, blood samples were taken for DNA extraction, and molecular genetic analysis was performed. The strategy for molecular analysis was to amplify the coding regions of the long and middle wavelength-sensitive cone opsin genes and the upstream locus control region by polymerase chain reaction and to examine these fragments for mutations by sequencing of DNA. The phenotype was almost identical in all 4 families, consisting of moderate to high myopia, astigmatism, moderately reduced acuity, and normal fundi. Electroretinography showed abnormal cone but normal rod responses. Psychophysical testing showed a selective impairment of long cones in combination with well-preserved middle cone and short cone function. There was no evidence to suggest that the phenotype was progressive. Molecular analysis of the X-linked opsin gene array in the 4 families indicated that affected males have inherited the same X-chromosome from their mother. In 2 families, a long/middle hybrid gene was detected. In a third family, the commonly described deleterious Cys203Arg amino acid substitution was identified in both the long and middle opsin genes. In the fourth family, the only abnormality was absence of a middle opsin exon 2; the cause of the protanopia in this family is uncertain. The X-linked cone dysfunction syndrome associated with myopia and dichromacy described here has many similarities to Bornholm eye disease, a condition previously mapped to Xq28. Except for the Cys203Arg substitution in one family, no alterations in the opsin gene array were identified that could underlie the cone dysfunction. It is therefore possible that the cone dysfunction may have a genetic origin different from that of the dichromacy.


Actin flow-dependent and -independent force transmission through integrins.
Integrin-dependent adhesions mediate reciprocal exchange of force and information between the cell and the extracellular matrix. These effects are attributed to the "focal adhesion clutch," in which moving actin filaments transmit force to integrins via dynamic protein interactions. To elucidate these processes, we measured force on talin together with actin flow speed. While force on talin in small lamellipodial adhesions correlated with actin flow, talin tension in large adhesions further from the cell edge was mainly flow-independent. Stiff substrates shifted force transfer toward the flow-independent mechanism. Flow-dependent force transfer required talin's C-terminal actin binding site, ABS3, but not vinculin. Flow-independent force transfer initially required vinculin and at later times the central actin binding site, ABS2. Force transfer through integrins thus occurs not through a continuous clutch but through a series of discrete states mediated by distinct protein interactions, with their ratio modulated by substrate stiffness.


Ethanol fermentation from lignocellulosic hydrolysate by a recombinant xylose- and cellooligosaccharide-assimilating yeast strain.
The sulfuric acid hydrolysate of lignocellulosic biomass, such as wood chips, from the forest industry is an important material for fuel bioethanol production. In this study, we constructed a recombinant yeast strain that can ferment xylose and cellooligosaccharides by integrating genes for the intercellular expressions of xylose reductase and xylitol dehydrogenase from Pichia stipitis, and xylulokinase from Saccharomyces cerevisiae and a gene for displaying beta-glucosidase from Aspergillus acleatus on the cell surface. In the fermentation of the sulfuric acid hydrolysate of wood chips, xylose and cellooligosaccharides were completely fermented after 36 h by the recombinant strain, and then about 30 g/l ethanol was produced from 73 g/l total sugar added at the beginning. In this case, the ethanol yield of this recombinant yeast was much higher than that of the control yeast. These results demonstrate that the fermentation of the lignocellulose hydrolysate is performed efficiently by the recombinant Saccharomyces strain with abilities for xylose assimilation and cellooligosaccharide degradation.


[Studies of the mixoploid variation in banana micropropagated plants].
A special type of variation--the mixoploid variation, which had a great effect on the variation in the production of banana vitroplants, was reported for the first time. By means of examining chromosome, isozymes (EST, MDH, POX) and endogenous hormones (iPAs, IAA), the varied characters of the mixoploid varianties during the propagation in vitro when cultured as explant were investigated. The rate of the chromosome aberration in cells was characterized by starting at a much higher level and rising more rapidly in the preceding 15 subcultures as compared with the control. The rate of the isozyme variation was higher obviously than that of the control. The plantlets cloned in vitro from the mixoploid variant were also studied. The experiment showed that both the variant rates of chromosome and phenotype rose obviously. The mixoploid variant can cause the rate of variation to rise during the micropropagation.